Effects of indoramin in rat vas deferens and aorta: concomitant alpha1-adrenoceptor and neuronal uptake blockade.
1. The actions of the alpha1-adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could result in self-cancelling actions. 2. Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA2 values of 7.38+/-0.05 (slope=0.98+/-0.03) and 6.78+/-0.14 (slope=1.08+/-0.06), respectively. 3. When the experiments were repeated in the presence of cocaine (6 microM) the potency (pA2) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72+/-0.07 (slope=1.10+/-0.05) while its potency remained unchanged in the aorta (pA2=6.69+/-0.12; slope=1.04+/-0.05). 4. In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79+/-0.07; slope=1.09+/-0.06). 5. It is suggested that indoramin blocks alpha1-adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not different from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA2 values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pKB values.
Pupo
A S
AS
Department of Pharmacology, Instituto de Biociências, UNESP, CEP 18600-000, Botucatu, Brazil.
Cavenaghi
D L
DL
Campos
M
M
Lucena Morais
P
P
Jurkiewicz
N H
NH
Jurkiewicz
A
A
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D007217:Indoramin / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014649:Vas Deferens / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D014662:Vasoconstrictor Agents; D007217:Indoramin; D003042:Cocaine; D009638:Norepinephrine