Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine can induce lethal cardiovascular events, including myocardial infarction and ventricular fibrillation. The mechanisms responsible for these cardiotoxic effects of cocaine remain largely to be determined. Cocaine has both sympathomimetic (inhibition of neuronal uptake of norepinephrine) and local anesthetic (Na+ channel blockade) properties. Neurotransmitters released from cardiac sympathetic nerves bind to both alpha- and beta-adrenergic receptors eliciting a cascade of intracellular responses. Stimulation of beta-adrenergic receptors activates adenylate cyclase, increasing cyclic AMP levels, whereas alpha-adrenergic receptor stimulation activates phospholipase C, increasing inositol trisphosphate. These second messengers, in turn, elicit increases in cystolic calcium. Elevations in cystolic calcium can provoke oscillatory depolarizations of the cardiac membrane, triggering sustained action potential generation and extrasystoles. Cocaine also acts as a local anesthetic by inhibiting sodium influx into cardiac cells, which impairs impulse conduction and creates an ideal substrate for reentrant circuits. Thus, the adrenergic and anesthetic properties of cocaine could act synergistically to elicit and maintain ventricular fibrillation. Adrenergic receptor activation would trigger the event whereas sodium channel blockade would create the reentrant substrate to perpetuate the malignant arrhythmias.
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PMID:Mechanisms responsible for the cardiotoxic effects of cocaine. 218 73

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.
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PMID:Ins(1,4,5)P3 during myocardial ischemia and its relationship to the development of arrhythmias. 893 Aug 8

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.
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PMID:Ins(1,4,5)P3 and arrhythmogenic responses during myocardial reperfusion: evidence for receptor specificity. 932 97