Ins(1,4,5)P3 and arrhythmogenic responses during myocardial reperfusion : evidence for receptor specificity

Reperfusion of ischemic rat hearts initiates the generation of inositol(1,4,5)trisphosphate [Ins(1,4,5)P 3 ] and arrhythmias, provided that either norepinephrine or thrombin is present. In the current study, effects on endothelin-1 (ET-1) responses were investigated. Reperfusion of catecholamine-depleted, [ 3 H]inositol-labeled hearts in the presence of ET-1 caused an increase in [ 3 H]inositol phosphates (7,073 ± 1,004 to 17,300 ± 206 counts.min -1 . g tissue -1 , means ± SE, n = 4, P < 0.01), which was quantitatively greater than the release observed under normoxic conditions, but there was no increase in [ 3 H]Ins(1,4,5)P3. Gentamicin (150 μM) inhibited inositol phosphate responses in the presence of either norepinephrine or thrombin but did not inhibit the response to ET-1, providing additional evidence that the inositol phosphate response to ET-1 does not involve formation of Ins(1,4,5)P3, even under reperfusion conditions. In contrast to norepinephrine and thrombin, ET-1 did not initiate reperfusion arrhythmias (4.4% ventricular fibrillation compared with 0% ventricular fibrillation in catecholamine-depleted controls). The data provide strong evidence that the effect of ischemia-reperfusion on inositol phosphate responses is specific for particular receptor types and eliminates G proteins, phospholipase C enzymes, and substrate availability as the primary factors responsible for Ins(1,4,5)P 3 generation under reperfusion conditions.