Characterization of the alpha-adrenoceptors mediating positive inotropy of rat left atria by use of selective agonists and antagonists.

Positive inotropic responses to selective alpha-adrenoceptor agonists of isolated paced left atria and chronotropic responses of isolated spontaneously beating right atria of rats were examined. After establishing a cumulative concentration-response curve to isoprenaline, and washout, a concentration-response curve for phenylephrine, methoxamine, cirazoline, amidephrine or UK 14,304 was constructed in the presence of beta-adrenoceptor blockade by propranolol. The 4 alpha 1-selective agonists produced positive inotropic responses, the order of maximum effectiveness being methoxamine greater than phenylephrine greater than cirazoline greater than amidephrine. In terms of EC50 values, methoxamine was the least potent, the other 3 agonists having approximately equivalent potencies. The alpha 2-selective agonist UK 14,304 had no inotropic activity. Weak positive chronotropic activity occurred with phenylephrine, methoxamine and amidephrine; cirazoline exerted only negative chronotropy and UK 14,304 was without effect. Phenylephrine was examined in the absence or presence of prazosin (3 nM) or propranolol (1 microM). Propranolol failed to affect the concentration-response curve for left atrial tension, but prazosin displaced the curve to the right. This indicates that the inotropic responses obtained in the absence of antagonists were mediated solely via alpha-adrenoceptors. After displacement by prazosin there was a further shift by propranolol, suggesting the presence of a beta-adrenoceptor-mediated component at higher concentrations of phenylephrine. The right atrial rate responses to phenylephrine were unaffected by prazosin, but abolished by propranolol; beta-adrenoceptors only are therefore involved in this response. The pA2 values for antagonism of methoxamine-induced increases in left atrial tension by the alpha 1- and alpha 2-selective antagonists prazosin (9.05 +/- 0.06) and idazoxan (6.37 +/- 0.05), respectively, were consistent with the responses being mediated via alpha-adrenoceptors of the alpha 1-subtype. The pA2 value for prazosin was similar to that obtained for antagonism of methoxamine-induced contractions of rat aortic spirals (8.83 +/- 0.13).