Our results are consistent with the view that Ins(1,4,5)P3 release plays a pivotal role in mediating arrhythmias during early reperfusion. Agents inhibiting Ins(1,4,5)P3 release are antiarrhythmic and may have potential use clinically.

This study demonstrates that the development of reperfusion arrhythmias under these conditions depends on the release of Ins(1,4,5)P3.

Reperfusion of ischemic rat hearts initiates the generation of inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] 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, [3H]inositol-labeled hearts in the presence of ET-1 caused an increase in [3H]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 [3H]Ins(1,4,5)P3. Gentamicin (150 microM) 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)P3 generation under reperfusion conditions.

Inhibition of Ins 1,4,5P3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.

Background-We aimed to investigate the cardiac effects of left bundle-branch block (LBBB) using myocardial contrast echocardiography (MCE) to ascertain the value of MCE for detecting coronary artery disease (CAD) and to uncover the mechanism that affects the accuracy of single-photon emission computed tomography (SPECT) in these patients. Methods and Results-Sixty-three symptomatic LBBB patients (group A), 10 left ventricular ejection fraction-matched control subjects without LBBB and no CAD (group B), and 10 normal control subjects (group C) underwent resting echocardiography. Rest and vasodilator MCE and SPECT were undertaken in LBBB patients. Septal (SW) and posterior wall (PW) thickness, thickening, quantitative myocardial blood flow (MBF), and MBF reserve were measured. SW/PW thickness and percentage thickening ratios were lower (PϽ0.01 and PϽ0.05, respectively) in group A compared with both groups B and C, but resting SW/PW MBF and MBF reserve ratios were similar in all 3 groups. MBF reserve but not MBF was reduced in groups A and B (2.2Ϯ0.7 versus 2.2Ϯ0.2; Pϭ0.98) compared with group C (3.1Ϯ0.5; PϽ0.01). SW thickness was an independent predictor (Pϭ0.006) of SPECT perfusion defects in LBBB patients without CAD. MCE (92%) had a sensitivity similar to SPECT (92%); however, the specificity of MCE (95%) was superior (PϽ0.0001) to SPECT (47%) for the detection of CAD. Conclusions-Despite asymmetrical reduction in SW thickness and function, MBF is preserved and MBF reserve is homogeneously reduced in LBBB patients with left ventricular systolic dysfunction. Because of partial volume effects, the accuracy of SPECT for detecting CAD was significantly compromised compared with MCE in this patient cohort.