Reduction of cardiac outward currents by alpha-1 adrenoceptor stimulation: a subtype-specific effect?
In rat ventricular myocytes, the effects of alpha adrenoceptor stimulation on outward currents were studied by means of the whole cell voltage-clamp technique. Phenylephrine (30 microM) in the presence of propranolol (1 microM) to block beta adrenoceptors reduced voltage-activated transient outward current. Both components of transient outward current were affected, i.e., peak current (Ipeak) was reduced by 25.3 +/- 1.8%, the outward current at the end of a clamp step (Ilate) was reduced by 39.1 +/- 3.5% (n = 5; holding potential -40 mV, clamp step to +20 mV). In order to describe the alpha-1 adrenoceptor subtypes involved in this action, the effect of phenylephrine was also investigated after pretreatment of the cells with various antagonists. Pretreatment with prazosin (0.3 microM) abolished completely the phenylephrine effect. The alpha-1A adrenoceptor subtype-selective antagonists 5-methylurapidil and (+)-niguldipine (0.1 microM each) and the irreversible alpha-1B adrenoceptor subtype antagonist chloroethyl-clonidine (100 microM) blocked the phenylephrine effect on Ipeak, but merely attenuated the effect on Ilate, whereas pretreatment with a combination of chloroethylclonidine and (+)-niguldipine suppressed the phenylephrine-induced effect on both outward current components just like prazosin did. In conclusion, stimulation of both adrenoceptor subtypes is required for reduction of Ipeak, but stimulation of either alpha-1A or alpha-1B subtype is sufficient for reduction of Ilate. Therefore, stimulation of both alpha-1 adrenoceptor subtypes contributes to the phenylephrine-induced reduction in transient outward currents of isolated rat myocytes.
Department of Pharmacology, University of Essen, Germany.
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Wang
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Wettwer
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Gross
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Ravens
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical
D000317:Adrenergic alpha-Antagonists; D004095:Dihydropyridines; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; C057446:5-methylurapidil; D010656:Phenylephrine; C051731:chlorethylclonidine; D011433:Propranolol; D003000:Clonidine; C054074:niguldipine