Inositol phosphate metabolism during myocardial ischemia

Inositol phosphate release in intact heart in response to norepinephrine involves primarily release of inositol(1,4)bisphosphate (Ins(1,4)P2) rather than inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) but Ins(1,4,5)P3 release predominates under conditions of post-ischemic reperfusion. In the current study, effects of myocardial ischemia on inositol phosphate responses were examined. Global myocardial ischemia in rat ventricle caused a reduction in the content of [3H]Ins(1,4)P3 (70-90%) and [3H]Ins(1,4,5)P3 (46%) and altered the pattern of norepinephrine stimulation such that increases in [3H]Ins(1,4,5)P3 were observed. Simulated ischemia in isolated right atria or isolated ventricular myocytes (P alpha 2 16-20 mmHg. pH 6.7. KCl 10 mM) produced similar changes. Reduction in O2 in the absence of other changes reduced the content of [3H]Ins (1,4)P2 (79%) in right atria whereas hypoxia and reduced pH were required to alter the [3H]Ins(1,4,5)P3 response. Progressive reduction in atrial ATP content using metabolic inhibitors caused a parallel decrease in [3H]Ins(1,4,5)P3 content (r = 0.96) without affecting [3H]Ins(1,4)P2 or the isomers of InsP1, showing that levels of Ins(1,4)P2 and Ins(1,4,5)P3 are regulated differently in the heart. These findings show that effects of ischemia on inositol phosphates in heart are complex and multifactorial, with Ins(1,4)P2 being affected under more moderately ischemic conditions than required for alterations in Ins(1,4,5)P3. These studies also demonstrate that ischemia produces similar effects on the release and metabolism of inositol phosphates in heart regardless of the ischemic model or the myocardial preparation used.