Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide

Abstract

Background-Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro. Methods and Results-In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (PAMP; 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP 8 -37 , or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca 2ϩ release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic reticulum Ca 2ϩ ATPase and depletes intracellular Ca 2ϩ stores, attenuated the early increase in developed tension produced by ADM. In addition, inhibition of protein kinase C by staurosporine (10 nmol/L) and blockade of L-type Ca 2ϩ channels by diltiazem (1 mol/L) significantly decreased the sustained phase of ADM-induced increase in developed tension. Superfusion of atrial myocytes with ADM (1 nmol/L) in isolated left atrial preparations resulted in a marked prolongation of action potential duration between 10 and Ϫ50 mV transmembrane voltage, consistent with an increase in L-type Ca 2ϩ channel current during the plateau. Conclusions-Our results show that ADM enhances cardiac contractility via cAMP-independent mechanisms including Ca 2ϩ release from intracellular ryanodine-and thapsigargin-sensitive Ca 2ϩ stores, activation of protein kinase C, and Ca 2ϩ influx through L-type Ca 2ϩ channels. (Circulation. 1998;97:1062-1070.)Key Words: adrenomedullin Ⅲ contractility Ⅲ calcium Ⅲ peptides Ⅲ signal transduction A drenomedullin is a newly discovered, potent, vasorelaxing and natriuretic peptide that was originally isolated from human pheochromocytoma.1 The peptide, consisting of 52 amino acids in humans and 50 amino acids in the rat, is classified in the CGRP family.2,3 ADM may function as a paracrine and/or autocrine factor in the regulation of cardiac function, because high mRNA expression, 4 a considerable amount of ADM-like immunoreactivity, 5-7 and a high level of 125 I-ADM binding 8 have been found in the heart. In agreement with this hypothesis, ADM has been reported to increase cardiac output and left ventricular contractility in vivo 9,10 and exert a direct inotropic effect in vitro.11 Recently, the plasma concentration of circulating ADM has been shown to be increased in patients with congestive heart failure.5,12-14 Moreover, Jougasaki et al 5 reported that immunohistochemical staining for ADM is significantly increased...

Adrenomedullin increases cardiac sympathetic nerve activity in normal conscious sheep

“…Furthermore, NP is predominantly a venodilator and has no direct inotropic effect, both of which limit the cardiac output response to hypotension (Miletich & Ivankovich 1978, Bauer & Fung 1996. In contrast, AM is mainly an arterial vasodilator (Champion et al 1997, Cockcroft et al 1997 and may increase cardiac contractility (Parkes & May 1995, Szokodi et al 1998. The exaggerated heart rate response to AM observed in the present study may be due to increased sympathetic outflow from the central nervous system resulting in a greater rise in heart rate than that expected by baroreceptor activation alone.…”

“…AM's effect on cardiac output are likely to be multifactorial and could result from augmentation of efferent CSNA, alterations in cardiac preload or afterload, a direct positive inotropic action (Parkes & May 1995, Szokodi et al 1998 or via changes in heart rate. The present study demonstrates a substantial increase in cardiac output with AM quite distinct from NP, which had no observable effect.…”

Hemodynamic and hormonal effects of exogenous adrenomedullin administration in humans and relationship to insulin resistance

“…19 In addition, a cAMP-independent mechanism for the positive inotropic action of AM has been reported. 20 These data suggest that increased cardiac output, and probably heart rate, may be attributable not only to the decrease in cardiac afterload but also to the direct positive inotropic action of AM. PWV is a convenient indicator of arterial stiffness and is applicable in the casual and prognostic estimation of risk for cardiovascular events.…”

Aldosterone antisecretagogue and antihypertensive actions of adrenomedullin in patients with primary aldosteronism

“…AM has a cAMP-dependent and -independent positive inotropic effect on myocardium. 26,27 In addition to the decrease in cardiac afterload induced by vasodilation, cardiac output was markedly increased by AM administration. [9][10][11][12] The cumulative increase in BNP may reflect cardiac overload induced by prolonged infusion of AM.…”