Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels.
Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors.
Departamento de Farmacologia, Facultad de Farmacia, Universitat de Valencia, Spain.
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MD
Ivorra
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Chuliá
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C
Lugnier
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MP
D'Ocon
D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D002417:Cattle; D005071:Evoked Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*
D000996:Antitussive Agents; D001060:Aporphines; D015220:Calcium Channels; D010726:Phosphodiesterase Inhibitors; D011942:Receptors, Adrenergic, alpha; D011189:Potassium Chloride; C011686:boldine; D001058:Apomorphine; C005004:glaucine; D009638:Norepinephrine