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)

Our knowledge and understanding of the structure, mechanism of action and regulation of receptor-adenylate cyclase systems have increased dramatically in the last few years. A family of receptors (including the beta-adrenergic receptors) and guanine nucleotide regulatory proteins (G proteins) have been purified and cloned. Structure-function studies are beginning to provide insight into how the various components of the transmembrane signaling apparatus interact to promote alterations in the activity of the effector systems. Much effort has been devoted to understanding how various pathophysiologic conditions, such as ischemia or congestive heart failure, and the therapeutic methods used to treat such conditions perturb or regulate receptor systems. It has become abundantly clear that such regulation does occur but is not restricted to simple alterations in receptor number, and may well involve covalent modification (phosphorylation) of receptors or alteration in the ability of receptors to interact with G proteins. In addition, regulation of the quantity or functionality of the various G proteins and the catalytic unit of adenylate cyclase itself appear to occur. For example, recent evidence suggests that congestive heart failure in humans is associated with a decreased number of beta-adrenergic receptors as well as an increased quantity of the inhibitory G protein (Gi). These alterations may provide important insight into how to develop new therapeutic methods. Mechanisms generally responsible for transmembrane signaling, how the components are regulated by pathophysiologic conditions, and drugs used to treat disease states are discussed in detail.
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PMID:Adrenergic receptor responsiveness and congestive heart failure. 185 May 73

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 oxidative stress on beta-adrenoceptor function in the heart was determined. To this end ventricle membranes, field-stimulated rat left atria and field-stimulated rat right ventricle strips were exposed to 0.1 mM cumene hydroperoxide for 20 min. It was found that oxidative stress increased beta-adrenoceptor number and reduced c-AMP formation in the ventricle membranes. In the rat left atria and rat right ventricle strips the efficacy of beta-adrenoceptor agonists was reduced to approximately 30% of the control value, whereas maximal beta-adrenoceptor-mediated response was reduced to 50%. Using membranes from control atria and from atria exposed to oxidative stress, it was found that oxidative stress had no effect on beta-adrenoceptor density, nor on the affinity of (-)isoproterenol for the receptor. c-AMP production in membranes prepared from atria exposed to oxidative stress was reduced to approximately 30% of the c-AMP production in membranes prepared of control atria. In addition, it was found that the shape of the function that transduces the stimulus which is generated by receptor activation into an effect, is not altered by oxidative stress. It was concluded that the reduction of the efficacy of beta-adrenoceptor agonists by oxidative stress is probably caused by the reduction of c-AMP formation. Because the efficacy of forskolin and of dibutyryl c-AMP was not affected by oxidative stress, the reduced c-AMP formation is probably caused by an impaired coupling between the receptor and adenylate cyclase. The reduction of maximal beta-adrenoceptor-mediated response might be the result of cytotoxic aldehydes that are produced during oxidative stress. In ischemia, catecholamine release and subsequent beta-adrenoceptor hyperstimulation lead to cardiotoxicity. As shown in the present study, oxidative stress reduces beta-adrenoceptor function. This might represent a protective physiological feedback mechanism that protects the heart against excessive beta-adrenoceptor stimulation.
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PMID:Reduction of beta-adrenoceptor function by oxidative stress in the heart. 198 Sep 2

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (lCBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, lCBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The lCBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at lCBF less than 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between lCBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.
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PMID:Autoradiographic analysis on second-messenger systems and local cerebral blood flow in ischemic gerbil brain. 199 99

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

Diastolic heart failure is characterized by increased resistance to diastolic filling of one or both cardiac ventricles. Although some degree of diastolic failure exists in most patients presenting clinically with heart failure, a substantial subset of patients have relatively pure diastolic heart failure with normal systolic function. Diastolic heart failure can be due to structural abnormalities that increase resistance to ventricular inflow, and these structural abnormalities can be extramyocardial (e.g., constrictive pericarditis and mitral stenosis) or intramyocardial (e.g., fibrosis and amyloidosis). In addition to structural abnormalities, physiological derangement of myocardial inactivation and relaxation can contribute importantly to diastolic dysfunction in patients with heart failure. There is mounting evidence that advanced myocardial hypertrophy is associated with increased resistance to ventricular diastolic inflow due to both structural alteration (increased wall thickness and altered collagen matrix) and impaired diastolic relaxation of the hypertrophied myocardium. Physiological mechanisms for impaired relaxation in advanced hypertrophy remain controversial but can include disordered function of myocardial sarcoplasmic reticulum, subendocardial ischemia, and altered adenylate cyclase function. Diastolic dysfunction can play an important role in the genesis of flash pulmonary edema seen in patients with ischemic heart disease because myocardial ischemia is associated with a decline in relaxation rate, increased resistance to early diastolic filling, and in some cases, a striking upward shift in the left ventricular diastolic pressure-volume relation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diastolic dysfunction and congestive heart failure. 213 51

To determine the contribution of altered beta-receptor function in the vasculature to the increased peripheral vascular resistance seen in hypertension, the effects of intra-arterial infusions of isoproterenol and epinephrine on forearm blood flow were determined in 11 male normotensive subjects and 11 male hypertensive subjects during 10 and 250 mmol/day sodium diets. Increased sodium intake from 10 to 250 mmol produced contrasting effects in the hypertensive and normotensive subjects. In the hypertensive subjects, sensitivity to isoproterenol decreased when sodium intake increased (median effective dose increased from 39 [95% confidence limits, 30 to 50] to 70 [95% confidence limits, 42 to 116] ng/min, p less than 0.05). On the other hand, in the normotensive subjects increased sodium intake resulted in an increased sensitivity to isoproterenol induced vasodilation (median effective dose decreased from 52 [38 to 71] to 29 [22 to 38] ng/min, p less than 0.01). No change occurred in sensitivity to epinephrine or in the maximum vasodilatory response to ischemia during dietary changes. Changes in beta-receptors on lymphocyte membranes paralleled the changes seen in vascular sensitivity so that the proportion of receptors exhibiting high affinity for agonists, a reflection of receptor adenylate cyclase coupling, decreased in the hypertensive subjects from 38.0% +/- 3.8% when they were receiving 10 mmol/day sodium to 29.6% +/- 2.7% when they were receiving 250 mmol/day sodium (p less than 0.01). However, the proportion increased from 32.4% +/- 3.7% for normotensive subjects receiving 10 mmol/day sodium to 47.1% +/- 7.8% for normotensive subjects receiving 250 mmol/day sodium (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low sodium intake corrects abnormality in beta-receptor-mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro. 216 58

The endogenous level of epidermal cyclic AMP does not remain constant but increases rapidly and transiently after removal of the tissue; this is known as the "ischemia" effect. UVB-irradiated epidermis which shows increased beta-adrenergic response revealed an increased ischemia effect, while psoriatic involved epidermis which shows decreased beta-adrenergic response revealed a decreased ischemia effect. Because of the similar rise-and-fall pattern between the ischemia effect and the beta-adrenergic response, the mechanism of the ischemia effect was investigated, especially in terms of the beta-adrenergic relationship. The ischemic rise of epidermal cyclic AMP was well preserved after 6 h pretreatment at 4 degrees C, and, following the pretreatment, the skin markedly increased its cyclic AMP level by the 37 degrees C treatment with 1 mM isobutylmethyl xanthine. The addition of propranolol or cimetidine at the time of 37 degrees C treatment (following the 4 degrees C pretreatment) had no effect on the ischemia effect; both skin groups markedly increased their cyclic AMP levels to an extent similar to that of the control skin. However, the addition of propranolol at the time of both preincubation (at 4 degrees C) and incubation (at 37 degrees C) markedly decreased the ischemic rise of cyclic AMP. Similar treatment by cimetidine had no effect on the ischemia effect. There was no significant difference in cyclic AMP phosphodiesterase activities among skin groups by propranolol or cimetidine pretreatment. These results indicate that the so-called ischemic rise of epidermal cyclic AMP is actually the beta-adrenergic adenylate cyclase-dependent process. Our results also indicate that the magnitude of the "ischemic" rise of cyclic AMP is generally parallel to the beta-adrenergic responsiveness of epidermis.
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PMID:"Ischemic" rise of epidermal cyclic AMP is a beta-adrenergic adenylate cyclase-dependent process. 242 5

The recovery of coronary flow and cardiac work was studied in isolated guinea pig hearts (working-heart preparation) after successive bolus injections of leukotriene D4 (LTD4) at increasing doses (0.01-1,000 ng). LTD4 caused an immediate (within 1 min) reduction in coronary flow and cardiac work and an increase in myocardial NADH fluorescence. There was limited spontaneous recovery at any dose and at the end of the cumulative LTD4 study, coronary flow recovered only from 41.4 +/- (SE) 3.5 (n = 10) to 53.5 +/- 4.7% of initial values, and cardiac work recovered from 21.2 +/- 4.1 to 33.1 +/- 5.6% (P less than 0.05). Adenosine (1 X 10(-6) M) or iloprost (1 X 10(-7) M) restored coronary flow but not cardiac work after LTD4 injections, in contrast to full recovery of cardiac work observed in hearts subjected to a similar degree of ischemia induced by reducing the coronary flow by a peristaltic pump, or hypoxia caused by reducing PO2 of the perfusion fluid. Adenosine (1 X 10(-6) M) and forskolin (1 X 10(-6) M) in combination, or iloprost (1 X 10(-7) M) and isoproterenol (1 X 10(-8) M) in combination, restored both coronary flow and cardiac work to control levels. Myocardial NADH levels, which increased immediately after LTD4 injections, returned to normal after perfusion with adenosine or iloprost. The data suggest that LTD4 has a prolonged vasoconstrictive effect on the heart. Reversal of this effect by compounds that stimulate adenylate cyclase of the vascular tissue (adenosine, prostacyclin) revealed a direct suppressive effect on the myocardium independent of the vascular effect and myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inducers of adenylate cyclase reverse the effect of leukotriene D4 in isolated working guinea pig heart. 243 50

Several studies indicate that myocardial ischemia causes a redistribution of beta-adrenergic receptors from a presumably intracellular compartment to the cell surface. However, a decreased adenylate cyclase and contractile responsiveness to beta-adrenergic stimuli has also been reported. The aim of the present study was to investigate possible ischemia-induced changes in myocardial beta-adrenoceptor coupling to adenylate cyclase. Myocardial ischemia was induced by hydraulic occlusion of the LAD in mongrel dogs anesthetized with isoflurane. After 90 min of ischemia, tissue samples were removed from the ischemic and nonischemic regions for tissue catecholamine determinations and for the preparation of particulate fractions from tissue homogenates. Saturation experiments on microsomal fractions obtained from the ischemic and control areas did not reveal any significant changes in the calculated dissociation constant for (-)[125I]iodocyanopindolol binding nor in the calculated receptor density. Likewise, the relative numbers of beta 2-adrenergic receptors were comparable in both preparations (approximately 20%). On the other hand, the proportion of beta-adrenoceptors stabilized in the high-affinity state by (-)isoproterenol was significantly reduced in the ischemic region when compared with the control myocardium (17 +/- 5 vs. 41 +/- 4%). This change was accompanied by a significant decrease in the intrinsic activity of (-)isoproterenol in stimulating adenylate cyclase activity. We propose that the initial uncoupling of the beta-adrenoceptor from its effector is a physiologically important, protective mechanism which guards the ischemic myocardium against the deleterious effect of excessive sympathetic stimulation.
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PMID:Effects of ischemia on the canine myocardial beta-adrenoceptor-linked adenylate cyclase system. 244 7


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