Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to explore alterations in the life cycle of adrenergic receptors and the Gs protein in the heart of ischemic animals. In initial experiments left anterior descending coronary artery occlusion was performed in guinea pigs. Sarcolemmal (SL) and light vesicle (LV) (presumably intracellular) fractions were prepared. Both fractions contained a substantial number of beta-adrenergic receptors and alpha 1-adrenergic receptors: the relative proportion of beta-adrenergic receptors in LV/SL was greater than for alpha 1-adrenergic receptors. Myocardial ischemia produced a rapid externalization of beta-adrenergic receptors from LV to SL. alpha 1-adrenergic receptors also increased in SL but without an apparent externalization from LV. Pretreatment of animals with either the non-selective beta-antagonist propranolol or the beta 1-selective antagonist atenolol increased the number of SL beta-receptors and blunted the ischemia-induced increase in SL beta-adrenergic receptors. Treatment with the partial agonist pindolol did not cause up-regulation of beta-receptors, and did not block ischemia-induced externalization. In the second part of this study, we have begun to examine post-receptor events in a rat model of myocardial ischemia. Ligation of the distal left main coronary artery in the rat led to an increase in SL beta-receptors. As G proteins play a pivotal role in transducing receptor occupancy to activation of effector molecules, we measured levels of Gs which stimulates adenylate cyclase activity, using an ELISA technique. In rat SL the amount of alpha s markedly decreased within 15 min of coronary occlusion. There was no transfer of Gs activity to the light vesicle fraction. These studies indicate the dynamic nature of adrenergic receptors and the alpha s protein in the sarcolemma in myocardial ischemia. Changes in adrenergic receptor number and in G protein expression may contribute to the altered pathophysiology of the ischemic heart.
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PMID:Beta-adrenergic receptors and the Gs protein in myocardial ischemia and injury. 196 4

The effect of 1 hour of myocardial ischemia on the function of the stimulatory guanine-nucleotide-binding protein Gs was examined. This study follows our recent finding that myocardial ischemia increases the density of beta-adrenoreceptors in a conscious canine model while having the opposite effect on the activity of adenylate cyclase. Coronary artery occlusion was induced in five conscious dogs and verified by measurement of blood flow using the Doppler and microsphere techniques. Alterations in the level and function of Gs were examined in sarcolemmal membranes prepared from ischemic and nonischemic regions of the left ventricle. After 1 hour of coronary artery occlusion, the functional activity of sarcolemmal Gs, as determined by reconstitution with cyc- membranes, decreased by 27 +/- 7% in the ischemic zone. Cholera toxin labeling performed in parallel with the reconstitution studies demonstrated a similar decrease of 28 +/- 7%. This was associated with decreases in basal activity and decreases in adenylate cyclase activity stimulated by GTP, GTP plus isoproterenol, sodium fluoride, and forskolin. Thus, a defect distal to the beta-adrenoreceptor occurs in the transduction of adrenergic signals to the heart as a consequence of 1 hour of ischemia.
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PMID:One hour of myocardial ischemia decreases the activity of the stimulatory guanine-nucleotide regulatory protein Gs. 255 29

It has been proposed that increases in tissue cyclic adenosine monophosphate during ischemia may be responsible for the induction of arrhythmias that occur during the early minutes of ischemia. We have tested this hypothesis using the isolated perfused rat heart with coronary artery occlusion for 30 minutes. In control hearts, after a transient small rise, cyclic adenosine monophosphate content remained close to its preischemic value (3.0 +/- 0.1 nM/g dry weight) throughout the period of occlusion. Eight percent (1/12) of the hearts fibrillated. Ninety-two percent (11/12) of the hearts exhibited ventricular tachycardia, and the mean total number of premature ventricular complexes was 528 +/- 121. Inclusion of epinephrine (1.0 microM) in the perfusion fluid elevated cyclic adenosine monophosphate prior to coronary occlusion (to 10.7 +/- 0.6 nM/g dry weight) and also throughout the ischemic period. It also increased arrhythmias such that 83% (20/24) of hearts fibrillated, 100% exhibited ventricular tachycardia, and the mean number of premature ventricular complexes increased to 747 +/- 86. Inclusion of forskolin (0.2 microM), which stimulates adenyl cyclase independently of the beta-receptor, increased cyclic adenosine monophosphate content to a greater extent than epinephrine, to 14.1 +/- 0.9 nM/g dry weight before the onset of ischemia and to 8.2 +/- 0.4 nM/g dry weight after 30 minutes of ischemia. Despite the large increase in cyclic adenosine monophosphate, there was no increase in rhythm disturbances which were less than those seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The genesis of arrhythmias during myocardial ischemia. Dissociation between changes in cyclic adenosine monophosphate and electrical instability in the rat. 299 4

It has been demonstrated that brief periods of coronary artery occlusion before a prolonged period of sustained occlusion paradoxically protect the myocardium against infarction. The mechanisms involved in this phenomenon, termed "ischaemic preconditioning" (IPC) are still not clear, although it has been established that opioid receptors are involved. The aim of this study was to probe some of the plausible mechanisms involved in the phenomenon by using an in vivo model of myocardial infarction in intact rat, a model that allows electro-cardiographic and enzymatic in addition to morphometric evaluation of the development of 24-hour myocardial infarction. Selective opioid delta-receptor agonist (DADLE) and antagonist (natrindole), and opioid kappa-receptor agonist (U-50488H) and antagonist (nor-BNI) were used. To clarify some of the mechanisms of IPC, we used selective inhibitors of the anticipated cellular systems involved. Pertussis toxin (inhibitor of adenylate cyclase G(I/o) protein), glibenclamide (inhibitor of K(ATP ) channel) and chelerythrine (inhibitor of PKC) were used. Results obtained showed that: Both opioid delta- and kappa-receptors were involved in the beneficial effect of IPC, although we were unable to differentiate between opioid receptor subtypes (delta1, delta2 and kappa1, kappa2). Opioid delta- and kappa-receptors displayed different effects in IPC. After 30 minutes of left coronary occlusion and 2-hour reperfusion, opioid delta-receptor agonist DADLE significantly decreased (p < 0.05) the infarct size (by 66%--from % IS/AAR 59.80 in the control, untreated infracted rats to % 20.40), without a significant effect (p > 0.05) on the occurrence of early arrhythmias. Opioid kappa-receptor agonist U-50488H produced mainly antiarrhythmic effects. It decreased % IS/AAR by 44%, reduced the occurrence of early arrhythmias by 77%, and decreased ventricular ectopic beats by 80%. Both opioid delta- and kappa-receptor agonists significantly reduced (p < 0.05 ) early (2-hour) mortality by 22% and 19% respectively. The above opioid delta- and kappa-receptor cardiac effects were abolished by the use of respective specific opioid delta- and kappa-receptor antagonists. The beneficial effects of opioid delta- and kappa-receptor agonists persisted for at least 24 hours post-infarction. It is most likely that both opioid delta- and kappa-receptors act via common cellular mechanisms involving: activation of ATP-sensitive (sarcolemmal) K+ channel via G(I/o) proteins (based on the results of our experiments with K(ATP) channel antagonist, glibenclamide); phosphatidylinositol pathway via activation of protein kinase C (judging from the results of our experiments with the inhibitor of PKC, chelerythrine); and the recently proposed "cross talk" between beta (1)-adrenergic and opioid receptors in cardiac myocytes (involving inhibition of adenylate cyclase by G(I/o) proteins). Exploring the possibility of this signaling pathway will be the next step in our experimental studies.
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PMID:Mechanisms of opioid delta (delta) and kappa ( kappa) receptors' cardioprotection in ischaemic preconditioning in a rat model of myocardial infarction. 1274 44