Chronotropic response to (+/-)-CGP12177 in right atria of stressed rats

Foot-shock stress changes the sensitivity of the rat right atria to beta1- and beta2-adrenoceptor (AR) agonists. We investigated whether the same stress protocol also changes the atrial sensitivity to the non conventional agonist, (+/-)-CGP12177. Concentration-response curves to (+/-)-CGP12177, a beta1- and beta2-adrenoceptor antagonist with agonist properties at the putative beta4-adrenoceptors, were obtained in the absence and presence of propranolol (200 nM or 2 microM), CGP20712A 10 nM plus ICI118,551 50 nM, or CGP20712A (1 microM or 3 microM), in right atria from rats submitted to three daily foot-shock sessions (120 mA pulses of 1.0 s duration applied at random intervals of 5-25 s over 30 min) and killed after the third session. The pD2 for (+/-)-CGP12177 was not influenced by foot-shock stress. The stimulant effect of (+/-)-CGP12177 was resistant to blockade by 200 nM and 2 microM (+/-)-propranolol, and to combined blockade by CGP20712A and IC1118,551. However, in right atria from stressed rats given 200 nM propranolol, the concentration-response curve to the agonist was shifted 2.0-fold to the right. CGP20712A shifted the concentration-response curve to (+/-)-CGP12177 to the right by 4.6- (1 microM) and 19-fold (3 microM) in atria of control rats, and by 2.2- (1 microM) and 43-fold (3 microM) in atria of stressed rats. Maximum response to CGP12177 was not affected by propranolol or CGP20712A in concentrations ranging from 0.1 nM to 10 microM. These results show that the chronotropic effect of (+/-)-CGP12177 is mediated by atypical beta4-adrenoceptors. In constrast with to beta1-and (or) beta2-AR, this receptor is resistant to the effects of foot-shock stress, suggesting that the putative beta4-AR is a different receptor from a low affinity state of beta1-adrenoceptor, as previously proposed, unless both proposed isoforms of beta1-adrenoceptor show independent stress-induced behavior.