VASOPRESSIN-1 RECEPTOR-MEDIATED INCREASE IN DELAYED RECTIFIER POTASSIUM CURRENT IN VENTRICULAR CELLS OF GUINEA-PIG HEARTS

The delayed rectifier potassium current (I-K) is modulated by [Ca2+](i) and by protein kinase A (PKA) and C (PKC) in heart cells. Although the signal transduction pathway from receptors to I-K channels in relation to [Ca2+](i) and PKA has been extensively analyzed, receptor mechanisms that promote PKC activation have scarcely been studied. In the present study, the effects of arginine vasopressin (AVP) on I-K were studied in single ventricular cells of guinea-pig hearts using a whole-cell voltage-clamp method. AVP 0.01-1 mu M increased I-K in a concentration-dependent manner. The changes in I-K and I-Ca were abolished by a specific V-1 receptor antagonist, OPC-21268 (1 mu M). The increase in I-K was antagonized by specific PKC inhibitors, staurosporine 1 nM or H-7 10 mu M. In isolated guinea-pig ventricular papillary muscles, AVP 0.1-3 mu M decreased the force of contraction in a concentration-dependent manner. The intracellular Ca2+ concentration could not have been affected by AVP at these concentrations because the resting tension was kept constant. The negative inotropic effect of AVP was antagonized by OPC-21268 (10 mu M) but not by a specific V-2 receptor antagonist, OPC-31260 (10 mu M). These results indicate that the effect of AVP on I-K can be mediated through V-1 receptors which couple to phosphoinositide hydrolysis and PKC activation in ventricular cells of the guinea-pig heart.