α₁-Adrenergic agonists selectively suppress voltage-dependent K⁺ currents in rat ventricular myocytes

The effects of α₁-adrenergic agonists on the waveforms of action potentials and voltage-gated ionic currents were examined in isolated adult rat ventricular myocytes by the whole-cell patch-clamp recording technique. After 'puffer' applications of either of two α₁ agonists, phenylephrine and methoxamine, action-potential durations were increased. In voltage-clamped cells, phenylephrine (5-20 μM) or methoxamine (5-10 μM) reduced the amplitudes of Ca²⁺-independent voltage-activated outward K⁺ currents (I(out)); neither the kinetics nor the voltage-dependent properties of I(out) were significantly affected. The effects of phenylephrine or methoxamine on I(out) were larger and longer-lasting at higher concentrations and after prolonged or repeated exposures; in all experiments, however, I(out) recovered completely when puffer applications were discontinued. The suppression of I(out) is attributed to the activation of α₁-adrenergic receptors, as neither β- nor α₂-adrenergic agonists had measurable effects on I(out); in addition, the effect of phenylephrine was attenuated in the presence of the α antagonist phentolamine (10 μM), but not in the presence of the β antagonist propranolol (10 μM). Voltage-gated Ca²⁺ currents, in contrast, were not altered measurably by phenylephrine or methoxamine and no currents were activated directly by these agents. Suppression of I(out) was also observed during puffer applications of either of two protein kinase C activators, phorbol 12-myristate 13-acetate (10 nM-1 μM) and 1-oleoyl-2-acetylglycerol (60 μM). We conclude that the activation of α₁-adrenergic receptors in adult rat ventricular myocytes leads to action-potential prolongation as a result of the specific suppression of I(out) and that this effect may be mediated by activation of protein kinase C.