RESUMO
1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.
Assuntos
Benzazepinas/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão Renovascular/tratamento farmacológico , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Benzazepinas/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Fisiológicos Cardiovasculares , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Prazosina/farmacologia , Ioimbina/farmacologiaRESUMO
Full alpha 1-adrenoceptor agonists, such as (-)-norepinephrine, produce vasoconstriction in the rat aorta primarily through the mobilization of intracellular stores of calcium, whereas partial alpha 1-adrenoceptor agonists, such as (-)-dobutamine, produce vasoconstriction primarily through the translocation of extracellular calcium. The different pools of calcium utilized by full and partial alpha 1-adrenoceptor agonists have been proposed to result from the activation of different alpha 1-adrenoceptor subtypes. The irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine, selectively eliminates only that component of an alpha 1-adrenoceptor-mediated response in the rat aorta that is dependent upon the mobilization of intracellular stores of calcium. In order to determine whether in the rat aorta there exist two distinct alpha 1-adrenoceptor subtypes linked separately to the mobilization of intracellular and extracellular calcium, we utilized the full and partial alpha 1-adrenoceptor agonists, (-)-norepinephrine and (-)-dobutamine, respectively, and the irreversible antagonist, phenoxy-benzamine, as pharmacologic tools in a classical receptor-protection study to probe these alpha 1-adrenoceptor-mediated vasoconstrictor process(es). Our logic was that if the intracellular and extracellular pools of calcium were coupled to different alpha 1-adrenoceptor subtypes, then only (-)-norepinephrine, and not (-)-dobutamine, would protect against alpha 1-adrenoceptor alkylation by phenoxybenzamine, since phenoxybenzamine only eliminates the process that depends on intracellular calcium. Alternatively, if both (-)-norepinephrine and (-)-dobutamine produce a similar degree of alpha 1-adrenoceptor protection against phenoxybenzamine, our results would suggest that a single alpha 1-adrenoceptor subtype exists which activates both the translocation of extracellular calcium and the mobilization of intracellular calcium. Phenoxybenzamine (30 nM) abolished contractions of the rat aorta produced by (-)-norepinephrine, as expected. Pretreatment of the tissues with either (-)-norepinephrine or (-)-dobutamine, at concentrations that produced equivalent degrees of alpha 1-adrenoceptor occupancy, resulted in equal protection against alkylation of alpha 1-adrenoceptors by phenoxybenzamine, arguing against the existence of two distinct alpha 1-adrenoceptor subtypes in the rat aorta. These results are consistent with our previous hypothesis that two different signal-transduction processes may be activated in the rat aorta by a single alpha 1-adrenoceptor population, with the intrinsic efficacy of the agonist determining which signal-transduction process is activated.
Assuntos
Músculo Liso Vascular/fisiologia , Fenoxibenzamina/farmacologia , Receptores Adrenérgicos alfa/fisiologia , Transdução de Sinais/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Alquilação , Animais , Aorta Torácica , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Endotélio Vascular/fisiologia , Masculino , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
In the rat vasculature, a single alpha 1-adrenoceptor may be coupled to two distinct G proteins, one of which regulates phospholipase C activity and is insensitive to pertussis toxin, and another which regulates calcium channel function and is highly sensitive to inhibition by pertussis toxin. alpha 1-Adrenoceptor agonists may in theory activate both pathways, but the efficiency of alpha 1-adrenoceptor coupling to the pertussis-toxin-insensitive pathway is low relative to the other pathway that couples the alpha 1-adrenoceptor to calcium channels. As such, only full agonists with high intrinsic efficacy can activate both pathways, whereas partial agonists, by virtue of their lower intrinsic efficacies, are less able to activate the pertussis-toxin-insensitive pathway, thereby rendering partial alpha 1-adrenoceptor agonists more sensitive than full alpha 1-adrenoceptor agonists to inhibition by calcium channel blockers and pertussis toxin.
Assuntos
Vasos Sanguíneos/fisiologia , Receptores Adrenérgicos alfa/fisiologia , Transdução de Sinais/fisiologia , Animais , Cálcio/metabolismo , Proteínas de Ligação ao GTP/fisiologia , Músculo Liso Vascular/fisiologiaRESUMO
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.