Possible mechanisms of positive inotropic action of synthetic human calcitonin gene-related peptide in isolated rat atrium

The effect of synthetic human calcitonin gene-related peptide (hCGRP) on the isolated and electrically driven left atria of rats were investigated. The peptide at concentrations of 3×10 −9−3×10 −7 M produced positive inotropic effects on the left atria in a dose-dependent manner. Verapamil (10 −5 M) and adenosine (10 −4 M) reduced the positive inotropic effect of hCGRP at concentrations of 3×10 −9 and 3×10 −8 M, but not at that of 3×10 −7 M. Ouabain (5×10 −5 M) inhibited the effect of hCGRP in concentrations of 3×10 −7 and 3×10 −8 M, but not in that of 3×10 −9 M. Simultaneous pretreatment with verapamil (10 −5 M) and ouabain (5×10 −5 M) suppressed the positive inotropy by hCGRP at all concentrations tested. On the other hand, tetrodotoxin (10 −6 M) potentiated only the positive inotropic effect of 3×10 −7 M hCGRP. Metoprolol (10 −7 M) and theophilline (10 −3 M) did not affect the inotropic effect of hCGRP. These results suggest that the positive inotropic effect of hCGRP is not mediated by β-adrenoceptors but by two distinct mechanisms of action, (a) which was inhibited by verapamil but not by ouabain (facilitation of Ca ++ influx in lower concentrations of hCGRP) and (b) which was blocked by ouabain but not by verapamil and potentiated by tetrodotoxin (inhibition of Na +/Ca ++ exchange mechanism at higher concentrations of hCGRP).