Studies on the Mode of Vasodilating Action of Carvedilol

SUMMARYInvestigations were performed on isolated rat aortic strips and in pithed rats in order to elucidate the mechanism of vasorelaxation or the acute blood pressure lowering effect induced by carvedilol. In particular, the possible role of the β-receptor-stimulating activities or α-blocking properties has been investigated. β2-stimulation can be ruled out, since preincubation of isolated vessels with the β2-receptor blocker ICI 118.551 does not influence the vasorelaxing activity of carvedilol. Additionally, its optical enantiomers also induce the same vasorelaxing effect in vitro. In contrast to the standard α-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of α-receptor agonists at hypotensive doses, but inhibition of the effects of α-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential α-blocking activity of carvedilol. For example, the dose required for a specific inhibitory effect on norepinephrine responses observed in pithed rats is at least 20 times higher than that required for a decrease in blood pressure in spontaneously hypertensive rats. Furthermore, the α-blocking activity is at least 20 times lower than the β-blocking activity, whereas hypotension and β-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the α-blocking activity does not contribute substantially to the decrease in blood pressure at doses normally used. It is suggested that a not yet defined postreceptor mechanism is involved in the vasorelaxing and acute blood pressure lowering activity of carvedilol.