Studies on the mode of vasodilating action of carvedilol.
Investigations 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 beta-receptor-stimulating activities or alpha-blocking properties has been investigated. beta 2-stimulation can be ruled out, since preincubation of isolated vessels with the beta 2-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 alpha-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of alpha-receptor agonists at hypotensive doses, but inhibition of the effects of alpha-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential alpha-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 alpha-blocking activity is at least 20 times lower than the beta-blocking activity, whereas hypotension and beta-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the alpha-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.
Sponer
G
G
Department of Experimental Cardiovascular Research, Boehringer Mannheim GmbH, F.R.G.
Strein
K
K
Müller-Beckmann
B
B
Bartsch
W
W
D000818:Animals; D001011:Aorta; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007741:Labetalol / Q000494:pharmacology; D009126:Muscle Relaxation; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol; D009599:Nitroprusside; D007741:Labetalol; D009638:Norepinephrine