Adrenomedullin (ADM), the product of the vascular endothelial and smooth muscle cells, and cardiomyocytes, is considered to be a local factor controlling vascular tone, cardiac contractility and renal sodium excretion. The aim of this article was to review the existing data on the effect of different types of exercise on plasma ADM concentration in healthy men. The results of studies on the effect of dynamic exercise on the plasma ADM are contradictory. Some authors reported an increase in plasma ADM, while others showed a slight decrease or did not observe any changes. The inverse relationship between plasma ADM and mean blood pressure observed during maximal exercise support the concept that ADM might blunt the exercise-induced systemic blood pressure increase. Positive relationships between increases in plasma ADM and those in noradrenaline, atrial natriuretic peptide (ANP) or interleukin-6 observed during prolonged exercise suggest that the sympathetic nervous system and cytokine induction may be involved in ADM release. Increased secretion of ADM and ANP during this type of exercise may be a compensatory mechanism attenuating elevation of blood pressure and preventing deterioration of cardiac function. Studies performed during static exercise have showed an increase in plasma ADM only in older healthy men. Positive correlations between increases in plasma ADM and those in noradrenaline and endothelin-1 may indicate the interaction of these hormones in shaping the cardiovascular response to static exercise. Inverse relationships between exercise-induced changes in plasma ADM and those in cardiovascular indices may be at least partly associated with inotropic action of ADM on the heart. Interactions of ADM with vasoactive peptides, catecholamines and hemodynamic factors demonstrate the potential involvement of this peptide in the regulation of blood pressure and myocardial contractility during exercise.
There are two types of exercise, dynamic (isotonic) and static (isometric), depending on the kind of muscle contraction. Both dynamic and static exercise cause an increase in heart rate and cardiac output. During dynamic exercise the increase in cardiac output results mostly from an accelerated heart rate. Stroke volume also increases, due to a larger preload and myocardial contractility. Systolic blood pressure increases linearly with the workload and diastolic blood pressure shows only minor changes or tends to decrease in the normotensives. Total peripheral resistance decreases as a result of vasodilatation induced mainly by local metabolic factors in the working muscles.
Static exercise in healthy people is characterized by a large increase in systolic and diastolic arterial blood pressure resulting from the combination of increased cardiac output and sympathetically mediated vasoconstriction in both visceral organs and inactive skeletal muscles (Victor et al., 1989a; Middlekauff et al., 1997; Momen et al., 2003). The increase in cardiac output results primarily from an accelerated heart rate. Stroke volume during static hand grips at loads greater than 20% of the maximal voluntary contraction (MVC) can be significantly reduced due to the increased left ventricular afterload (Bezucha et al., 1982; Chapman and Elliot, 1988).
Neural mechanisms of cardiovascular regulation during exercise
The hemodynamic responses to exercise are regulated by central and peripheral mechanisms. The central mechanism, termed as “central command”, involves parallel activation of motor and cardiovascular centers (Goodwin et al., 1972). The neural signals from the motor cortex irradiate to autonomic neurons in the brainstem, leading to sympathetic activation and parasympathetic withdrawal (Dipla et al., 2012; Iellamo, 2001; Nobrega et al., 2014; Williamson 2010, 2015). The peripheral neural mechanism involves signals arising from contracting skeletal muscle receptors (mechanoreflex and metaboreflex), arterial baroreceptors (baroreflex) and arterial chemoreceptors (arterial chemoreflex). Reflex input from the exercising skeletal muscle to cardiovascular regulatory centers within the medulla oblongata has been termed as the “exercise pressor reflex” (Kaufman et al., 1984; McCloskey and Mitchell, 1972; Megan et al., 2011; Mitchell et al., 1983). The exercise pressor reflex is especially prominent during static exercise, where increases in intramuscular pressure limit the blood flow to active skeletal muscle. Both central command and the exercise pressor reflex stimulate cardiac sympathetic nerve activity and are involved in the resetting of the carotid baroreflex during exercise (Iellamo et al., 1997; Gallagher et al., 2006; Tsuchimochi et al., 2009).
The exercise pressor reflex is triggered by stimulation of sensory receptors located on unencapsulated endings of group III (thinly myelinated fibers) and group IV (unmyelinated fibers) afferent nerve fibers. The endings of group III afferents terminate in the skeletal muscle collagenous connective tissue and respond mainly to mechanical stimuli (mechanoreflex), while the endings of group IV afferents terminate within the walls of small capillaries, venules and lymphatic vessels of skeletal muscle, and respond mainly to metabolic changes in the contracting muscles (metaboreflex). It has been shown that the group IV afferents release vasodilator peptides such as substance P and calcitonin gene-related peptide (CGRP) (Kruger et al., 1989; von During and Andres, 1990). Metabolic by-products following muscle contraction such as hydrogen ions, lactic acid, adenosine monophosphate (AMP), adenosine-5′-diphosphate (ADP), inosine monophosphate (IMP), diprotonated inorganic phosphate and reactive oxygen species have the ability to stimulate both metabo- and mechanoreceptors and therefore, play an important role in evoking the exercise pressor reflex (Green, 1997; Hanna and Kaufman, 2004; Kaufman et al., 1983; Kaufman and Rybicki, 1987; Rotto et al., 1990; Zając et al., 2015). It is considered that intramuscular acidosis is one of the most important factors that triggers metaboreflexmediated increases in muscle sympathetic nerve activity (Pryor et al., 1990; Rotto et al., 1989; Victor et al. 1988). It has been demonstrated that mechanical stimulation of muscle afferents contributes to the initial blood pressure response during contraction, while metabolic stimuli are necessary to maintain this response (Baum et al., 1995). Endo et al. (2013) suggested that the muscle mechanoreflex also played an important role in mediating vasoconstriction within inactive limbs.
The exercise pressure reflex has been shown to increase sympathetic nerve activity to the non-exercising muscle, heart and kidneys (Hill et al., 1996; Mark et al., 1985; McCloskey et al., 1972; Momen et al., 2003; Saito, 1995; Saito et al., 1990). In the heart, sympathetic stimulation increases heart rate and heart muscle contractility as well as accelerates atrioventricular conduction (Kaufman and Forster, 1996; Matsukawa et al., 1994; Mitchell, 1983). Kaufman et al. (1984, 1996) showed that the magnitude of the cardiovascular reflex response to muscle contraction was dependent on active muscle mass and magnitude of force or tension production. Stebbins et al. (2002) found that increases in heart rate and mean arterial pressure as well as activation of central command and muscle metabolite-induced stimulation of the exercise pressor reflex during static and dynamic contraction in humans seemed to be similar when peak tension and tension-time index were equal. In the kidneys, enhanced sympathetic nerve activity causes arteriolar renal vasoconstriction, reduces the renal blood flow and glomerular filtration rate, increases renin release with activation of the renin-angiotensinaldosterone system, increases tubular sodium and water reabsorption (Matsukawa et al., 1990; Middlekauff et al., 2001; Momen et al., 2003; Victor et al., 1989b). This results in increased peripheral vascular resistance and thus arterial blood pressure. The sympathetic efferent nerves to the adrenal medulla and hypothalamus control the secretion of adrenal catecholamines and vasopressin, which contribute to adjustments in vascular resistance.
Activation of neurohormonal systems as well as shear stress enhance production and release of endothelin-1 (ET-1) by vascular endothelial cells (Wang et al., 2002). Endothelin-1 causes vasoconstriction, increases sympathetic activity, potentiates the vasoconstrictor action of noradrenaline and stimulates the renin-angiotensin-aldosterone system (Bruno et al., 2011; Miller et al., 1989). Endothelin-1, catecholamines as well as hemodynamic shear stress stimulate production and secretion of adrenomedullin (ADM) and nitric oxide (NO) by vascular endothelial and smooth muscle cells to oppose vasoconstriction (Cardillo et al., 2000; Cardillo et al., 2009; Haynes and Webb 1998). Production and secretion of ADM are linked to the endothelin-B receptors subtype (ETB-R) (Jougasaki et al., 1998). Adrenomedullin reduces the activity of the sympathetic nervous system as well as secretion of endothelin-1 and catecholamines (Andreis et al., 1997; Del Bene et al., 2000; Khan et al., 1999; Kohno et al., 1995a; Tschakovsky et al., 2002; Yűksel et al., 2002).
The aim of this article was to review the existing data on the effect of different types of exercise on plasma ADM concentration and to describe the relations between exercise-induced changes in plasma ADM and those in both humoral and hemodynamic factors.
Structure of adrenomedullin
Human ADM is a 52-amino acid peptide with one intramolecular disulfide bridge and with an amidated tyrosine at the carboxy terminus (Kitamura et al., 2012). Adrenomedullin gene is located on chromosome 11 and its expression can be regulated by substances acting through protein kinase A, protein kinase C and cytokine receptor gp130 (Ishimitsu et al., 2003). This peptide was first identified in pheochromocytoma of the human adrenal gland and belongs to the calcitonin gene-related peptide family. Synthesis of adrenomedullin starts with the precursor molecules, termed preproadrenomedullin and proadrenomedullin, mainly in endothelial and vascular smooth muscle cells in response to shear stress, ischemia, hypoxia, acidosis and under the influence of catecholamines, angiotensin II, vasopressin and cytokines (Hasbak et al., 2002; Kitamura et al., 2002; Krzeminski et al., 2006a, 2006b; Nagata et al., 1999; Niebauer and Cooke, 1996; Sugo et al., 1994, 1995a, 1995b). Its presence has also been shown in the adrenal medulla, heart, lung, gastrointestinal organs, kidneys and the central nervous system. Hirayama et al. (1999) found that the ADM and ET-1 could be synthesized and secreted from human cardiac myocytes and that the expression and function of ADM receptors were modulated by humoral and mechanical factors in myocardium. Immunohistochemical staining showed the presence of ADM in atria, ventricles and muscular layer of the aorta in the dog heart (Jougasaki et al., 1995b). Some vasoactive substances, such as angiotensin II and ET-1 have been shown to stimulate the production and secretion of ADM from both vascular smooth muscle cells and cardiomyocytes (Mishima et al., 2001; Sugo et al., 1995b; Tsuruda et al., 1998). Nishikimi et al. (2003) suggested that both mechanical stress and cytokines were important stimuli for ADM production in the heart. Tsuruda et al. (2000) reported enhanced gene expression and production of ADM in cultured cardiomyocytes in response to static stretching.
Mechanisms of adrenomedullin action
Adrenomedullin acts through calcitonin receptor-like receptor (CRLR) associated with one of the three receptor-activity-modifying proteins: RAMP1, RAMP2 or RAMP3 (Nikitenko et al., 2006; Sexton et al., 2001). Co-expression of RAMP1 with CRLR produces a CGRP receptor, whereas co-expression of RAMP2 or RAMP3 with CRLR produces an ADM receptor (Eguchi et al., 1994b; Kamitani et al., 1999; McLatchie et al., 1998). However, Nagoshi et al. (2002) found that ADM could also bind with the CRLR/RAMP1 complex. Some authors believe that ADM acts on the heart by specific membrane receptor AM-R cDNA located on the surface of rat cardiomyocytes (Kapas et al., 1995; Miller et al., 1996). This receptor appears to be a relatively unique member of a family of membrane receptors associated with G protein. The vasodilator action of ADM is mainly mediated by endothelium-derived NO (Feng et al., 1994; Hirata et al., 1995; Miura et al., 1995; Yukihito et al., 2004). ADM increases endothelial NO synthase (eNOS) activity by elevating intracellular free calcium concentration (Boussery et al., 2004; Shimekake et al., 1995) or by activating phosphatidylinositol 3-kinase and protein kinase B/Akt (Nishimatsu et al., 2001). It has also been shown that ADM increases interleukin-1 (IL-1) induced NO synthesis by enhancing the expression of inducible NO synthase (iNOS) in vascular smooth muscle cells (Hattori et al., 1999; Ikeda et al., 1996a).
Adrenomedullin increases intracellular cyclic adenosine monophosphate (cAMP) by stimulation of adenylyl cyclase and activation of protein kinase A (cAMP/PKA signaling pathway) as well as increases cyclic guanosine 3’5'monophosphate (cGMP) by stimulation of NO-activated guanylyl cyclases and activation of cGMP-dependent protein kinase (PKG) (NO/cGMP/PKG signaling pathway) (Chini et al., 1995; Coppock et al., 1996; Kohno et al., 1995b; Sato et al., 1997). Zhang and Hintze (2001) suggested that cAMP increased NO through activation of protein kinase A and subsequent phosphorylation of endothelial NOS by protein kinase B through a phosphatidylinositol 3-kinase– mediated effect. It has been shown that ADM-induced increases in NO are mediated by activation of protein kinase A and phosphatidylinositol 3-kinase (Boo, 2006; Nishimatsu et al., 2001).
Adrenomedullin has also been shown to activate other signal transduction mechanisms including potassium-ATP channels (Sakai et al., 1998) and c-fos expression (Moody et al., 1997; Sato and Autelitano, 1995). Furthermore, in an isolated perfused rat heart ADM induced both Ca2+ release from Ca2+ stores and activation of protein kinase C (PKC) via cAMP-independent mechanisms (Szokodi et al., 1998). Lamping (2001) suggested that relaxation of vascular smooth muscle to selected endothelium-independent agents was mediated by an interaction between cGMP and cAMP pathways.
Physiological action of adrenomedullin
Many studies have revealed a wide range of biological actions of ADM on cardiovascular, renal and endocrine systems, the central nervous system as well as cellular growth and differentiation (Hinson et al., 2000; Jougasaki et al., 1995a, 1995c; Lainchbury et al., 1997; Nicholls, 2004; Parkes and May, 1997; Samson et al., 1999). Adrenomedullin is a potent vasodilator that reduces systemic and pulmonary vascular resistance, induces renal vasodilation, increases the glomerular blood flow and filtration rate, sodium excretion and myocardial contractility, as well as inhibits renin release, decreases plasma aldosterone and vasopressin levels (He et al., 1995; Hinson, 2000).
The vasodilatory action of ADM may be mediated by endothelium-derived NO and/or vasoactive prostanoids (endothelium-dependent vasodilation) as well as by an increase in intracellular cAMP (endothelium-independent vasodilation) (Eguchi et al., 1994a; Ishizaka et al., 1994).
The effect of ADM on myocardial contractility is controversial. Some authors believe that ADM has a positive inotropic effect (Ihara et al., 2000; Szokodi et al., 1996, 1998), while others that it has a negative inotropic effect mediated by the NO-cGMP pathway (Ikenouchi et al., 1997) or has no effect on myocardial contractility (Lainchbury et al., 2000). It has been shown that ADM inotropic action is mediated via CRLR/RAMP2 or CRLR/RAMP3 complexes and involves the activation of adenylyl cyclase and cyclic AMP production in cardiomyocytes (Bell and McDermott, 1994; Ihara et al., 2000; McLatchie et al., 1998; Sato et al., 1997; Szokodi et al., 1998). It has also been shown that ADM has an ability to rapidly facilitate intracellular Ca2+ release and enhance cardiac contractility via mechanisms involving Ca2+ release from intracellular ryanodine-and thapsigarginsensitive Ca2+ stores, activation of protein kinase C and protein kinase A, as well as Ca2+ influx through L-type Ca2+ channels (Huang et al., 1999; Szokodi et al., 1998). In addition, ADM dilates the coronary artery and attenuates myocardial remodeling (Lainchbury et al., 1997; Nicholls, 2004; Rademaker et al., 2003).
Some authors reported a strong link between plasma ADM and the renin-angiotensinaldosterone system (Charles et al., 2000, 2003; Krzeminski et al., 2012). Angiotensin II increases the expression of ADM-mRNA and inotropic action of ADM onthe heart (Mishima et al., 2003; Onitsuka et al., 2005; Romppanen et al., 1997).
Hypotensive, diuretic and inotropic properties of ADM and its interactions with vasoactive substances demonstrate the potential involvement of this peptide in the regulation of blood pressure and cardiac contractility as well as in maintenance of water and electrolyte homeostasis during exercise.
Adrenomedullin and dynamic exercise
Studies on the effect of dynamic exercise on plasma ADM concentration have yielded contradictory results. Tanaka et al. (1995) reported an increase of plasma ADM during three 4-min steps of submaximal cycle exercise (workloads: 25, 50 and 75 Watts) in healthy subjects and in patients with various diseases. The increase of adrenomedullin was inversely related to systolic blood pressure. Similarly, Piquard et al. (2000) found a significant increase in plasma ADM during maximal bicycle exercise both in normal subjects and in the heart transplant recipients. Tanaka et al. (1995) suggested that the exercise-induced quantity of ADM released to the circulation was too small to directly affect the blood pressure so it may rather reflect the increased activity as an autocrine or a paracrine factor. The paracrine mechanism was also suggested by Meeran et al. (1997). On the other hand, Nishikimi et al. (1997) and Morimoto et al. (1997) did not find any changes in plasma ADM during two 4-min steps of submaximal exercise (workloads: 40 and 80 Watts) in normotensive healthy subjects. Similarly, Poveda et al. (1998) and Dursun et al. (2012) did not observe any changes in plasma levels of ADM in response to a treadmill stress test or a cycle exercise test until volitional exhaustion in both young and old healthy volunteers. Nishikimi et al. (1997) suggested that ADM secretion did not respond to short-lasting stimuli since it was regulated by gene expression.
The results of the study performed during graded bicycle ergometer exercise until exhaustion in healthy young men (Krzeminski et al., 2003) showed a slight decrease in plasma ADM concentration at the end of exercise. This was accompanied by significant increases in plasma noradrenaline (NA), adrenaline (A), growth hormone and lactate. Plasma ADM at the end of exercise correlated negatively with systolic blood pressure, mean blood pressure and blood lactate. A positive correlation was found between the exercise-induced decrements of plasma ADM and diastolic blood pressure. The authors concluded that the decrease in peripheral resistance and metabolic acidosis might be involved in the inhibition of ADM secretion during exhausting exercise in healthy young men. It seems to be very likely that a decrease in plasma ADM results from increased bounding of the peptide to the receptors on the endothelium and vascular smooth muscle cells or other tissues (Eguchi et al., 1994b; Ishiyama et al., 1993; Meeran et al., 1997; Nandha et al., 1996; Shimekake et al., 1995). Meeran et al. (1997) suggested that the proximity of vascular smooth muscle cells to endothelial cells resulted in a much higher concentration of ADM around these cells than in the plasma. The authors concluded that ADM prevented the excessive blood pressure increase during exhausting exercise in healthy men.
The results of the study performed during prolonged submaximal dynamic exercise (90 min at 70% of maximal oxygen uptake (VO2max)) in healthy young men (Krzeminski et al., 2006a) revealed a significant increases in plasma ADM and interleukin-6 (IL-6) concentrations at the 90th min of exercise. The plasma NA, A, atrial natriuretic peptide (ANP), lactate as well as plasma renin activity (PRA) were elevated already at the 30th min of exercise. Positive correlations were found between plasma ADM and NA, ANP or IL-6. The exercise-induced increases in plasma ADM correlated positively with those in plasma NA and inversely with changes in diastolic blood pressure. Plasma renin activity correlated positively with plasma NA and ANP. A significant positive correlation between plasma NA and PRA indicates the existence of a link between the increased activity of the sympathetic nervous system and stimulation of the renin-angiotensin-aldosterone system during prolonged exercise in healthy men. A negative correlation between the exercise-induced changes in plasma ADM and diastolic blood pressure indicates a participation of ADM in the regulation of blood pressure during prolonged dynamic exercise. The authors suggested that an increase in sympathetic nervous activity and cytokine induction may be involved in plasma ADM release during prolonged submaximal exercise and that the increase in plasma ADM and ANP secretion may be a compensatory mechanism against further elevation of blood pressure. In view of reports indicating that the ADM gene expression in vascular smooth muscle and adrenal cells is stimulated by protein kinase C and/or protein kinase A and submitted to feedback from cAMP level (DaPrada et al., 1979; Ishimitsu et al., 1994), it is possible that noradrenaline stimulates the expression of mRNA-ADM in vascular smooth muscle cells and cardiac myocytes through α-1 (activation of protein kinase C) and β (activation of protein kinase A and cAMP) adrenergic receptors (Isumi et al., 1998). A positive correlation between plasma ADM and ANP suggests the possibility of direct stimulation of ADM secretion in the heart by hemodynamic changes. The results of experiments using cultured cardiomyocytes imply that mechanical stress and cytokines are important stimuli for ADM production in the heart (Dawson et al., 2005; Middleton et al., 2006). Horio et al. (1999) demonstrated that ADM augmented endothelin1-stimulated ANP secretion from cardiac myocytes at least partly via the cAMPindependent mechanism. Some studies showed that ADM inhibited both ANP gene expression in cultured cardiac myocytes and ANP secretion from isolated atrium (Kaufman and Deng, 1998; Sato et al., 1995, 1997).
Adrenomedullin and ANP suppress the activity of the renin-angiotensin-aldosterone system, antagonize the effect of endothelin-1 and angiotensin-II and thus prevent an increase in peripheral vascular resistance (TPR) as well as preserve the renal blood flow. Several studies revealed that ADM induced sustained reductions in plasma aldosterone levels despite a rise in plasma renin activity (Charles et al., 2001, 2003; Neri et al., 2002; Rademaker et al., 2002). Both of these peptides may contribute to the regulation of vascular tone through the cAMP-related mechanism and NO-cGMP signaling mechanisms (Hayakawa et al., 1999; Rebuffat et al., 2001).
Thus, it seems likely that the increase in plasma ADM and ANP secretion during prolonged exercise may be a compensatory mechanism against further elevation of blood pressure and plays an important role in maintaining cardiac performance.
Adrenomedullin and static exercise
There are only few studies focusing on changes in plasma ADM concentration induced by static exercise in healthy men. The results of a study performed during static handgrip exercise (6 min at 30% MVC) in healthy young and older men (Krzeminski et al., 2002, 2012) showed significant increases in plasma ADM and ET-1 concentration, and in PRA only in the older subjects. The increases in plasma NA and A were significantly greater in the older than in the younger subjects. The exercise-induced increases in plasma ADM correlated positively with those of NA, PRA, ET-1 and left ventricular ejection time (LVET) as well as negatively with changes in TPR, stroke volume (SV), the pre-ejection period (PEP) and PEP/LVET ratio.
The authors suggested that a positive relationship between the exercise-induced changes in plasma ADM and those in plasma ET-1 and NA might indicate the interaction of these hormones in shaping the cardiovascular response to static exercise in healthy elderly subjects. It seems likely that ADM, ET-1 and angiotensin II with their opposite vasoactive properties can contribute to the maintenance of vascular tone during static exercise in older men.
The increased plasma catecholamines concentration indicates that static exercise causes a progressive activation of the sympathetic nervous system. Inverse relationships between exercise-induced changes in plasma ADM and those in TPR may be associated with vasodilator action of ADM on arterial vessels (Cockcroft et al., 1997). It has been shown that ADM increases both intracellular cAMP and nitric oxide (NO) in vascular endothelial cells and smooth muscle cells by activation of adenylyl cyclase and inducible endothelial NO synthase (Eguchi et al., 1994a; Hattori et al., 1999; Ishizaka et al., 1994; Kohno et al., 1995; Zhang and Hintze, 2001). It has been demonstrated that cAMP-dependent pathway is involved in cytokine-induced NO production by vascular smooth muscle cells (Hirokawa et al., 1994; Ikeda et al., 1996a; Imai et al., 1994; Koide et al., 1993). Some have authors found that ADM can act by both NO-dependent and potassium ATP (KATP) channel-dependent mechanisms (Sabates et al., 1997; Terata et al., 2000). Bolotina et al. (1994) demonstrated that NO may directly activate calcium-dependent potassium channels in vascular smooth muscle cells. Shimekake et al. (1995) demonstrated that not only the cAMPrelated mechanism, but also the NO-cGMP pathway may be involved in the mechanism of ADM-induced vasodilation. Nitric oxide stimulates soluble guanylyl cyclase, producing increased concentrations of cyclic GMP in vascular smooth muscle cells. The cyclic GMP activates GMP-dependent kinases that decrease intracellular calcium, producing relaxation (Majid et al., 1996; Moncada et al., 1991). It has also been demonstrated that NO reduces the production of vasoconstrictive substances such as endothelin-1 through a cGMP-dependent mechanism as well as inhibits the release of norepinephrine from sympathetic nerve terminals (Boulanger and Luscher, 1990).
Inverse relationships between static handgrip-induced changes in plasma ADM and those in PEP, PEP/LVET ratio, peak velocity and mean acceleration of the blood flow in the ascending aorta, and mean velocity of circumferential fiber shortening might be at least partly associated with inotropic action of ADM on the heart (Krzeminski et al., 2009, 2012; Krzeminski and Pawlowska-Jenerowicz, 2012). It should be noted that the PEP/LVET ratio has been proposed as a sensitive inverse index of left ventricular myocardial performance (Lewis et al., 1977; Martin et al., 1971; Weissler et al., 1969, 1972, 1980). A significant correlation was found between the PEP/LVET ratio and the left ventricular ejection fraction determined angiographically in patients with cardiovascular diseases (Ahmet et al., 1972; Garrad et al., 1970; Lewis et al., 1980; Stack et al., 1981; Weissler et al., 1980).
Similarly, the peak velocity and mean acceleration of the ascending aortic blood flow correlate well with the ratio of rise in pressure during isovolumetric contraction to the isovolumetric contraction time (peak dP/dt). The peak dP/dt ratio is sensitive to changes in myocardial contractility, insensitive to changes in the afterload and only mildly affected by changes in the preload (Rhodes et al., 1993). An inverse relationship between changes in left ventricular dp/dt and PEP was found in healthy man (Martin et al., 1971).
Adrenomedullin has been reported to activate the adenylate cyclase-cAMP system in isolated cardiac myocytes, which is one of the major pathways for the regulation of myocardial contractility (Sato et al., 1997; Stangl et al., 2000; Szokodi et al., 1996). Some authors have reported that ADM increases cardiac contractility via a specific adrenomedullin, calcium-dependent mechanism. The authors have suggested that ADM-induced inotropic positive action that may involve Ca2+ release from intracellular ryanodineand thapsigargin-sensitive Ca2+ stores, enhances Ca2+ influx from sarcoplasmic reticulum through L-type Ca2+ channels as well as activation of protein kinase C and protein kinase A (Bell and McDermott, 1994; Huang et al., 1999; Ihara et al., 2000; McLatchie et al., 1998; Szokodi et al. 1998). Bäumer et al. (2002) reported that ADM can indirectly increase cardiac contractility by improving myocardial perfusion.
Thus, it seems likely that ADM acts to increase left ventricular function during static exercise by both a decrease in systemic vascular resistance (afterload) and an increase in myocardial contractility.
There is little data available on the effect of different types of exercise on plasma adrenomedullin concentration in healthy man. Moreover, the results of studies on the effect of dynamic exercise on plasma ADM are contradictory. However, they provide evidence that the sympathetic nervous system and cytokine induction may be involved in ADM release during prolonged endurance exercise. Increased secretion of ADM and ANP during this type of exercise may be a compensatory mechanism attenuating elevation of blood pressure and preventing deterioration of cardiac function such as cardiac fatigue. The inverse relationship between plasma ADM and mean blood pressure observed during maximal exercise supports the concept that ADM might blunt the exercise-induced systemic blood pressure increase.
There is little data showing increases in plasma ADM during static exercise and the investigations were related to older healthy man. Positive correlations between exercise-induced increases in plasma ADM and those in plasma and static exercise. It seems likely that ADM noradrenaline and endothelin-1 indicate the contributes not only to cardiovascular adaptation interaction of these hormones in shaping the to exercise, but also to the prevention of acute and cardiovascular response to static exercise. long-term cardiovascular complications in Relationships between static exercise-induced endurance athletes. Determination of plasma changes in plasma ADM and those in ADM levels might be considered as a useful and cardiovascular indices might be at least partly non-invasive tool for evaluation of hemodynamics associated with inotropic action of ADM on the and cardiac function. Thus, plasma ADM levels heart. could potentially be used as a biomarker or early
Interactions of ADM with vasoactive indicator of cardiovascular dysfunction peptides, catecholamines and cardiovascular in endurance athletes and powerlifters or indices demonstrate the potential involvement of weightlifters. this peptide in the regulation of blood pressure and myocardial contractility during both dynamic
Ahmet SS Levinson GE Schwarz CJ Ettinger PO. Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man. Circulation 1972; 46: 559-571
Andreis PG Neri G Prayer-Galetti T Rossi GP Gottardo G Malendowicz LK and Nussdorfer GG. Effects of adrenomedullin on the human adrenal glands: an in vitro study. J Clin Endocrinol Metab 1997; 82: 1167-1170
Baum K Selle K Leyk D Essfeld D. Comparison of blood pressure and heart rate responses to isometric exercise and passive muscle stretch in humans. Eur J Appl Physiol 1995; 70: 240-245
Bäumer AT Schumann C Cremers B Itter G Linz W Jockenhövel F Böhm M. Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide. J Appl Physiol 2002; 92: 1058-1063
Bell D McDermott BJ. Calcitonin gene-related peptide stimulates a positive contractile response in rat ventricular cardiomyocytes. J Cardiovasc Pharmacol 1994; 23: 1011-1021
Bezucha GR Lenser MC Hanson PG Nagle FJ. Comparison of hemodynamic responses to static and dynamic exercise. J Appl Physiol Respir Environ Exerc Physiol 1982; 53: 1589-1593
Boo YC. Shear stress stimulates phosphorylation of protein kinase A substrate proteins including endothelial nitric oxide synthase in endothelial cells. Exp Mol Med 2006; 38: 63-71
Bolotina VM Najibi S Palacino JJ Pagano PJ Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1994; 368: 850-853
Boulanger C Luscher TF. Release of endothelin from the porcine aorta: inhibition by endothelium-derived nitric oxide. J Clin Invest 1990; 85: 587-590
Boussery K Delaey C Van de Voorde J. Influence of adrenomedullin on tone of isolated bovine retinal arteries. Invest Ophthalmol Vis Sci 2004; 45: 552-559
Bruno RM Sudano I Ghiadoni L Masi L Taddei S. Interactions between sympathetic nervous system and endogenous endothelin in patients with essential hypertension. Hypertension 2011; 57: 79-84
Cardillo C Kilcoyne CM Cannon RO Panza JA. Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo. Hypertension 2000; 35: 1237-1241
Cardillo C Schinzari F Melina D Mores N Bosello S Peluso G Zoli A Ferraccioli G. Improved endothelial function after endothelin receptor blockade in patients with systemic sclerosis. Arthritis Rheum 2009; 60: 1840-1844
Chapman JH Elliott PW. Cardiovascular effects of static and dynamic exercise. Eur J Appl Physiol Occup Physiol 1988; 58: 152-157
Charles CJ Rademaker MT Richards AM Cooper GJ Coy DH Nicholls MG. Adrenomedullin attenuates pressor response to angiotensin II in conscious sheep. J Cardiovasc Pharmacol 2000; 36: 526-532
Charles CJ Lainchbury JG Nicholls MG Rademaker MT Richards AM Troughton RW. Adrenomedullin and the renin–angiotensin–aldosterone system. Regul Pept 2003; 112: 41-49
Charles CJ Nicholls MG Rademaker MT Richards AM. Comparative actions of adrenomedullin and nitroprusside: interactions with ANG II and norepinephrine. Am J Physiol Regul Integr Comp Physiol 2001; 281: R1887-1894
Chini EN Choi E Grande JP Burnett JC Dousa TP. Adrenomedullin suppresses mitogenesis in rat mesangial cells via cAMP pathway. Biochem Biophys Res Commun 1995; 215: 868-873
Cockcroft JR Noon JP Gardner-Medwin J Bennett T. Haemodynamic effects of adrenomedullin in human resistance and capitance vessels. Br J Clin Pharmacol 1997; 44: 57-60
Coppock HA Owji AA Bloom SR Smith DM. A rat skeletal muscle cell line (L6) expresses specific adrenomedullin binding sites but activates adenylate cyclase via calcitonin gene-related peptide receptors. Biochem 1996; 318: 241-245
DaPrada M Zurcher G. Radioenzimatic assay of plasma and urinary catecholamines in man and various animal species. Physiological and pharmacological applications. In: Radioimmunoassay of Drugs and Hormones in Cardiovascular Medicine. A. Albertini M. DaPrada A. Pescar (eds). Elsevier North Holland Biomedical Press Amsterdam 112-119; 1979
Dawson EA Shave R George K Whyte G Ball D Gaze D Collinson P. Cardiac drift during prolonged exercise with echocardiographic evidence of reduced diastolic function of the heart. Eur J Appl Physiol 2005; 94: 305-309
Del Bene R lazzeri C Barletta G Vecchiarino S Guerra CT Franchi F La Villa G. Effects of low-dose adrenomedullin infusion on cardiac function and systemic hemodynamics in man. Clinical Physiol 2000; 20: 457-465
Dipla K Nassis GP Vrabas IS. Blood pressure control at rest and during exercise in obese children and adults. J Obes 2012;
Dursun N Yürekli M Özdoğan K. Effect of physical activity on plasma adrenomedullin concentration and its relationship with nitric oxide in athletes. Erciyes Med J 2012; 34: 1-6
Eguchi S Hirata Y Iwasaki H Sato K Watanabe TX Inui T Nakajima K Sakakibara S Marumo F. Structure–activity relationship of adrenomedullin a novel vasodilatory peptide in cultured rat vascular smooth muscle cells. Endocrinology 1994a; 135: 2454-2458
- Export Citation
Eguchi S, Hirata Y, Iwasaki H, Sato K, Watanabe TX, Inui T, Nakajima K, Sakakibara S, Marumo F. Structure–activity relationship of adrenomedullin, a novel vasodilatory peptide, in cultured rat vascular smooth muscle cells.)| false Endocrinology, 1994a; 135: 2454-2458 10.1210/endo.135.6.7988431
Eguchi S Hirata Y Kano H Sato K Watanabe Y Watanabe TX Nakajima K Sakakibara S Marumo F. Specific receptors for adrenomedullin in cultured rat vascular smooth muscle cells. FEBS Lett 1994b; 340: 226-230
Endo MY Hayashi N Koba S Morizono Y Ueoka H Fujihara C Fukuba Y. Muscle mechanoreflex mediates vasoconstriction in inactive limb in rats. J Phys Fitness Sports Med 2013; 2: 381-384
Feng CJ Kang B Kaye AD Kadowitz PJ Nossaman BD. L-NAME modulates responses to adrenomedullin in the hindquarters vascular bed of the rat. Life Sci 1994; 55: L433-L438
Gallagher KM Fadel PJ Smith SA Strømstad M Ide K Secher NH Raven PB. The interaction of central command and the exercise pressor reflex in mediating baroreflex resetting during exercise in humans. Exp Physiol 2006; 91: 79-87
Garrard CL Jr Weissler AM Dodge HT. The relationship of alterations in systolic time intervals to ejection fraction in patients with cardiac disease. Circulation 1970; 42: 455-462
Goodwin GM McCloskey DI Mitchell JH. Cardiovascular and respiratory responses to changes in central command during isometric exercise at constant muscle tension. J Physiol 1972; 226: 173-190
Hanna RL Kaufman MP. Activation of thin-fiber muscle afferents by a P2X agonist in cats. J Appl Physiol 2004; 96: 1166-1169
Hasbak P Lundby C Olsen NV Schifter S Kanstrup IL. Calcitonin gene-related peptide and adrenomedullin release in humans: effects of exercise and hypoxia. Regul Pept 2002; 108: 89-95
Hattori Y Nakanishi N Gross SS Kasai K. Adrenomedullin augments nitric oxide and tetrahydrobioptein synthesis in cytokine-stimulated vascular smooth muscle cells. Cardiovasc Res 1999; 44: 207-214
Hayakawa H Hirata Y Kakoki M Suzuki Y Nishimatsu H Nagata D Suzuki E Kikuchi K Nagano T Kangawa K Matsuo H Sugimoto T Omata M. Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat. Hypertension 1999; 33: 689-693
- Export Citation
Hayakawa H, Hirata Y, Kakoki M, Suzuki Y, Nishimatsu H, Nagata D, Suzuki E, Kikuchi K, Nagano T, Kangawa K, Matsuo H, Sugimoto T, Omata M. Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat.)| false Hypertension, 1999; 33: 689-693 10.1161/01.HYP.33.2.689
Haynes WG Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 1998; 16: 1081-1098
He H Bessho H Fujisawa Y Horiuchi K Tomohiro A Kita T Aki Y Kimura S Tamaki T Abe Y. Effects of a synthetic rat adrenomedullin on regional hemodynamics in rats. Eur J Pharmacol 1995; 273: 209-214
Hill JM Adreani CM Kaufman MR. Muscle reflex stimulates sympathetic postganglionic efferents innervating triceps surae muscles of cats. Am.J.Physiol 1996; 271: 38-43
Hinson JP Kapas S Smith DM. Adrenomedullin a multifunctional regulatory peptide. Endocr Rev 2000; 21: 138-167
Hirata Y Hayakawa H Suzuki Y Suzuki E Ikenouchi H Kohmoto O Kimura K Kitamura K Eto T Kangawa K Matsuo H Omata M. Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. Hypertension 1995; 25: 790-795
Hirayama N Kitamura K Imamura T Kato J Koiwaya Y Tsuji T Kangawa K Eto TJ. Molecular forms of circulating adrenomedullin in patients with congestive heart failure. Endocrinol 1999; 160: 297-303
Hirokawa K O’Shaughnessy K Moore K Ramrakha P Wilkins MR. Induction of nitric oxide synthase in cultured vascular smooth muscle cells: the role of cyclic AMP. Br J Pharmacol 1994; 112: 396-402
Horio T Nishikimi T Yoshihara F Matsuo H Takishita S Kangawa K. Effects of adrenomedullin on cultured rat cardiac myocytes and fibroblasts. Eur J Pharmacol 1999; 382: 1-9
Huang MH Knight PR III Izzo JL Jr. Ca2+-induced Ca2+ release involved in positive inotropic effect mediated by CGRP in ventricular myocytes. Am J Physiol Regul Integr Comp Physiol 1999; 276: 259-264
Iellamo F Legramante JM Raimondi G Peruzzi G. Baroreflex control of sinus node during dynamic exercise in humans: effects of central command and muscle reflexes. Am J Physiol 1997; 272: 1157-1164
Iellamo F. Neural mechanisms of cardiovascular regulation during exercise. Review article. Autonomic Neuroscience: Basic and Clinical 2001; 90: 66-75
Ihara T Ikeda U Tate Y Ishibashi S Shimada K. Positive inotropic effects of adrenomedullin on rat papillary muscle. Eur J Pharmacol 2000; 390: 167-172
Ikeda U Kanbe T Shimada K. Adrenomedullin increases inducible nitric oxide synthase in rat vascular smooth muscle cells stimulated with interleukin-1. Hypertension 1996a; 27: 1240-1244
Ikeda U Kanbe T Kawahara Y Yokoyama M Shimada K. Adrenomedullin augments inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes. Circulation 1996b; 94: 2560-2565
Ikenouchi H Kangawa K Matsuo H Hirata Y. Negative inotropic effect of adrenomedullin in isolated adult rabbit cardiac ventricular myocytes. Circulation 1997; 95: 2318-2324
Imai T Hirata Y Kanno K Marumo F. Induction of nitric oxide synthase by cyclic AMP in rat vascular smooth muscle cells. J Clin Invest 1994; 93: 543-549
Ishimitsu T Nishikimi T Saito Y Kitamura K Eto T Kangawa K Matsuo H Omae T Matsuoka H. Plasma levels of adrenomedullin a new identified hypotensive peptide in patients with hypertension and renal failure. J Clin Invest 1994; 94: 2158-2161
Ishimitsu T Tsukada K Minami J Ono H Matsuoka H. Variations of human adrenomedullin gene and its relation to cardiovascular diseases. Hypertens Res 2003; 26: 129-134
Ishiyama Y Kitamura K Ichiki Y Nakamura S Kida O Kangawa K Eto T. Hemodynamic effect of a novel hypotensive peptide human adrenomedullin in rats. Eur J Pharmacol 1993; 241: 271-276
Ishizaka Y Tanaka M Kitamura K Kangawa K Minamino N Matsuo H Eto T. Adrenomedullin stimulates cyclic AMP formation in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 1994; 200: 642646
Isumi Y Shoji H Sugo S Tochimoto T Yoshioka M Kangawa K Matsuo H Minamino N. Regulation of adrenomedullin production in rat endothelial cells. Endocrinology 1998; 139: 838-846
Jougasaki M Wei CM McKinley LJ Burnett JC Jr. Elevation of circulating and ventricular adrenomedullin in human congestive heart failure. Circulation 1995a; 92: 286-289
Jougasaki M Wei CM Heublein DM Sandberg SM Burnett JC Jr. Immunohistochemical localization of adrenomedullin in canine heart and aorta. Peptides 1995b; 16: 773-775
Jougasaki M Wei CM Aarhus LL Heublein DM Sandberg SM Burnett JC Jr. Renal localization and actions of adrenomedullin: a natriuretic peptide. Am J Physiol 1995c; 268: F657-663
Jougasaki M Schirger JA Simari RD Burnett JC Jr. Autocrine role for the endothelin-B receptor in the secretion of adrenomedullin. Hypertension 1998; 32: 917-922
Kamitani S Asakawa M Shimekake Y Kuwasako K Nakahara K Sakata T. The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells. FEBS Lett 1999; 448: 111-114
Kapas S1 Catt KJ Clark AJ. Cloning and expression of cDNA encoding a rat adrenomedullin receptor. J Biol Chem 1995; 270: 25344-25347
Kaufman MP Waldrop TG Rybicki KJ Ordway GA Mitchell JH. Effects of static and rhythmic twitch contractions on the discharge of group III and IV muscle afferents. Cardiovasc Res 1984; 18: 663-668
Kaufman MP Longhurst JC Rybicki KJ Wallach JH Mitchell JH. Effects of static muscular contraction on impulse activity of groups III and IV afferents in cats. J Appl Physiol 1983; 55: 105-112
Kaufman MP Rybicki KJ. Discharge properties of group III and IV muscle afferents: their responses to mechanical and metabolic stimuli. Circ Res 1987; 61: 160-165
Kaufman MP Forster HV. Reflexes controlling circulatory ventilatory and airway responses to exercise. Section 12: Exercise: Regulation and Integration of Multiple Systems. II. Control of Respiratory and Cardiovascular Systems. In: Rowell LB Shepherd JT editors. Handbook of Physiology. New York: Oxford University Press 381-447; 1996
Kaufman S Deng Y. Adrenomedullin suppresses atrial natriuretic factor (ANF) secretion from isolated atrium. Life Sci 1998; 63: 1017-1022
Khan S Michaud D Moody TW Anisman H Merali Z. Effects of acute restraint stress on endogenous adrenomedullin levels. NeuroReport 1999; 10: 2829-2833
Kitamura K Kangawa K Kawamoto M Ichiki Y Nakamura S Matsuo H Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. 1993. Biochem Biophys Res Commun 2012; 425: 548-555
Kitamura K Kangawa K Eto T. Adrenomedullin and PAMP: discovery structures and cardiovascular functions. Microsc Res Tech 2002; 57: 3-13
Kohno M Kano H Horio T Yokokawa K Yasunari K Takeda T. Inhibition of endothelin production by adrenomedullin in vascular smooth muscle cells. Hypertension 1995a; 25: 1185-1190
Kohno M Yokokawa K Yasunari K Kano H Horio T Takeda T. Stimulation of cyclic adenosine monophosphate formation by the novel vasorelaxant peptide adrenomedullin in cultured rat mesangial cells. Metabolism 1995b; 44: 10-12
Koide M Kawahara Y Nakayama I Tsuda T Yokoyama M. Cyclic AMP-elevating agents induce an inducible type of nitric oxide synthase in cultured vascular smooth muscle cells. J Biol Chem 1993; 268: 24959-24966
Kruger L Silverman JD Mantyh PW Sternini C Brecha NC. Peripheral patterns of calcitonin-gene-related peptide general somatic sensory innervation: cutaneous and deep terminations. J Comp Neurol 1989; 280: 291-302
Krzeminski K Kruk B Wojcik-Ziolkowska E Kozera J Cybulski G Nazar K. Effect of static handgrip on plasma adrenomedullin concentration in patients with heart failure and in healthy subjects. J Physiol Pharmacol 2002; 53: 199-210
Krzeminski K Mikulski T Kruk B Nazar K. Plasma adrenomedullin response to maximal exercise in healthy subjects. J Physiol Pharmacol 2003; 54: 225-232
Krzeminski K Mikulski T Nazar K. Effect of prolonged dynamic exercise on plasma adrenomedullin concentration in healthy young men. J Physiol Pharm 2006a; 57: 571-581
Krzeminski K Nazar K Cybulski G Mikulski T. Effect of adrenergic blockade on plasma adrenomedullin concentration during static handgrip in patients with heart failure. Clin Physiol Funct Imaging 2006b; 26: 328-334
Krzeminski K Cybulski G Nazar K. Relationships between plasma adrenomedullin concentration and systolic time intervals during static handgrip in patients with heart failure. Clin Physiol Funct Imaging 2009; 29: 114-122
Krzeminski K Cybulski G Ziemba A Nazar K. Cardiovascular and hormonal responses to static handgrip in young and older healthy men. Eur J Appl Physiol 2012; 112: 1315-1325
Krzeminski K Pawłowska-Jenerowicz W. The relationships between plasma adrenomedullin and endothelin-1 concentrations and doppler echocardiographic indices of left ventricular function during static exercise in healthy men. Journal of Human Kinetics 2012; 33: 81-89
- Export Citation
Krzeminski K, Pawłowska-Jenerowicz W. The relationships between plasma adrenomedullin and endothelin-1 concentrations and doppler echocardiographic indices of left ventricular function during static exercise in healthy men.)| false Journal of Human Kinetics, 2012; 33: 81-89 10.2478/v10078-012-0047-z
Lainchbury JG Cooper GJ Coy DH Jiang NY Lewis LK Yandle TG Richards AM Nicholls MG. Adrenomedullin: a hypotensive hormone in man. Clin Sci Colch 1997; 92: 467-472
Lainchbury JG Meyer DM Jougasaki M Burnett JC Jr Redfield MM. Effects of adrenomedullin on load and myocardial performance in normal and heart-failure dogs. Am J Physiol Heart Circ Physiol 2000; 279: 1000-1006
Lamping K. Interactions between NO and cAMP in the regulation of vascular tone arteriosclerosis Thromb and Vasc Biol 2001; 21: 729-730
Lewis RP Boudoulas H Ruff P Kates RE. Systolic time intervals for the diagnosis and management of coronary artery disease. In: Systolic time intervals (Eds. W.F. List J.S. Gravenstein and D.H. Spodick). Springer-veralg Berlin Heidelberg New York; 1980
Lewis RP Rittgers SE Forrester WF Boudoulas H. A critical review of the systolic time intervals. Circulation 1977; 36: 146-158
Majid DS Kadowitz PJ Coy DH Navar LG. Renal responses to intraarterial administration of adrenomedullin in dogs. Am J Physiol 1996; 270: 200-205
Mark AL Victor RG Nerhed C Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans. Circ Res 1985; 57: 461-469
Martin CE Shaver JA Leonard JJ. Direct correlation of systolic time intervals with internal indices of left ventricular function in man. Circulation 1971; 44: 419-431
Matsukawa K Wall PT Wilson LB Mitchell JH. Reflex responses of renal nerve activity during isometric muscle contraction in cats. Am J Physiol 1990; 259: 1380-1388
Matsukawa K Wall PT Wilson LB Mitchell JH. Reflex stimulation of cardiac sympathetic nerve activity during static muscle contraction in cats. Am J Physiol 1994; 267: 821-827
McCloskey DI Mitchell JH. Reflex cardiovascular and respiratory responses originating in exercising muscle. J Physiol 1972; 224: 173-186
McLatchie LM Fraser NJ Main MJ Wise A Brown J Thompson N Solari R Lee MG Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998; 393: 333-339
Meeran K O’Shea D Upton PD Small CJ Ghatei MA Byfield PH Bloom SR. Circulating adrenomedullin does not regulate systemic blood pressure but increases plasma prolactin after intravenous infusion in humans: a pharmacokinetic study. J Clin Endocrinol Metab 1997; 82: 95-100
Megan N Murphy Mizuno M Mitchell JH Smith SA. Cardiovascular regulation by skeletal muscle reflexes in health and disease. Am J Physiol Heart Circ Physiol 2011; 301: 1191-1204
Middlekauff HR Niztsche EU Hoh CK Hamilton MA Fonarow GC Hage A Moriguchi J D. Exaggerated muscle mechanoreflex control of reflex renal vasoconstriction in heart failure. J Appl Physiol 2001; 90: 1714-1719
Middlekauff HR Niztsche EU Nguyen AH Hoh CK Gibbs GG. Modulation of renal cortical blood flow during static exercise in humans. Circ Res 1997; 80: 62-68
Middleton N Shave R George K Whyte G Hart E Atkinson G. Left ventricular function immediately following prolonged exercise: A meta-analysis. Med Sci Sports Exerc 2006; 38: 681-687
Miller WL Redfield MM Burnett JC Jr. Integrated cardiac renal and endocrine actions of endothelin. J Clin Invest 1989; 83: 317-320
Miller MJ Martinez A Unsworth EJ Thiele CJ Moody TW Elsasser T Cuttitta F. Adrenomedullin: expression in human tumour cell lines and its potential role as an autocrine growth factor. J Biol Chem 1996; 271: 23345-23351
Mitchell JH Kaufman MF Iwamoto GA. The exercise pressor reflex: Its cardiovascular effects afferent mechanisms and central pathways. Ann Rev Physiol 1983; 45: 229-242
Mishima K Kato J Kuwasako K Ito K Imamura T Kitamura K Eto T. Effects of endothelin on adrenomedullin secretion and expression of adrenomedullin receptors in rat cardiomyocytes. Biochem Biophys Res Commun 2001; 287: 264-269
Mishima K Kato J Kuwasako K Imamura T Kitamura K Eto T. Angiotensin II modulates gene expression of adrenomedullin receptor components in rat cardiomyocytes. Life Sci 2003; 73: 1629-1635
Miura K Ebara T Okumura M Matsuura T Kim S Yukimura T Iwao H. Attenuation of adrenomedullininduced renal vasodilatation by NG-nitro L-arginine but not glibenclamide. Br J Pharmacol 1995; 115: 917-924
Momen A Leuenberger UA Ray CA Cha S Handly B Sinoway LI. Renal vascular responses to static handgrip: the role of the muscle mechanoreflex. Am J Physiol Heart Circ Physiol 2003; 285: 1247-1253
Moncada S Palmer RM Higgs EA. Nitric oxide physiology pathophysiology and pharmacology. Pharmacol Rev 1991; 43: 109-142
Moody TW Miller MJ Martinez A Unsworth E Cuttitta F. Adrenomedullin binds with high affinity elevates cyclic AMP and stimulates c-fos mRNA in C6 glioma cells. Peptides 1997; 18: 1111-1115
Morimoto A Nishikimi T Takaki H Okano Y Matsuoka H Takishita S Kitamura K Miyata A Kangawa K Matsuo H. Effect of exercise on plasma adrenomedullin and natriuretic peptide levels in myocardial infarction. Clin Exp Pharmacol Physiol 1997; 24: 315-320
- Export Citation
Morimoto A, Nishikimi T, Takaki H, Okano Y, Matsuoka H, Takishita S, Kitamura K, Miyata A, Kangawa K, Matsuo H. Effect of exercise on plasma adrenomedullin and natriuretic peptide levels in myocardial infarction.)| false Clin Exp Pharmacol Physiol, 1997; 24: 315-320 10.1111/j.1440-1681.1997.tb01194.x
Nagata D Hirata Y Suzuki E Kakoki M Hayakawa H Goto A Ishimitsu T Minamino N Ono Y Kangawa K Matsuo H Omata M. Hypoxia-induced adrenomedullin production in the kidney. Kidney Int 1999; 55: 1259-1267
Nagoshi Y Kuwasako K Ito K Uemura T Kato J Kitamura K Eto T. The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8–37)-sensitive adrenomedullin receptor. Eur J Pharmacol 2002; 450: 237-243
- Export Citation
Nagoshi Y, Kuwasako K, Ito K, Uemura T, Kato J, Kitamura K, Eto T. The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8–37)-sensitive adrenomedullin receptor.)| false Eur J Pharmacol, 2002; 450: 237-243 10.1016/S0014-2999(02)02184-2
Nandha KA Taylor GM Smith DM Owji AA Byfield PG Ghatei MA Bloom SR. Specific adrenomedullin binding sites and hypotension in the rat systemic vascular bed. Regul Pept 1996; 62: 145-151
Neri G Bova S Malendowicz LK Mazzocchi G Nussdorfer GG. Simulated microgravity impairs aldosterone secretion in rats: possible involvement of adrenomedullin. Am J Physiol Regul Integr Comp Physiol 2002; 283: 832-836
Niebauer J Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am Coll Cardiol 1996; 28: 1652-1660
Nikitenko LL Blucher N Fox SB Bicknell R Smith DM Rees MCP. Adrenomedullin and CGRP interact with endogenous calcitonin-receptor-like receptor in endothelial cells and induce its desensitisation by different mechanisms. J Cell Sci 2006; 119: 910-922
- Export Citation
Nikitenko LL, Blucher N, Fox SB, Bicknell R, Smith DM, Rees MCP. Adrenomedullin and CGRP interact with endogenous calcitonin-receptor-like receptor in endothelial cells and induce its desensitisation by different mechanisms)| false . J Cell Sci, 2006; 119: 910-922 10.1242/jcs.02783
Nishikimi T Morimoto A Iscsikawa K Saito Y Kangawa K Matsuo H Kitamuran K Takishita S Matsuoka H. Different secretion patterns of adrenomedullin brain natriuretic peptide and atrial natriuretic peptide during exercise in hypertensive and normotensive subjects. Clin Exper Hypertens 1997; 19: 503 518
- Export Citation
Nishikimi T, Morimoto A, Iscsikawa, K Saito Y, Kangawa K, Matsuo H, Kitamuran K, Takishita S, Matsuoka H. Different secretion patterns of adrenomedullin, brain natriuretic peptide, and atrial natriuretic peptide during exercise in hypertensive and normotensive subjects.)| false Clin Exper Hypertens, 1997; 19: 503 518 10.3109/10641969709084511
Nishikimi T Yoshihara F Mori Y Kangawa K Matsuoka H. Cardioprotective effect of adrenomedullin in heart failure. Hypertens Res 2003; 26 Suppl: S121-127
Nishimatsu H Suzuki E Nagata D Moriyama N Satonaka H Walsh K Sata M Kangawa K Matsuo H Goto A Kitamura T Hirata Y. Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res 2001; 89: 63-70
- Export Citation
Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo H, Goto A, Kitamura T, Hirata Y. Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta.)| false Circ Res, 2001; 89: 63-70 10.1161/hh1301.092498
Nobrega A O’Leary D Silva BM Marongiu E Piepoli M Crisafulli A. Neural Regulation of Cardiovascular Response to Exercise: Role of Central Command and Peripheral Afferents. BioMed Res Int 2014; 3: 478965. DOI:
Onitsuka H Imamura T Yamaga J Kuwasako K Kitamura K Eto T. Angiotensin II Stimulates Cardiac Adrenomedullin Production and Causes Accumulation of Mature Adrenomedullin Independently of Hemodynamic Stress in Vivo. Horm Metab Res 2005; 37: 281-285
- Export Citation
Onitsuka H, Imamura T, Yamaga J, Kuwasako K, Kitamura K, Eto T. Angiotensin II Stimulates Cardiac Adrenomedullin Production and Causes Accumulation of Mature Adrenomedullin Independently of Hemodynamic Stress in Vivo.)| false Horm Metab Res, 2005; 37: 281-285 10.1055/s-2005-861471
Parkes DG May CN. Direct cardiac and vascular actions of adrenomedullin in conscious sheep. Br J Pharmacol 1997; 120: 1179-1185
Piquard F Charloux A Mettauer B Epailly E Lonsdorfer E Popescu S Lonsdorfer J Geny B. Exercise-induced increase in circulating adrenomedullin is related to mean blood pressure in heart transplant recipients. J Clin Endocrinol Metab 2000; 85: 2828-2831
- Export Citation
Piquard F, Charloux A, Mettauer B, Epailly E, Lonsdorfer E, Popescu S, Lonsdorfer J, Geny B. Exercise-induced increase in circulating adrenomedullin is related to mean blood pressure in heart transplant recipients)| false . J Clin Endocrinol Metab, 2000; 85: 2828-2831 10.1210/jcem.85.8.6734
Poveda JJ Berrazueta JR Ochoteco A Montalban C Garcia-Unzueta MT Fernandez C Pena N Amado JA. Age-related responses of vasoactive factors during acute exercise. Horm Metab Res 1998; 30: 668-672
Pryor SL Lewis SF Haller RG Bertocci LA Victor RG. Impairment of sympathetic activation during static exercise in patients with muscle phosphorylase deficiency (McArdle's disease). J Clin Invest 1990; 85: 1444-1449
Rademaker MT Charles CJ Espiner EA Nicholls MG Richards AM. Long-termadrenomedullin administration in experimental heart failure. Hypertension 2002; 40: 667-672
Rademaker MT Cameron VA Charles CJ Lainchbury JG Nicholls MG Richards AM. Adrenomedullin and heart failure. Regul Pept 2003; 112: 51-60
Rebuffat P Malendowicz LK Nussdorfer GG Mazzocchi G. Stimulation of endogenous nitric oxide production is involved in the inhibitory effect of adrenomedullin on aldosterone secretion in the rat. Peptides 2001; 22: 923-926
Rhodes J Udelson JE Marx GR Shmid CH Konstam MA Hijazi ZM Bova SA Fulton DR. A new noninvasive method for the estimation of peak dP/dt. Circulation 1993; 88: 2693-2699
Romppanen H Marttila M Magga J Vuolteenaho O Kinnunen P Szokodi I Ruskoaho H. Adrenomedullin gene expression in the rat heart is stimulated by acute pressure overload: blunted effect in experimental hypertension. Endocrinology 1997; 138: 2636-2639
Rotto DM Schultz HD Longhurst JC Kaufman MP. Sensitization of group III muscle afferents to static contraction by products of arachidonic acid metabolism. J Appl Physiol 1990; 68: 861-867
Rotto DM Stebbins CL Kaufman MP. Reflex cardiovascular and ventilatory responses to increasing H+ activity in cat hindlimb muscle. J Appl Physiol 1989; 67: 256-263
Sabates BL Pigott JD Choe EU Cruz MP Lippton HL Hyman AL Flint LM Ferrara JJ. Adrenomedullin mediates coronary vasodilation through adenosine receptors and K+ATP channels. J Surg Res 1997; 67: 163-168
Saito M. Differences in muscle sympathetic nerve response to isometric exercise in different muscle groups. Eur J Appl Physiol 1995; 70: 26-35
Saito M Naito M Mano T. Different responses in skin and muscle sympathetic nerve activity to static muscle contraction. J Appl Physiol 1990; 69: 2085-2090
Sakai K Saito K Ishizuka N. Adrenomedullin synergistically interacts with endogenous vasodilators in rats: a possible role of K-ATP channels. Eur J Pharmacol 1998; 359: 151-159
Sato A Autelitano DJ. Adrenomedullin induces expression of c-fos and AP-1 activity in rat vascular smooth muscle cells and cardiomyocytes. Biochem Biophys Res Commun 1995; 217: 211-216
Sato A Canny BJ Autelitano DJ. Adrenomedullin stimulates cAMP accumulation and inhibits atrial natriuretic peptide gene expression in cardiomyocytes. Biochem Biophys Res Commun 1997; 230: 311314
Shimekake Y Nagata K Ohta S Kambayashi Y Teraoka H Kitamura K Eto T Kangawa K Matsuo H. Adrenomedullin stimulates two signal transduction pathways cAMP accumulation and Ca2+ mobilization in bovine aortic endothelial cells. J Biol Chem 1995; 270: 4412-4417
- Export Citation
Shimekake Y, Nagata K, Ohta S, Kambayashi Y, Teraoka H, Kitamura K, Eto T, Kangawa K, Matsuo H. Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells.)| false J Biol Chem, 1995; 270: 4412-4417 10.1074/jbc.270.9.4412
Stack RS Sohn YH Weissler AM. Accuracy of the systolic time intervals in detecting abnormal left ventricular performance in coronary artery disease. Am J Cardiol 1981; 47: 603-609
Stangl V Dschietzig T Bramlage P Boye P Kinkel HT Staudt A Baumann G Felix SB Stangl K. Adrenomedullin and myocardial contractility in the rat. Eur J Pharmacol 2000; 408: 83-89
Stebbins CL Walser B Jafarzadeh M. Cardiovascular responses to static and dynamic contraction during comparable workloads in humans. Am J Physiol Regul Integr Comp Physiol 2002; 283: 568-575
Sugo S Minamino N Kangawa K Miyamoto K Kitamura K Sakata J Eto T Matsuo H. Endothelial cells actively synthesize and secrete adrenomedullin. Biochem Biophys Res Commun 1994; 201: 1160-1166
Sugo S Minamino N Shoji H Kangawa K Kitamura K Eto T Matsuo H. Interleukin-1 tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun 1995a; 207: 25-32
- Export Citation
Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, Matsuo H. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells.)| false Biochem Biophys Res Commun, 1995a; 207: 25-32 10.1006/bbrc.1995.1148
Sugo S Minamino N Shoji H Kangawa K Matsuo H. Effects of vasoactive substances and cAMP related compounds on adrenomedullin production in cultured vascular smooth muscle cells. FEBS Lett 1995b; 369: 311-314
Szokodi I Kinnunen P Ruskoaho H. Inotropic effect of adrenomedullin in the isolated perfused rat heart. Acta Physiol Scand 1996; 156: 151-152
Szokodi I Kinnunen P Tavi P Weckstrom M Toth M Ruskoaho H. Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin a new inotropic peptide. Circulation 1998; 97: 1062-1070
Tanaka M Kitamura K Ishizaka Y Ishiyama Y Kato J Kangawa K Eto T. Plasma adrenomedullin in various diseases and exercise -induced change in adrenomedullin in healthy subjects. Internal Med 1995; 34: 728-733
Terata K Miura H Liu Y Loberiza F Gutterman DD. Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K+ channels. Am J Physiol Heart Circ Physiol 2000; 279: 26202626
Tschakovsky ME Sujirattanawimol K Ruble SB Valic Z Joyner MJ. Is sympathetic neural vasoconstriction blunted in the vascular bed of exercising human muscle? J Physiol 2002; 541: 623-635
Tsuchimochi H Hayes SG McCord JL Kaufman MP. Both central command and exercise pressor reflex activate cardiac sympathetic nerve activity in decerebrate cats. Am J Physiol Heart Circ Physiol 2009; 1157-1163
Tsuruda T Kato J Kitamura K Imamura T Koiwaya Y Kangawa K Komuro I Yazaki Y Eto T. Enhanced adrenomedullin production by mechanical stretching in cultured rat cardiomyocytes. Hypertension 2000; 35:1210-1214
Victor RG Bertocci LA Pryor SL Nunnally RL. Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans. J Clin Invest 1988; 82: 1301-1305
Victor RG Pryor SL Secher NH Mitchell JH. Effects of partial neuromuscular blockade on sympathetic nerve responses to static exercise in humans. Circ. Res 1989a; 65: 468-476
Victor RG Rotto DM Pryor SL Kaufman MP. Stimulation of renal sympathetic activity by static contraction: evidence for mechanoreceptor-induced reflexes from skeletal muscle. Circ Res 1989b; 64: 592-599
Von During M Andres KH. Topography and ultrastructure of group III and IV nerve terminals of cat's gastrocnemius-soleus muscle. In: Zenker W Neuhuber WL editors. The Primary Afferent Neuron: A Survey of Recent Morpho-functional Aspects. New York: Plenum 35-41; 1990
- Export Citation
Von During M, Andres KH. Topography and ultrastructure of group III and IV nerve terminals of cat's gastrocnemius-soleus muscle. In: Zenker W, Neuhuber WL, editors. The Primary Afferent Neuron: A Survey of Recent Morpho-functional Aspects. New York: Plenum, 35-41; 1990)| false 10.1007/978-1-4613-0579-8_3
Wang GX Cai SX Wang PQ Ouyang KQ Wang YL Xu SR. Shear-induced changes in endothelin-1 secretion of microvascular endothelial cells. Microvasc Res 2002; 63: 209-217
Weissler AM Harris WS Schoenfeld CD. Bedside technics for the evaluation of ventricular function in man. Am J Cardiol 1969; 23: 577-583
Weissler AM Stack RS Sohn YH. The accuracy of the systolic time intervals as a measure of left ventricular function. In: Systolic time intervals (Ed. W.F. List J.S. Gravenstein and D.H. Spodick). Springer-Verlag Berlin Heidelberg New York; 1980
Weissler AM Lewis RP Leighton RF. The systolic time intervals as a measure of left ventricular performance in man. In: PN Yu JF Goodwin (Eds.) Progress in Cardiology. Lea and Febiger Philadelphia 1972; 1: 155-183
Williamson J W. The relevance of central command for the neural cardiovascular control of exercise. Exp Physiol 2010; 95: 1043-1048
Williamson JW. Autonomic responses to exercise: Where is central command? Autonomic neuroscience: basic and clinical 2015; 188: 3-4
Yukihito H Yoshizumi M. Exercise and endothelial function: Role of endothelium-derived nitric oxide and oxidative stress in healthy subjects and hypertensive patients. Pharm and Therap 2004; 102: 87-96
Yűksel S Akbay A Yrekli M. Contribution of adrenomedullin to homeostatic response to cold stress in rat model. Pathophysiology 2002; 8: 243-247
Zając A Chalimoniuk M Maszczyk A Gołaś A Langfort J. Central and Peripheral Fatigue During Resistance Exercise - A Critical Review. J Hum Kinet 2015; 49: 159-169
Zhang X Hintze TH. C-AMP signal transduction cascade a novel pathway for the regulation of endothelial nitric oxide production in coronary blood vessels. Arterioscler Thromb Vasc Biol 2001; 21:797-803