Comparison of the chronotropic effect and the cyclic AMP accumulation induced by beta 2-agonists in rat heart cell culture.

Abstract

1 The chronotropic response and the variation in cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation induced by isoprenaline and six beta 2-selective agonists (fenoterol, salmefamol, soterenol, zinterol, salbutamol and formoterol) were analyzed on cultured heart cells of the rat. 2 The compounds elicited an enhancement of the frequency, but the time course of the variation of the beating rate was not identical for all of them. A rapid onset was observed for isoprenaline, zinterol and formoterol while it was slower for fenoterol, salmefamol and salbutamol. 3 In contrast with isoprenaline, the beta 2-selective agonists gave concentration-beating frequency curves which were not sigmoidal. Their effects extended up to a concentration of 5 to 6 orders of magnitude. Nevertheless, the concentration at which the maximal effect occurred and the intrinsic activities of the various compounds agrees better with the responses observed on guinea-pig atria than with those on trachea. 4 All the beta 2-selective agonists increased the accumulation of cyclic AMP in rat heart cells with a maximal effect at 10(-5)M or less. The effects of beta 2-agonists on cyclic AMP production showed some analogies with those on beating frequency of the heart cells. The increase in cyclic AMP accumulation induced by beta 2-agonists also corresponded to their chronotropic effects on guinea-pig atria. Thus, the correlation coefficient between the inverse of the log of the concentration producing the half maximal cyclic AMP accumulation in cultured heart cells and the pD2 values on guinea-pig atria was 0.93. 5 It is concluded that, in contrast to what was observed in other models, the beta 2-selective agonists induce an increase in the production of cyclic AMP in rat heart cells. Furthermore, the effects of the beta 2-agonists on cyclic AMP accumulation and on beating rate in the heart cells may correspond with their beta 1-adrenoceptor potencies.