Involvement of Protein Kinase A and C in Norepinephrine- and Angiotensin II-Induced Modulation of Cardiac IKs

Abstract

Background/Aims: The slow component of the delayed rectifier K⁺ current (I_Ks) is one of the major repolarizing currents in the heart. Yet, the signaling mechanisms for norepinephrine- and angiotensin II-induced modulation of I_Ks in cardiac myocytes are far from being well understood. Methods: The whole-cell patch clamp technique was used to study the effects of norepinephrine and angiotensin II on I_Ks in guinea pig cardiac myocytes. Results: Both the α₁- and β-adrenoceptor inhibitors attenuated norepinephrine-induced enhancement of I_Ks, which was also significantly depressed by inhibitors of protein kinase A and C. Angiotensin II-induced inhibition of the I_Ks was inhibited by angiotensin type 1 receptor blocker losartan and protein kinase C inhibitor. Conclusions: Norepinephrine and angiotensin II modulated I_Ks with opposite effects and distinct mechanisms. The activation of protein kinase A was the major component of the norepinephrine-induced activation of I_Ks while the activation of protein kinase C was responsible for the angiotensin II-induced inhibition of I_Ks. There was crosstalk between the α₁- and β-adrenoceptor that also contributed to the norepinephrine-induced enhancement of I_Ks. This current study provides new insight into the cellular signaling mechanisms of norepinephrine and angiotensin II, the two important modulators of cardiovascular function.