RESUMEN
SK&F 89124 (4-[2-(N,N-di-n-propylamino)ethyl]-7-hydroxy-2(3H) indolone) can be considered as a derivative of N,N-di-n-propyldopamine (DPDA) in which the meta-hydroxyl is replaced by a cyclic amide function. SK&F 89124 is at least one order of magnitude more potent than DPDA as an agonist at peripheral inhibitory prejunctional dopamine receptors (DA2 receptors) in the isolated perfused rabbit ear artery. A potent agonist action of SK&F 89124 at the DA2 receptor can also be demonstrated by inhibition of radioactive overflow from prelabelled canine coronary artery or saphenous vein, and in the anesthetized dog as an inhibition of the tachycardia induced by cardioaccelerator nerve stimulation or the increase in hind-limb perfusion pressure induced by stimulation of the lumbar sympathetic chain. SK&F 89124 is a potent inhibitor of the binding of [3H]spiroperidol to D2 receptors in bovine pituitary homogenates. High concentrations of SK&F 89124 do not activate the adenylate cyclase D1 receptor in rat caudate homogenates, nor produce activation of alpha 2-adrenoceptors or H2-histamine receptors in the guinea pig atrium. Although some alpha 1-adrenoceptor mediated vasoconstriction is produced in the rabbit ear artery and rabbit aorta, the concentrations required are several orders of magnitude higher than those active at the DA2 receptor. From these data it is evident that this structural modification can increase both the potency and selectivity of DPDA as a DA2 receptor agonist. The potency and selectivity of SK&F 89124 make this agent a useful tool for determination of the functional role of the DA2 receptor.
Asunto(s)
Antihipertensivos/farmacología , Dopaminérgicos , Indoles/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Bovinos , Núcleo Caudado/enzimología , Perros , Oído/irrigación sanguínea , Estimulación Eléctrica , Femenino , Cobayas , Corazón/efectos de los fármacos , Miembro Posterior/irrigación sanguínea , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/inervación , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Conejos , Ratas , Ratas Endogámicas , Flujo Sanguíneo Regional/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Conducto Deferente/efectos de los fármacosRESUMEN
The pharmacologic profile of the novel beta-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the beta 1-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the beta 2-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 mumol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for beta 1-adrenoceptors of 0.8 nmol/l and beta 2-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the alpha 1-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a KB of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 mumol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of alpha 2-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KCl (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 mumol/l), consistent with the notion that carvedilol may be a calcium channel antagonist. Support for this hypothesis was obtained in KCl (70 mmol/l) depolarized rabbit aorta where carvediol (10 mumol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent beta 1-, beta 2- and alpha 1-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of the compound.