Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide

被引:166
作者
Szokodi, I
Kinnunen, P
Tavi, P
Weckström, M
Tóth, M
Ruskoaho, H
机构
[1] Univ Oulu, Dept Pharmacol & Toxicol, Bioctr Oulu, FIN-90220 Oulu, Finland
[2] Univ Oulu, Dept Physiol, Bioctr Oulu, FIN-90220 Oulu, Finland
[3] Semmelweis Univ Med, Sch Med, Dept Cardiovasc Surg, Budapest, Hungary
[4] Semmelweis Univ Med, Sch Med, Dept Internal Med 1, Budapest, Hungary
关键词
adrenomedullin; contractility; calcium; peptides; signal transduction;
D O I
10.1161/01.CIR.97.11.1062
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 ABM, 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 Ca2+ release channel opener, suppressed the overall ADM-induced positive inotropic effect. Pretreatment with thapsigargin (30 nmoI/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 mu 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 -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.
引用
收藏
页码:1062 / 1070
页数:9
相关论文
共 59 条
[21]   INVOLVEMENT OF CAMP-DEPENDENT PROTEIN-KINASE IN REGULATION OF HEART CONTRACTILE-FORCE [J].
KEELY, SL ;
CORBIN, JD .
AMERICAN JOURNAL OF PHYSIOLOGY, 1977, 233 (02) :H269-H275
[22]   ENDOTHELIN ENHANCES THE CONTRACTILE RESPONSIVENESS OF ADULT-RAT VENTRICULAR MYOCYTES TO CALCIUM BY A PERTUSSIS TOXIN-SENSITIVE PATHWAY [J].
KELLY, RA ;
EID, H ;
KRAMER, BK ;
ONEILL, M ;
LIANG, BT ;
REERS, M ;
SMITH, TW .
JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (04) :1164-1171
[23]   MECHANISMS OF ATRIAL AND BRAIN NATRIURETIC PEPTIDE RELEASE FROM RAT VENTRICULAR MYOCARDIUM - EFFECT OF STRETCHING [J].
KINNUNEN, P ;
VUOLTEENAHO, O ;
RUSKOAHO, H .
ENDOCRINOLOGY, 1993, 132 (05) :1961-1970
[24]   IDENTIFICATION AND HYPOTENSIVE ACTIVITY OF PROADRENOMEDULLIN N-TERMINAL-20 PEPTIDE (PAMP) [J].
KITAMURA, K ;
KANGAWA, K ;
ISHIYAMA, Y ;
WASHIMINE, H ;
ICHIKI, Y ;
KAWAMOTO, M ;
MINAMINO, N ;
MATSUO, H ;
ETO, T .
FEBS LETTERS, 1994, 351 (01) :35-37
[25]   ADRENOMEDULLIN - A NOVEL HYPOTENSIVE PEPTIDE ISOLATED FROM HUMAN PHEOCHROMOCYTOMA [J].
KITAMURA, K ;
KANGAWA, K ;
KAWAMOTO, M ;
ICHIKI, Y ;
NAKAMURA, S ;
MATSUO, H ;
ETO, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 192 (02) :553-560
[26]   BLOCK OF STRETCH-ACTIVATED ATRIAL-NATRIURETIC-PEPTIDE SECRETION BY GADOLINIUM IN ISOLATED RAT ATRIUM [J].
LAINE, M ;
ARJAMAA, O ;
VUOLTEENAHO, O ;
RUSKOAHO, H ;
WECKSTROM, M .
JOURNAL OF PHYSIOLOGY-LONDON, 1994, 480 :553-561
[27]  
LYTTON J, 1991, J BIOL CHEM, V266, P17067
[28]  
MEISSNER G, 1986, J BIOL CHEM, V261, P6300
[29]  
MORGAN JP, 1991, NEW ENGL J MED, V325, P625
[30]  
MOSCHELLA MC, 1993, J CELL BIOL, V266, P1109