From the Department of Cardiovascular Surgery and First Department of
Internal Medicine, Semmelweis University Medical School, Budapest, Hungary
(I.S., M.T.), and Departments of Pharmacology and Toxicology (P.K., H.R.) and
Physiology (P.T., M.W.), Biocenter Oulu, University of Oulu, Finland.
Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi
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,
CGRP8–37, 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 Ca2+ release channel
opener, suppressed the overall ADM-induced positive inotropic effect.
Pretreatment with thapsigargin (30 nmol/L), which inhibits sarcoplasmic
reticulum Ca2+ ATPase and depletes intracellular
Ca2+ 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
Ca2+ channels by diltiazem (1 µmol/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 -50 mV transmembrane voltage,
consistent with an increase in L-type Ca2+ channel
current during the plateau.
Conclusions—Our results show that ADM enhances cardiac
contractility via cAMP-independent mechanisms including
Ca2+ release from intracellular ryanodine- and
thapsigargin-sensitive Ca2+ stores, activation of protein
kinase C, and Ca2+ influx through L-type Ca2+
channels.
© 1998 American Heart Association, Inc.
Basic Science Reports
Evidence for cAMP-Independent Mechanisms Mediating the Effects of Adrenomedullin, a New Inotropic Peptide
Key Words: adrenomedullin • contractility • calcium • peptides • signal transduction
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