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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant arrhythmias and the spreading of the infarcted zone in acute myocardial ischemia may be influenced by the sympathetic system. It has been known for quite some time that acute ischemia leads to an increased release of endogenous catecholamines. Adaptive mechanisms at the postsynaptic level such as receptor desensitization, which are operative under normoxic conditions, are abolished in acute myocardial ischemia. On the contrary, three newly characterized, distinct mechanisms lead to a transiently increased activity of the beta-adrenergic system in the early phase of acute ischemia: 1) Functionally coupled beta-adrenergic receptors are rapidly and persistently increased at the cell surface due to the impairment of beta-agonist-promoted uncoupling and internalization. 2) Despite the reversible increase of inhibitory, muscarinic M2 receptors, the inhibitory pathway of the adenylyl cyclase systems becomes ineffective since the coupling protein, Gi, is rapidly impaired. Both the Gi-linked GTPase-activity and the binding of [gamma-35S]GTP are reduced by 25-30% without any loss of the total protein. Stimulatory effects prevail at the G-protein level since in the early period of ischemia the stimulatory G-protein, Gs, remains intact. 3) The adenylyl cyclase is transiently sensitized by about 30%. This increased activity is closely associated with the partially purified enzyme and may be due to a rapidly reversible covalent modification. Prolonged ischemia, in contrast, results in a general decrease of the cyclase activity notwithstanding any changes at the receptor or G-protein level. The individual mechanisms may play distinct and/or complimentary roles in the early sensitization of the adenylyl cyclase system in acute myocardial ischemia.
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PMID:Supersensitivity of the adenylyl cyclase system in acute myocardial ischemia: evaluation of three independent mechanisms. 196 6

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

Increasing therapeutic use is made of purines for the treatment of ischemic heart disease, but little is known about regulatory mechanisms involved. Therefore we perfused isolated rat hearts with 0.02 mmol/l [8-14C]hypoxanthine or inosine. Under normoxic conditions about 1% is taken up by the heart and partially used for synthesis of ATP and GTP at a rate of 0.4 and 0.1 nmol X min-1 X g dry wt-1, respectively. After relatively mild ischemia (coronary flow reduction of 70% for 20 min), no increase in myocardial purine uptake is observed, but ATP and GTP synthesis rates are doubled (P less than 0.001). D-Ribose stimulates the hypoxanthine incorporation rate in normoxic perfused rat hearts to 1.1 and 0.5 nmol X min-1 X g dry wt-1 for ATP and GTP, respectively, which is further increased during postischemic perfusion. About 80% of the [8-14C]inosine or [8-14C]hypoxanthine passes through the heart unchanged, while 15% is converted to (hypo)xanthine and uric acid. We conclude from these experiments that inosine and hypoxanthine incorporation into ATP and GTP is at least partly regulated by the availability of 5-phosphoribosyl-1-pyrophosphate.
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PMID:Enhanced ATP and GTP synthesis from hypoxanthine or inosine after myocardial ischemia. 619 29

Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.
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PMID:Derangements in myocardial purine and pyrimidine nucleotide metabolism in patients with coronary artery disease and left ventricular hypertrophy. 621 Sep 11

Sarcolemmal membranes from pig hearts express a homogenous class of binding sites for [3H]PGE1. Competition binding studies with EP receptor suptype selective ligands suggest an EP3 receptor subtype. The GTP analogue GTP gamma S reduced affinity without changing binding capacity, indicating a G protein coupled EP3 receptor. Regional myocardial ischemia (60 min) in anesthetized, open-chest pigs caused a 50% increase of the number of binding sites while GTP gamma S still decreased [3H]PGE1 binding, suggesting intact G protein coupling. Myocardial ischemia may, therefore, modify myocardial actions of prostaglandins.
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PMID:Regulation of prostaglandin receptors in myocardial ischemia. 771 98

A brief antecedent period of myocardial ischemia and reperfusion can delay cellular injury during a subsequent ischemic condition. Recent observations suggest that this protective mechanism depends on the continued activation of adenosine A1 receptors and Gi proteins. During acute myocardial ischemia, sufficient amounts of adenosine for maximal activation of adenosine A1 receptors are released, independent of a preconditioning ischemia. Hence, the protective mechanism of ischemic preconditioning may not exclusively be explained by activation of adenosine A1 receptors. As a working hypothesis, an increased responsiveness of Gi proteins toward receptor-mediated activation, leading to an increased response of Gi-regulated effectors, was tested in this study. In 47 anesthetized dogs, ischemia was induced by proximal ligation of the left anterior descending coronary artery. Animals underwent either a single period of 5 minutes of ischemia (n = 9), a single period of 15 minutes of ischemia (n = 10), 5 minutes of ischemia followed by 15 minutes of reperfusion (n = 8), 15 minutes of ischemia followed by 60 minutes of reperfusion (n = 5), or 5 minutes of ischemia followed by 15 minutes of reperfusion and a second period of 5 minutes of ischemia (n = 15). Sarcolemmal membranes were prepared from the central ischemic area and from the posterior left ventricular wall, which served as the control. During ischemia, carbochol-stimulated GTPase decreased by 38% (control, 33.5 +/- 17.7; ischemia, 24.2 +/- 15 pmol.min-1.mg protein-1; n = 9; P < .001). The decrease in carbachol-stimulated GTPase activity was associated with a 45% decrease in carbachol-mediated inhibition of adenylyl cyclase (control, 28.9 +/- 2.4% maximal inhibition; ischemia, 15.1 +/- 2.6% maximal inhibition; n = 5; P < .001). Prolongation of the ischemic period to 15 minutes did not lead to a further reduction of the Gi-mediated signal transduction. The binding properties of muscarinic receptors were not affected by ischemia. Furthermore, as demonstrated by carbachol-stimulated binding of [gamma-35S]GTP to sarcolemmal membranes, high- and low-affinity binding sites for the muscarinic antagonist carbachol, the EC50 for carbachol-stimulated GTPase activity and the substrate dependency of the high-affinity GTPase, the interaction between muscarinic receptors and inhibitory G proteins, and GTP binding to G proteins were not altered (n = 14). Immunoblotting with alpha 1- and alpha 2-specific antibodies did not indicate a loss of Gi proteins during ischemia that could explain the reduced GTPase activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Impaired function of inhibitory G proteins during acute myocardial ischemia of canine hearts and its reversal during reperfusion and a second period of ischemia. Possible implications for the protective mechanism of ischemic preconditioning. 772 3

Acute ischemic heart disease is associated with alterations in the cardiac adenylate cyclase system response, although the specificity and mechanism of these events are unknown. We studied the characteristics of inhibitory (G(i)) and stimulatory (Gs) GTP-binding regulatory proteins (G proteins) of adenylate cyclase in erythrocyte membranes of patients (n = 16) with nonacute ischemic heart disease resulting from coronary atherosclerosis. Gs was measured by reconstitution with the resolved catalytic unit of adenylate cyclase and by cholera toxin-catalyzed ADP-ribosylation of a 42-kD protein; G(i) was tested as a 41-kD substrate of pertussis toxin-catalyzed ADP-ribosylation. Gs activity was decreased by 27 +/- 2% in the cholate extract and by 25 +/- 3% in the supernatant of guanosine 5'-(gamma-thio)triphosphate-treated membranes. The amount of cholera toxin substrate was decreased by 33 +/- 3%, and the pertussis toxin substrate was increased by 27 +/- 5% compared with healthy subjects (n = 10). All changes in G-protein characteristics appear to be specific relative to other erythrocyte membrane proteins and hemoglobin. Those patients who have a decreased Gs possess approximately normal Gi, and those with increased G(i) showed no change in Gs. Patients with increased G(i) (normal Gs) exhibited more severe deterioration of their coronary arteries than did patients with decreased Gs (normal G(i)) (P < .05), but these two groups did not differ significantly in serum lipids, hormones, drug therapy, historical data, or baseline assessment (P < 0.05).
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PMID:The GTP-binding regulatory proteins, Gs and G(i), are altered in erythrocyte membranes of patients with ischemic heart disease resulting from coronary atherosclerosis. 834 99

The loss of 5'-nucleotides (especially ATP and GTP) from cardiac muscle cells is a distinguishing feature of myocardial ischemia. Isolated adult rat cardiac myocytes were used as a model system to determine whether GTP depletion could affect (1) the ability of the myocytes to synthesize cyclic GMP (cGMP), or (2) the ability of the myocytes to respond to alpha-adrenergic challenge. Myocytes were made anoxic for 30- or 60-min periods, then challenged with either 1 mM sodium nitroprusside (NaNP) for 1 min or 40 microM norepinephrine (NE) for 20 min. The cells were extracted and the extracts assayed for cyclic GMP (NaNP challenge) or phosphoinositides (NE challenge). When challenged with NaNP, anoxic myocytes made up to five-fold more cGMP than aerobic controls (1401 +/- 353 fmol cGMP/mg cell protein in anoxic cells v 121 +/- 23 fmol/mg in aerobic controls). Phosphoinositide turnover was reduced in anoxic cells v aerobic controls. Stimulation of this pathway by NE was reduced two-fold after 30 min of anoxia, and abolished after 60 min of anoxia. Similar results were obtained with 30 microM and 60 microM phenylephrine. The authors concluded that nucleotide depletion under anoxic conditions has no effect on the production of cyclic GMP, but may interfere with the linkage of alpha-adrenergic receptors to phosphatidylinositol breakdown.
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PMID:Effect of anoxia on cyclic nucleotides and inositol phosphate turnover in cardiac myocytes. 889 44

Adenosine (ADO) is an important endogenous protective metabolite of the heart which also exerts beneficial effects when exogenously supplied before or after ischemia. Previous studies established that after initial massive release of ADO, its endogenous production could be significantly reduced following myocardial ischemia. However, the mechanism and consequences of this phenomenon are not clear. We investigated whether this suppressed endogenous ADO production could be reversed by a transient supply of exogenous ADO during reperfusion. Furthermore, we studied the recovery of mechanical function, coronary flow and myocardial nucleotide levels after this intervention. Three concentrations of ADO were applied: 1 microM, which exerts maximal vasodilatation: 30 microM, optimal for adenylate resynthesis: and 1 mM which exerts a cardioplegic effect. Rat hearts perfused in the Langendorff mode were divided into five groups (n = 6-9 per group): all hearts had transient (30-s) ischemia at 20 min (TI-1) and 70 min (TI-3) of perfusion. Group 1 (control) had an additional transient (30-s) ischemia at 45 min (TI-2). Group 2 (ischemic control) had 10-min ischemia at 30 min: groups 3, 4 and 5 also had 10-min ischemia at 30 min but were reperfused for the initial 15 min with 1 microM, 30 microM or 1 mM ADO. Developed tension, coronary flow and coronary effluent purines and pyrimidines were measured throughout the 75-min experimental period. Nucleotide content was evaluated in freeze-clamped hearts at the end of the experiment. Endogenous ADO release to the coronary effluent increased immediately after TI-1 in all groups. This increase was similar after TI-1 and after TI-3 in control, while it was reduced to 30% in ischemic control group. In the 30 microM ADO group the increase in endogenous ADO release after TI-3 was restored and was similar to that after TI-1. A similar trend was observed with 1 mM ADO, while in 1 microM group recovery of endogenous ADO release after TI-3 was not observed. The highest recovery of developed tension (+ S.E.) occurred with 1 microM and 30 microM ADO (72 +/- 3% and 72 +/- 5% of pre-ischemic value, respectively) compared to 53 +/- 5% and 63 +/- 5% in ischemic control and 1 mM ADO groups, respectively (P <0.05). Coronary flow was restored 30 s after 10 min ischemia in hearts treated with 1 microM and 30 microM ADO, whereas more than 2 min were necessary in ischemic control or 1 mM ADO groups. Furthermore, hyperemic response after TI-3 was significantly enhanced in the 1 microM or 30 microM ADO groups. ATP content at the end of reperfusion was highest in the 30 microM ADO group (18.9 +/- 0.5 micromol/g dry wt.) as compared to ischemic control. 1 microM or 1 mM ADO groups (15.2 +/- O.6, 16.4 +/- 0.4, and 17.2 +/- 0.4 micromol/g dry wt. respectively). Concentrations of other nucleotide triphosphates (GTP, UTP and CTP) were similar in all hearts subjected to 10-min ischemia. In summary, depressed endogenous ADO production in the post-ischemic heart could be ameliorated by transient supply of exogenous ADO during reperfusion at 30 microM concentration. This effect was found to be related to the elevation of the adenine nucleotide pool. However, restoration of endogenous ADO production was not necessary for improvement in the recovery of mechanical function by exogenous ADO.
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PMID:Exogenous adenosine, supplied transiently during reperfusion, ameliorates depressed endogenous adenosine production in the post-ischemic rat heart. 904 48

The action of prostacyclin, prostaglandin E1 (PGE1), and their mimetics on myocardial function includes changes in contractility, electrophysiological properties, and protection from injury caused by transient myocardial ischemia. This study was undertaken to investigate the basic properties of myocardial E-type prostaglandin (EP) receptors. Ligand binding studies using an enriched preparation of sarcolemmal membranes prepared from pig hearts revealed a single class of binding sites for [3H]PGE1, with a Kd of 3.7 nmol/L and a Bmax of 92 fmol/mg protein. Competition experiments indicated highest affinity for EPs, suggesting an EP receptor. In addition, the EP receptor subtype-selective agonists sulprostone (EP1 and EP3) and M&B 28.767 (EP3) were active, suggesting the presence of an EP3 receptor subtype. PGE1 stimulated sarcolemmal GTPase and inhibited sarcolemmal adenylyl cyclase activity, indicating EP3 receptor coupling to an inhibitory G protein (Gi). Additional in vivo experiments showed that intracoronary infusion of PGE1 (1 nmol/min) decreased isoprenaline-stimulated left ventricular contractile activity without altering systemic vascular resistance. This inhibition of beta-adrenergic effects is compatible with the known myocardial anti-ischemic action of prostaglandins. Further experiments examined EP3 receptor density and G-protein coupling in sarcolemma from ischemic and reperfused ischemic myocardium. In anesthetized open-chest minipigs, occlusion of the left anterior descending coronary artery for 60 minutes increased EP3 receptor density by 50%, whereas receptor affinity was unchanged. This upregulation was prevented by pretreatment with colchicine (2 mg/kg i.v.), indicating microtubule-dependent receptor externalization. Northern hybridization showed comparable EP3 receptor mRNA expression in control and ischemic myocardium. The increase of receptor protein was reversed during 60 minutes of reperfusion. G-protein coupling proved to be intact in ischemic and reperfused ischemic myocardial tissue, as shown by preserved GTP-gamma-S-induced decrease of [3H]PGE1 binding. These data demonstrate for the first time that myocardial receptors for PGE1 belong to the EP3 subtype. The properties of this receptor include inhibition of adenylyl cyclase and upregulation during regional myocardial ischemia, suggesting an involvement in the anti-ischemic activity of E- and I-type prostaglandins.
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PMID:Expression, function, and regulation of E-type prostaglandin receptors (EP3) in the nonischemic and ischemic pig heart. 935 53


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