β-Blocking Agents with Vasodilating Action

beta-Adrenoceptor-blocking drugs in current use can be separated into two main groups: those nonselective and those selective for beta 1-receptors. Members of each group reduce cardiac output and lead to an increase in peripheral resistance with a concomitant reduction in blood flow. beta-Blocking drugs not only may occupy the receptor preventing stimulation but also may have intrinsic sympathomimetic activity. Those with marked partial agonist activity at the beta 2-receptor giving some beta 2-mediated vasodilation can be regarded as the first multiple-action beta-blocking drugs. Subsequently, drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed; prizidolol followed but has been withdrawn because of toxicity. Several other agents have been described, including bucindolol, carvedilol, celiprolol, dilevalol (one of the isomers of labetalol), and medroxolol. Three mechanisms have been reported to be responsible for peripheral vasodilation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in humans. Inhibition of alpha-stimulation had been found with labetalol, medroxalol, and carvedilol and suggested with celiprolol. beta 2-Mediated vasodilation has been demonstrated by, for example, celiprolol and dilevalol; evidence of a vasodilation independent of alpha-blockade or beta 2-stimulation has been reported with celiprolol and carvedilol.