Activity of amylin at CGRP1-preferring receptors coupled to positive contractile response in rat ventricular cardiomyocytes.
Calcitonin gene-related peptide (CGRP) exerts a positive contractile response directly in rat ventricular cardiomyocytes. This response is mediated by receptors of the CGRP1-subtype. Amylin is 46% homologous with CGRP and binds to receptors selective for CGRP in a range of tissues. The ability of amylin to influence ventricular contractility has been assessed using cardiomyocytes isolated from the ventricles of adult rats. Cardiomyocytes were subjected to biphasic electrical stimulation at 0.5 Hz. CGRP produced a concentration-dependent positive contractile response which became maximal 4 min after initial stimulation. CGRP increased the contractile amplitude maximally at 1 nM and to a value which was 23.3% greater than in the absence of peptide (EC50 value = 21 pM). Amylin increased the contractile amplitude maximally at 20 nM and to a value which was 17.3% greater than in the absence of peptide (EC50 value = 216 pM). In the presence of amylin (20 nM), the concentration-dependence of the contractile response to CGRP was shifted to the left, so that the response became maximal when CGRP was present at 50 pM. In the presence of CGRP8-37 (100 nM), a selective antagonist at CGRP1-preferring receptors, the concentration-dependence of the contractile response to CGRP was shifted to the right (dose ratio = 54). Similarly, in the presence of CGRP8-37 (100 nM), the contractile response to amylin was inhibited significantly (P < or = 0.01). Amylin8-37 (100 nM) did not inhibit the concentration-dependence of the contractile responses to CGRP and amylin significantly (dose ratios = 4.2 and 2.4, respectively). In conclusion, these data indicate that amylin exerts a contractile response directly in rat ventricular cardiomyocytes via CGRP1-preferring receptors. This effect could assume greater significance in non-insulin-dependent diabetes mellitus and in hypertensive states, in which the concentration of amylin is elevated in plasma.
Bell
D
D
Department of Therapeutics and Pharmacology, Queen's University of Belfast, UK.
McDermott
B J
BJ
D000682:Amyloid / Q000494:pharmacology*; D000818:Animals; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects*; D013268:Stimulation, Chemical
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D018015:Receptors, Calcitonin Gene-Related Peptide