Inhibition of inositol(1,4,5)trisphosphate generation by endothelin-1 during postischemic reperfusion: A novel antiarrhythmic mechanism

Abstract

Background - Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-1 causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P3) and arrhythmias. The present study investigates the effect of endothelin-1 on these responses. Methods and Results - Ins 1,4,5P3 generation was quantified by use of [3H] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [3H]Ins 1,4,5P3 from 2828 ± 265 to 5033 ± 650 cpm/g tissue in the presence of thrombin 2.5 IU/mL and to 4561 ± 286 cpm/g tissue in response to release of norepinephrine (n = 4, P < 0.01) in both cases. Reperfusion in the presence of endothelin-1 alone caused no change in Ins 1,4,5P3 (2762 ± 240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P3 responses to 2313 ± 197 and 1764 ± 168 cpm/g tissue, respectively (n = 4, P < 0.01 in both cases). Similar inhibitory interactions between endothelin-1 10 nmol/L and thrombin 2.5 IU/mL were observed under normoxic conditions in nonperfused ventricle, eliminating the possibility that excessive vasoconstriction was responsible. In parallel studies, endothelin-1 suppressed the development of reperfusion arrhythmias initiated by either thrombin (ventricular fibrillation, 75% to 39%, n = 16 to 18) or norepinephrine (83% to 8%, n = 12 to 22) (P < 0.01 in both cases). Conclusions - Inhibition of Ins 1,4,5P3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.