Electropharmacological analysis of the regulation of the cardiac K^+ channels by inositol trisphosphate.

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The muscarinic acetyicholine receptor-operated K^+ current (IK.ACh) plays an important role in the regulation of sinus node automaticity and atrial action potential repolarization. We examined purinergic P2-, endothelin ET-, bradykinin B_2-, histamine H_1-receptor-mediated the regulation ofIK.ACh in isolated guinea-pig atrial cells by use of the patch-clamp technique. 1) Nakaya, co-investigator, has reported that adenosin-5'-triphosphate (ATP) produced biphasic changes of IK.ACh, a transient increase followed by a sustained decrease, through P_2purinoceptor activation (Hara & Nakaya, Eur J Pharmacol, 324 : 295-303, 1997). 2) Nakaya has also reported that the inhibitory effect of ET-3 but not ET-l on the preactivated IK.ACh was almost abolished by intracellular loading of inositol 1,4,5-trisphosphate (IP_3), indicating the involvement of IP_3 (Yamaguchi et al, Am J Physiol 273 : H1745-H1753, 1997). 3) We have reported that bradykinin markedly inhibited IK.ACh through B_2 receptor activation and the inhibitory effect of bradykinin was attenuated by calphostin C, a protein kinase C (PKC) inhibitor, or genistein, a tyrosine kinase (TK) inhibitor, indicating that B_2-receptor-mediated activation ofTK or PKC may be involved in the IK.ACh inhibition (Sakamoto et al, Br J Pharmacol 125 : 283-292, 1998). 4) Histamine (THIS) produced biphasic changes of IK.ACh through Hi receptors. Although the inhibitory effect of HIS on IK.ACh was not affected by PKC or TK inhibitor, intracellular loading of phosphatidylinositol 4,5-bisphosphate (PIP_2) significantly attenuated the inhibitory effect of HIS on IK.ACh. These results suggest that PIP2 hydrolysis may be involved in the H_1-receptor-mediated inhibition of IK.ACh, and that there are some differences in the intracellular signal transduction system involved in the IK.ACh regulation among these receptors.