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.