Oral administration of carvedilol and prazosin inhibits the prostaglandin F2 alpha- and noradrenaline-induced contraction of human hand veins in vivo.
Carvedilol is a beta-blocker with additional vasodilating activity. This study was performed in order to determine whether the vasodilator action of orally administered carvedilol in man is based upon an alpha-adrenoceptor antagonism exclusively or if evidence for an additional mechanism could be confirmed. The influence of carvedilol (50 mg p.o.) and prazosin (2 mg p.o.) upon the vasoconstrictor effect of noradrenaline and prostaglandin F2 alpha, infused into superficial hand veins, was established in 8 healthy male volunteers. Increasing dosages of the vasoconstrictors below their threshold of systemic activity were employed in order to obtain dose-response curves of the hand veins congested at a venous occlusion pressure of 40 mmHg. These dose-response curves were repeated 1 and 3.5 h after oral administration of either carvedilol, prazosin, or placebo. The ex vivo, in vitro alpha 1-receptor occupancy in plasma was measured before and after each vasoconstrictor dose-response curve, using an alpha 1-radioreceptor binding assay. Washout periods of 48 h were kept between study days, investigating the influence of one orally administered drug upon one of the local vasoconstrictor dose-response curves at a time. In the alpha 1-radioreceptor assay, plasma concentrations from 0.9- to 1.7-fold the equilibrium dissociation constant (Ki) of carvedilol could be evaluated 1 as well as 3.5 h after medication, corresponding with a receptor occupancy of 44%-63%. After prazosin, 9-13 times the Ki values were determined, which amounts to an alpha 1-adrenoceptor occupation of about 90%-93%.(ABSTRACT TRUNCATED AT 250 WORDS)
Beermann
C
C
Zentrum für Kardiovaskuläre Pharmakologie, ZeKaPha GmbH, Mainz-Wiesbaden.
Schloos
J
J
Belz
G G
GG
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077261:Carvedilol; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006225:Hand / Q000098:blood supply*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011224:Prazosin / Q000493:pharmacokinetics / Q000494:pharmacology*; D011412:Propanolamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D016037:Single-Blind Method; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D011942:Receptors, Adrenergic, alpha; D014665:Vasodilator Agents; D000077261:Carvedilol; D015237:Dinoprost; D009638:Norepinephrine; D011224:Prazosin