Electropharmacological study of receptor-mediated regulation of cardiac Na^+-activated K^+ channels

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The Na<@D1+@>D1-activated K<@D1+@>D1 (K<@D2Na@>D2) channel has a large unitary conductance and is activated by an increase in the Na<@D1+@>D1 concentration at the inner side of the sarcolemma. It has been postulated that the K<@D2Na@>D2 channels may be activated not only in pathological conditions such as myocardial ischemia and digitalis toxicity but also in physiological conditions. However, it has not been determined whether cardiac K<@D2Na@>D2 channels are regulated by some receptor mechanisms. In this study I examined the effects of beta-adrenoceptor and endothelin (ET) receptor stimulation on the K<@D2Na@>D2 current in guinea pig ventricular cells by using patch clamp techniques. The K<@D2Na@>D2 current was activated by intracellular loading of 50 mM Na<@D1+@>D1 and extracellular application of 10 muM ouabain. Endothelin-1 (ET-1) at a concentration of 10 nM inhibited the K<@D2Na@>D2 current by 21(]SY.+-。[)4% (n=5), which was blocked by the selective ET<@D2A@>D2 receptor antagonis … More t BQ-485 (100 nM).Endothelin-3 (ET-3,30 nM) failed to inhibit the K<@D2Na@>D2 current. Neither protein kinase C inhibitor (staurosporine, calphostin C) nor intracellular loading of inositol 1,4,5-trisphosphate (IP<@D23@>D2) affected the K<@D2Na@>D2 current inhibition by ET-1. Isoproterenol (ISO,1-1000 nM) also inhibited the K<@D2Na@>D2 current in a concentration-dependent manner. The ISO (100 nM) -induced decrease of the K<@D2Na@>D2 current was abolished by 10 muM atenolol but not by 100 nM ICI 118,551, indicating the involvement of beta<@D21@>D2-adrenoceptors. Forskolin (10 muM) also inhibited the K<@D2Na@>D2 current and the ISO-induced K<@D2Na@>D2 current inhibition was attenuated by the intracellular loading of protein kinase inhibitor peptide. Therefore, cAMP-protein kinase A pathway plays an important role in the beta<@D21@>D2-adrenoceptor-mediated inhibition of the K<@D2Na@>D2 current. Thus, both ET<@D2A@>D2 receptor an beta<@D21@>D2-adrenoceptor stimulation inhibit the cardiac K<@D2Na@>D2 current and modulate the action potential repolarization in pathological as well as physiological conditions. Less