Different mechanisms of positive chronotropic actions of isoprenaline and noradrenaline on isolated guinea pig right atria revealed by pretreatment with rilmakalim.

In this study we tested the influence of activation of ATP-sensitive K+ channels (KATP) on the changes in automatism induced by isoprenaline, noradrenaline and phenylephrine. Experiments were performed on the spontaneously beating right atria isolated from guinea pig. The rate of spontaneously beating preparations was measured under different experimental conditions. Rilmakalim (formerly HOE 234) was used as an activator of KATP channels. Isoprenaline induced significant, concentration-dependent positive inotropic action. This effect was strongly attenuated only in the presence of selective blockers of beta1- (metoprolol), but not beta2-adrenoceptor subtype (ICI 11855). Pretreatment with 4 microM rilmakalim resulted in a significant increase in the described effects of isoprenaline on automatism of isolated right atria. Phenylephrine (1 to 100 microM) in the presence of 1 microM propranolol, did not cause any changes in automatism of guinea pig right atria. Slight but significant positive chronotropic action induced by noradrenaline at lower concentrations (0.1 to 10 microM) in the presence of 1 microM propranolol was significantly decreased by pretreatment with rilmakalim. However, the effects obtained at higher concentrations (30 and 100 microM) of noradrenaline were enhanced. Interactions mentioned above were prevented by addition of 3 microM glibenclamide. The results imply that positive chronotropic effect of noradrenaline in the presence of propranolol is mediated by adrenoceptor subtype different from alpha1-, beta1- and beta2-adrenoceptors.