Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased myocardial tissue cyclic AMP has been associated with both a positive inotropic and a proarrhythmic effect. We wished to determine whether two agents that increase myocardial cyclic AMP levels by different mechanisms would induce comparable changes in vulnerability of the heart to ventricular fibrillation (VF) and in the inotropic status. Using an isolated perfused rat heart model, we studied the effects of beta-adrenoceptor stimulation by isoproterenol (ISO) and direct activation of adenylate cyclase by forskolin. The ventricular fibrillation threshold (VFT) was taken as an index of the vulnerability to VF and peak left ventricular systolic pressure (LVSP) as a measure of the force of LV contraction. ISO resulted in a dose-related increase in tissue cyclic AMP with a corresponding decrease in VFT and a marked increase in LVSP. Forskolin produced a delayed but exponential increase in cyclic AMP at concentrations greater than 3 x 10(-7) M with relatively small increases in LVSP. With forskolin, the VFT decreased only at extremely high cyclic AMP levels, suggesting that the drug had increased cyclic AMP in a compartmentalized manner. The discrepant effects of ISO and forskolin on VFT could not be explained by changes in heart rate (HR). These results show that an increase in tissue cyclic AMP can have markedly different arrhythmogenic effects depending on the mechanism by which cyclic AMP is increased.
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PMID:Contrasting effects of cyclic AMP increase caused by beta-adrenergic stimulation or by adenylate cyclase activation on ventricular fibrillation threshold of isolated rat heart. 128 Jul 16

Calcitonin gene-related peptide is a 37-amino acid neuropeptide acting as a transmitter of nonadrenergic, noncholinergic nerves in the heart. Binding sites of high affinity have been reported in coronary arteries, in atria, and, of minor density, in ventricular myocardium. These sites are likely linked to G-proteins mediating modifications of ion channel opening probability and duration and to stimulation of adenylate cyclase activity and cAMP-mediated alterations of ion channel activities. In isolated and perfused guinea pig hearts, low concentrations of CGRP (1-3 nM) exerted no chronotropic effect, but increased coronary flow slightly. Atrioventricular conduction duration and effective refractory period of atrioventricular conduction were prolonged by 3 nM of CGRP. The higher concentration of 10 nM increased the sinus rate, and the effects on the atrioventricular node were counterbalanced. HV and QRS duration of the ECG remained essentially unchanged, but persistent ventricular fibrillation was inducible by burst stimulation in all CGRP-treated hearts. Results in human myometrial myocytes indicate that CGRP exerted direct G protein-mediated activation of potassium channels, leading to hyperpolarization and smooth muscle relaxation. Activation of potassium channels, most prominent in smooth muscle relaxation, is likely an additional factor in the cardiostimulatory profile of CGRP.
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PMID:Membrane actions of calcitonin gene-related peptide in cardiac and smooth muscle myocytes. 163 86

Acute severe myocardial ischemia and evolving myocardial infarction cause neural stimulation, increased levels of circulating catecholamines, and release of catecholamines from storage depots in the left ventricle, with consequent exposure of injured myocardial cells to relatively high concentrations of catecholamines during the transitional period in which myocyte injury becomes progressively more severe. beta-Adrenergic receptor numbers may be increased in the ischemic myocardium within 15-35 minutes of coronary artery occlusion and are associated with intact or enhanced coupling with the adenylate cyclase enzyme and elevated levels of cyclic adenosine monophosphate (AMP); their stimulation may mediate ventricular fibrillation. The administration of beta-adrenergic blockers before or within the first few minutes after coronary artery occlusion prevents or attenuates the development of ventricular fibrillation. beta-Receptor numbers are increased in the ischemic myocardium at 60 minutes of coronary artery occlusion but are uncoupled from the adenylate cyclase enzyme at the level of the G protein and/or catalytic unit. However, with reperfusion after 60 minutes of coronary artery occlusion, the increase in ischemic-region beta-adrenergic receptor numbers persists, and adenylate cyclase responsiveness to beta-receptor stimulation is restored. If a catecholamine is administered, increases in cyclic AMP and activated phosphorylase occur in ischemic-reperfused myocardium. These data indicate that beta-adrenergic mechanisms may play an important role in arrhythmogenesis and may contribute to myocyte injury during severe and intense myocardial ischemia and evolving myocardial infarction.
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PMID:Alterations in beta-adrenergic receptors, adenylate cyclase, and cyclic AMP concentrations during acute myocardial ischemia and reperfusion. 197 23

Sympathetic overactivity in myocardial ischemia is closely associated with the progression of myocyte injury and the incidence of malignant arrhythmias. Adrenergic stimulation of the ischemic myocardium is predominantly due to increased local noradrenaline concentrations in the heart, whereas plasma catecholamine levels are of minor relevance. During the first few minutes of ischemia, efferent sympathetic nerves are activated. Excessive accumulation of noradrenaline, however, is prevented since adenosine, formed in the ischemic myocardium, suppresses exocytotic noradrenaline release, and released noradrenaline is rapidly removed as long as catecholamine reuptake is functional. With progression of ischemia to more than 10 min, the myocardium is no longer protected against excess catecholamine accumulation in the interstitial space, since local metabolic release mechanisms become increasingly important. This release, which is independent of central sympathetic activity and from extracellular calcium, occurs in two steps: First, noradrenaline escapes from its intracellular storage vesicles and accumulates in the cytoplasm of the neuron. In a second, rate-limiting step, noradrenaline is transported across the plasma membrane into the interstitial space, using the neuronal uptake carrier in reverse of its normal transport direction. As a consequence of local metabolic catecholamine release, extracellular noradrenaline reaches 1000 times the normal plasma concentration within 20 min of ischemia. Studies using acute and chronic sympathetic denervation and antiadrenergic agents demonstrate that local metabolic, rather than centrally induced noradrenaline release is critically involved in the progression of ischemic cell damage within the occurrence of ventricular fibrillation in early ischemia. Myocardial ischemia results in a temporary supersensitivity of the myocytes to catecholamines. This is due to a twofold increase of alpha 1- and a 30% increase of beta-adrenergic receptor number at the cell surface. The sensitization of adenylate cyclase during the first 20 min of total ischemia is followed by a rapid inactivation of the enzyme. The beta-adrenergic hyperresponsiveness to catecholamines is therefore limited to the first few minutes of ischemia. The deleterious combination of extremely high noradrenaline concentrations with a temporarily enhanced responsiveness to catecholamines of the tissue is thought to accelerate the propagation of the wavefront of irreversible cell damage within the ischemic myocardium. Moreover, the inhomogenous distribution of catecholamine excess within the heart is considered to promote malignant arrhythmias by unmasking and enhancing electrophysiological disturbances in early ischemia.
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PMID:Cardiac sympathetic activity in myocardial ischemia: release and effects of noradrenaline. 209 11

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

Controversy exists about the role of an increased level of tissue cyclic adenosine 3'-5' monophosphate (cAMP) in the genesis of early ischemic ventricular arrhythmias. Evidence for an arrhythmogenic role for cAMP was proposed by Podzuweit et al. (1978) and Opie et al. (1979) who argued that ischemic ventricular fibrillation was associated with increased levels of tissue cAMP in the ischemic zone. Lubbe et al. (1978) found that infusion of dibutyryl (dBcAMP), or the beta-adrenergic stimulant epinephrine, or the phosphodiesterase inhibitor theophylline, all produced a marked fall in the ventricular fibrillation threshold and an increase in the duration of the vulnerable period of the isolated perfused rat heart. In contrast, Muller et al. (1986) recently showed that prevention of ventricular fibrillation by beta-adrenergic blockade is not directly associated with decreased levels of cAMP, while Manning et al. (1985) used forskolin to stimulate adenylate cyclase and found that the markedly elevated tissue cAMP levels in the rat heart did not promote ischemic or reperfusion arrhythmias. Some of these contradictions could be resolved if the electrophysiological mechanisms by which increased levels of cAMP might predispose to arrhythmias were better understood. It is known that intracellular injection of cAMP into cardiac myocytes can enhance delayed afterdepolarizations (DADs; Matsuda et al. 1982) and that DADs may explain certain arrhythmias such as those evoked by digitalis toxicity (Ferrier, 1977) or reperfusion (Ferrier et al. 1985).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by simulated ischemia or hypoxia of delayed afterdepolarizations provoked by cyclic AMP: significance for ischemic and reperfusion arrhythmias. 284 May 14

Defibrillation after prolonged ventricular fibrillation (VF) is frequently followed by asystole or electromechanical dissociation (EMD) which are usually fatal. We studied the effects of glucagon, a known inotropic and chronotropic agent, during 19 episodes of postcountershock asystole/EMD in nine dogs. Systolic and diastolic aortic (Ao), left ventricular, pulmonary arterial, and right atrial (RA) pressures were recorded as was the instantaneous Ao-RA difference (coronary perfusion pressure) and coronary sinus blood flow (CSF) during closed-chest CPR. VF was induced electrically; 2 min later, a 400-J transthoracic shock was given. Countershock was always followed by asystole (n = 12) or EMD (n = 7). Conventional closed-chest CPR with a mechanical device was begun 30 to 60 sec after countershock and continued for 2 to 3 min. If a perfusing rhythm did not occur, glucagon (1 mg) was given iv and CPR continued for 2 to 3 min more. Glucagon had no significant effect on intravascular pressures, the coronary perfusion gradient, or CSF when compared to CPR alone. However, in 14 or 19 postcountershock episodes unresponsive to CPR alone, glucagon restored effective spontaneous circulation, i.e., successful cardiac resuscitation, due to its effects on the intrinsic pacemaker discharge rate. Glucagon has been previously shown to stimulate myocardial adenyl cyclase via nonadrenergic mechanisms. We conclude that when postcountershock asystole/EMD occurs, glucagon has a direct and favorable effect on cardiac resuscitation outcome due to its effects on pacemaker discharge rate which is not mediated by changes in myocardial blood flow or coronary perfusion pressure.
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PMID:Postcountershock pulseless rhythms: hemodynamic effects of glucagon in a canine model. 356 24

Early experiments with the calcium antagonist verapamil showed that it could inhibit the transsarcolemmal influx of calcium ions induced by isoproterenol in ventricular myocardium without inhibiting the effect of beta stimulation to increase tissue cyclic AMP. Current views of the effects of the beta-receptor-adenylate cyclase-cyclic AMP system of the calcium channel suggest that both calcium antagonists and beta-adrenoceptor antagonists should inhibit transsarcolemmal calcium influx if calcium is the third messenger of beta-agonist catecholamines. When high concentrations of circulating catecholamines are added to normal isolated hearts, two of the effects include increased vulnerability to ventricular fibrillation and high rates of enzyme release. These effects are antagonized by beta-adrenoceptor inhibitors and by calcium antagonists, which suggests a classical second (cyclic AMP) and third (calcium) messenger effect. In the presence of coronary artery ligation, the ventricular fibrillation threshold falls and enzyme release is enhanced. Both effects are associated with an increased tissue cyclic AMP level in the ischemic zone and are susceptible to calcium antagonist procedures. Neither effect can be fully stopped by beta-adrenoceptor antagonism. Therefore the evidence from this model with coronary artery ligation favors the views that 1) cyclic AMP accumulates in ischemic tissue by a process not fully susceptible to inhibition by beta-adrenoceptor antagonists; and 2) calcium ions are associated with the development of ventricular fibrillation and enzyme release by a process susceptible to inhibition by calcium antagonist agents such as verapamil, nifedipine, and diltiazem.
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PMID:Calcium antagonists, ventricular fibrillation, and enzyme release in ischemic rat hearts. 613 39

Although the autonomic nervous system has been implicated in the formation of ventricular fibrillation, the precise mechanism by which this is mediated remains undetermined. In particular, the role of second messengers, generated by beta-adrenoceptor activation, has been postulated to mediate the pro-arrhythmic effects of the sympathetic nervous system. Thus, a 2 min occlusion of the left circumflex coronary artery was initiated during the last minute of exercise in canines with healed myocardial infarctions (produced by ligation of left anterior descending artery). Fifteen dogs were found to be susceptible to the formation of ventricular fibrillation while 17 animals were resistant. Nine resistant dogs were treated with the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX, 1 mg/kg) in combination with an infusion of 8-bromo-cAMP (100-150 micrograms/kg/min beginning 45 min prior to exercise). Heart rate and left ventricular dP/dtmax significantly increased, but failed to elicit, arrhythmias during the exercise and ischemia test. Nine resistant animals were also treated with the adenylate cyclase activator forskolin, (100 micrograms/kg), which provoked the same hemodynamic changes as the cyclic AMP infusion but also failed to induce ventricular fibrillation. Both forskolin (n = 3) and IBMX (n = 3) induced large increases in myocardial cAMP levels (control 5.2 +/- 0.5, forskolin 8.1 +/- 0.8 pmol/mg non-collagen protein; control 5.0 +/- 0.8, IBMX 6.8 +/- 0.3 pmol/mg non-collagen protein). Ten resistant animals were treated with the beta-adrenoceptor agonist isoproterenol (1-10 micrograms/kg/min), which failed to cause ventricular fibrillation despite significant increases in the hemodynamic parameters described above. Finally, experiments were repeated after 8-bromo-cAMP infusion and IBMX pretreatment in 8 susceptible animals with pharmacologic denervation (atropine+propranolol+prazosin). In spite of hemodynamic increases indicative of an increase in myocardial cyclic AMP levels, arrhythmias were not re-introduced. These data suggest that changes in cAMP may not be responsible for ventricular fibrillation in this model of sudden cardiac death.
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PMID:Effect of interventions that increase cyclic AMP levels on susceptibility to ventricular fibrillation in unanesthetized dogs. 751 86

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