Ca2+-induced Ca2+ release involved in positive inotropic effect mediated by CGRP in ventricular myocytes.
To investigate the effects and mechanisms of calcitonin gene-related peptide (CGRP) on ventricular contractility, ventricular myocytes isolated from adult rat and mouse hearts were exposed to CGRP. Myocyte contractility was assessed by a video edge motion detector, and the intracellular [Ca2+] transients were measured by a spectroflurophotometer in fura 2-loaded myocytes. CGRP exerted a potent concentration-dependent (10 pM-10 nM, EC50 = 44.1 pM) positive inotropism on rat ventricular myocytes. CGRP (1 nM) increased cell shortening during contraction by 140 +/- 40% above baselines and increased maximum velocity of contraction and relaxation by 98 and 106%, respectively. CGRP failed to produce any response in the presence of the CGRP1 receptor antagonist. CGRP induced similar inotropic response in mouse ventricular myocytes. CGRP increased the amplitude of [Ca2+] transients of ventricular myocytes by 120 +/- 25% above baseline and shortened the time of half-maximum myoplasmic Ca2+ clearance by 30 +/- 5%. Increase in intracellular Ca2+ mobilization by CGRP was dependent on Ca2+ influx through the activation of the L-type Ca2+ channel, because nifedipine blocked the CGRP-induced increase in [Ca2+] transients. Furthermore, CGRP failed to increase [Ca2+] transients after the inhibition of protein kinase A in ventricular myocytes. These data indicate that stimulation of mammalian ventricular myocardial CGRP1 receptors enhances [Ca2+] transients through the activation of protein kinase A, which in turn activates voltage-dependent L-type Ca2+ channels. These events lead to Ca2+-induced intracellular Ca2+ release and enhanced myocyte contraction and facilitated relaxation.
Huang
M H
MH
Departments of Medicine, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14209, USA.
Knight
P R
PR
Izzo
J L
JL
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009994:Osmolar Concentration; D051381:Rats; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology*
D015740:Calcitonin Gene-Related Peptide; D002118:Calcium