Peripheral Vasodilator and β-Adrenoceptor Blocking Properties of Several β-Adrenoceptor Antagonists

Abstract

The peripheral vasodilator and β₂-adrenergic blocking activity of 17 β-adrenoceptor antagonists were evaluated in the perfused dog hindlimb to determine whether a decrease in vascular resistance might contribute to their antihypertensive properties. The antagonists produced either a transient decrease in hindlimb perfusion pressure followed by either a sustained increase or a decrease in limb resistance with increasing doses. These effects were independent of the ability of the compounds to block vascular β₂-receptors. (±)-, (+)-Propranolol, (-)-alprenolol, bunitrolol, IPS-339, butoxamine, tolamolol, RMI-81968, labetalol and penbutalol produced transient dose-related reductions in hindlimb perfusion pressure (20–60 mm Hg). The greatest transient decrease in limb resistance was observed with penbutalol and IPS-339, but the transient vasodilator response following i.a. labetalol was more sustained than any of the compounds tested. Timolol and nadolol were devoid of acute vasodilator activity. A sustained decrease in hindlimb perfusion pressure was observed with increasing cumulative doses of bunitrolol, MK-761, labetalol, tolamolol, RMI-81968, while (+)- and (±)-propranolol, atenolol, metoprolol and nadolol and two β₂-selective antagonists, butoxamine and IPS-339 consistently elevated perfusion pressure. Pretreatment with phentolamine attenuated propranolol-induced increase i n hindlimb perfusion pressure, suggesting that the increase inresistance may be mediated reflexly secondary to hemodynamic changes or release of adrenal catecholamines. Timolol and (-)-alprenolol, two of the more potent B2-antagonists, did not produce any consistent sustained increase or decrease in perfusion pressure with increasing cumulative doses. The relative balance of these drugs i n blocking O-adrenoceptors (blockade of i . a . isoproterenol) vs decreasing hindlimb perfusion pressure suggests that of the compounds tested only labetalol produced sustained vasodilatation throughout i t s 6-adrenoceptor blocking dose/response regression curve. Thus, it is conceivable that of all the compounds evaluated, the vasodilator properties of only labetalol may contribute toits antihypertensive effect at O-adrenergic blocking doses.