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

Article

关键词: INOSITOL PHOSPHATE RELEASE;    MYOCARDIAL-ISCHEMIA;    SARCOPLASMIC-RETICULUM;    ARRHYTHMIAS;    RECEPTOR;    INS(1,4,5)P-3;    METABOLISM;    THROMBIN;    CALCIUM;    NORADRENALINE;   

DOI  :  10.1161/01.CIR.99.6.823

来源: SCIE

【 摘 要 】

Background-Reperfusion of ischemic rat hearts in the presence of thrombin or norepinephrine but not endothelin-l causes the generation of inositol 1,4,5-trisphosphate (Ins 1,4,5P(3)) and arrhythmias. The present study investigates the effect of endothelin-l on these responses. Methods and Results-Ins 1,4,5P(3) generation was quantified by use of [H-3] labeling and high-performance liquid chromatography as well as by mass analysis. Twenty minutes of global ischemia followed by 2 minutes of reperfusion increased [H-3]Ins 1,4,5P(3) 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 1,4,5P(3) (2762+/-240 cpm/g tissue), but when added together with thrombin or norepinephrine, endothelin-1 reduced the Ins 1,4,5P(3) 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 1,4,5P(3) generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.

【 授权许可】

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