title: Ins(1,4,5)P3 during myocardial ischemia and its relationship to the development of arrhythmias.
abstract: Reperfusion of globally ischemic rat hearts in vitro causes release of inositol(1,4,5) trisphosphate (Ins(1,4,5)P3) which is associated with the development of reperfusion arrhythmias. Both of these responses require the presence of a receptor agonist, either norepinephrine or thrombin, and both responses are inhibited by the aminoglycoside, gentamicin and the polyamine, spermine. In the current study, the role of Ins(1,4,5)P3 in the development of arrhythmias under ischemic conditions was addressed. Arrhythmias [ventricular premature beats, ventricular tachycardia and ventricular fibrillation (VF)] occurring over 25 min subsequent to coronary artery ligation were shown to be independent of endogenous norepinephrine or adrenergic receptor stimulation but were effectively inhibited by gentamicin (0.15-1.5 mM, 95% VF in controls compared with 0% VF, at 1.5 mM, P < 0.01) and spermine (5 mM, 40% VF, P < 0.01). Depletion of Ca2+ stores, including Ins(1,4,5)P3-sensitive Ca2+ stores, with thapsigargin (300 nM) reduced the incidence of ischemic arrhythmias (40% VF, P < 0.01). [3H]-Inositol-labeled right atria incubated under conditions of simulated ischemia retained the ability to respond to norepinephrine by releasing inositol phosphates. Under ischemic conditions, gentamicin (1.5 mM) caused a reduction in [3H]Ins(1,4,5)P3 without any effect on the other inositol phosphates. Similar effects of gentamicin were observed under ischemic conditions in the absence of norepinephrine (95 +/- 8 cpm/mg, mean +/- S.E.M., n = 4, v 29 +/- 4, P < 0.0] for 1.5 mM gentamicin). Agonist independent release of [3H]Ins(1,4,5)P3 under ischemic conditions required extracellular Ca2+ suggesting the operation of a Ca(2+)-activated phospholipase C. In agreement with this, release of [3H]Ins(1,4,5)P3 could be initiated by Ca2+ overload under normoxic conditions and this was inhibited by gentamicin. These findings show that Ca2+ overload can enhance release of Ins(1,4,5)P3 under ischemic conditions and provide evidence that this release is involved in the genesis of arrhythmias under these conditions.
authors.affiliation: Cellular Biochemistry Laboratory, Baker Medical Research Institute, Prahran, Melbourne, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Woodcock
authors.forename: K A
authors.initials: KA
authors.lastname: Lambert
authors.forename: X J
authors.initials: XJ
authors.lastname: Du
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D005839:Gentamicins / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007295:Inositol Phosphates / Q000096:biosynthesis; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000502:physiology
chemical_list: D005839:Gentamicins; D007295:Inositol Phosphates; D007476:Ionophores; D011941:Receptors, Adrenergic; D000001:Calcimycin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium; D009638:Norepinephrine