Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our goal was to better understand the mechanisms underlying muscarinic receptor actions on the ventricle in vivo. Therefore, we studied the effects of vagal stimulation on ventricular repolarization and of vagal tone on lethal arrhythmias induced by 30 minutes of left anterior descending coronary artery ligation in anesthetized cats. Experimental groups included normal control cats subjected only to coronary ligation and cats pretreated with atropine, pertussis toxin (PTX), or propranolol. All cats received bilateral cervical vagal stimulation (Vstim) at 1, 3, and 5 Hz for 1 minute at 10-minute intervals. Before coronary ligation, Vstim slowed sinus rate, prolonged the PR interval, and lowered blood pressure. Most important from the point of view of electrophysiological function was a vagally induced acceleration of ventricular repolarization in paced and unpaced hearts, which could be explained by the effects of acetylcholine (ie, shortening the subepicardial muscle action potentials). The effect on repolarization was blocked by atropine or PTX but not by propranolol. The extent of sinus slowing and acceleration of repolarization was directly related to the level of functional PTX-sensitive G protein (P < .05). Coronary occlusion was performed during atrial pacing such that the heart rate in all groups was equal. The incidence of ventricular fibrillation (VF) was 10% in the control group and 50% and 54% in atropine and PTX groups, respectively (P < .05). During atrial pacing before coronary occlusion, a vagal index was calculated as percent QTc shortening during Vstim. When the vagal index was 13% to 26%, the incidence of VF during occlusion was zero. When the vagal index was 0% to 12%, VF was 52% (P < .01). Conclusions are as follows: (1) Vstim accelerates ventricular repolarization in cats via a pathway that incorporates a PTX-sensitive G protein and involves an altered gradient between epicardium and endocardium. (2) Removal of vagal tone during ischemia favors VF, as predicted by a vagal index.
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PMID:Mechanisms for vagal modulation of ventricular repolarization and of coronary occlusion-induced lethal arrhythmias in cats. 792 18

Adenosine, an important regulator of many cardiac functions, is produced by ectosolic and cytosolic 5'-nucleotidase. The activity of these enzymes is influenced by several ischemia-sensitive metabolic factors, e.g., ATP, ADP, H+, and inorganic phosphate. However, there is no clear evidence that adenosine itself affects 5'-nucleotidase activity. This study tested whether adenosine decreases the activity of ectosolic and cytosolic 5'-nucleotidase. Cardiomyocytes were isolated from adult male Wistar rats and suspended in the modified Hepes-Tyrode buffer solution. After stabilization, isolated cardiomyocytes were incubated with and without adenosine (10(-9) - 10(-4) M). Ectosolic and cytosolic 5'-nucleotidase activity was decreased by exogenous adenosine (ectosolic 5'-nucleotidase activity, 20.6 +/- 2.3 vs. 8.6 +/- 1.6 mumol/min per 10(6) cells [P < 0.05]; cytosolic 5'-nucleotidase activity, 2.47 +/- 0.58 vs. 1.61 +/- 0.54 mumol/min per 10(6) cells [P < 0.05] at 10(-6) M adenosine) after 30 min. The decrease in ectosolic and cytosolic 5'-nucleotidase activity was inhibited by 8-phenyltheophylline and pertussis toxin, and was mimicked by N6-cyclohexyladenosine, an adenosine A1 receptor agonist. Neither CGS21680C, and A2 receptor agonist, nor cycloheximide deactivated ectosolic and cytosolic 5'-nucleotidase. Thus, we conclude that activation of adenosine A1 receptors is coupled to Gi proteins and attenuates ectosolic and cytosolic 5'-nucleotidase activity in rat cardiomyocytes.
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PMID:Evidence for deactivation of both ectosolic and cytosolic 5'-nucleotidase by adenosine A1 receptor activation in the rat cardiomyocytes. 798 2

Oxygen free radicals have been implicated in the pathogenesis of ischemic cell injuries. These free radicals are normally scavenged by antioxidant enzymes. Adenosine is normally released during ischemia and protects against ischemic injuries by interacting with adenosine receptors (ARs). The mechanism underlying its cytoprotective action is unclear. In this report, we provide evidence that activation of a unique A3AR in rat basophilic leukemia cells (RBL-2H3) leads to a 2 to 3 fold increase in activity of superoxide dismutase, catalase and glutathione peroxidase and also increases in the activity of glutathione reductase. Similar increases in enzyme activity were elicited in bovine and human endothelial cells, rat cardiac myocytes and smooth muscle cells. Increases in enzyme activity were attenuated by theophylline (an antagonist of the A3AR) and by pertussis toxin, implicating a role of A3AR/Gi protein in the activation. Importantly, activation of the A3AR decreased the degree of lipid peroxidation in these cells. These data provide strong evidence that the cytoprotective action of adenosine during ischemic cell injuries is mediated, at least in part, via a novel mechanism-activation of the cellular antioxidant enzymes.
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PMID:Adenosine acts as an endogenous activator of the cellular antioxidant defense system. 800 80

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.
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PMID:Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction. 801 Aug 1

Adenosine and acetylcholine exert negative chronotropic and anti-adrenergic effects on nonischemic myocardium presumably via receptor coupling to the same or similar inhibitory guanine nucleotide binding protein (Gi). To determine whether the cardioprotective effect of adenosine is mediated via adenosine A1 receptor coupling to Gi proteins, isolated rat hearts, perfused at constant pressure and constant heart rate, were subjected to 30 min global normothermic (37 degrees C) ischemia and 45 min reperfusion. Untreated control hearts recovered 52 +/- 2% of preischemic left ventricular developed pressure (LVDP). Hearts treated for 10 minutes prior to ischemia with adenosine (100 microM) and the adenosine A1 receptor agonist cyclohexyladenosine (CHA, 0.25 microM) recovered 67 +/- 4% and 70 +/- 4%, respectively. Hearts treated with the non-specific muscarinic cholinergic agonist carbamylcholine (1 microM) exhibited similar enhanced postischemic recovery (70 +/- 3%). Pretreatment of rats with pertussis toxin (25 micrograms/kg i.p., 48 h prior to isolation) significantly reduced the negative chronotropic effects of adenosine and CHA. Pertussis toxin pretreatment also blocked the beneficial effects of adenosine (57 +/- 4% recovery) and CHA (49 +/- 4% recovery) on postischemic function. These results support the hypothesis that the salutary effect of adenosine on the ischemic myocardium is mediated via adenosine A1 receptor coupling to a pertussis toxin sensitive G protein, presumably Gi.
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PMID:Pertussis toxin blocks adenosine A1 receptor mediated protection of the ischemic rat heart. 823 Feb 43

The purpose of these studies was to examine the effects of hypoxia on alpha 1-adrenergic receptor (alpha 1AR) mediated phosphatidylinositol (PI) turnover in cultured neonatal rat cardiac myocytes. Cells were pre-labeled with [3H]-inositol and incubated for 1 h in either normoxia or hypoxia. Phenylephrine, an alpha 1AR agonist, was added at various time intervals (0-60 min) before termination of the incubation. There was a time-dependent release of radioactivity from the lipid fraction to the aqueous fraction with alpha 1AR stimulation. alpha 1AR-mediated PI turnover was biphasic in normoxic cells and monophasic in hypoxic cells. Using ion-exchange chromatography, radioactivity in the inositol trisphosphate (IP3) peak was increased with acute phenylephrine stimulation (5 min) in the normoxic cells, while inositol phosphate (IP) and inositol bisphosphate (IP2) were increased with chronic stimulation (60 min). After 5 min of alpha 1AR stimulation, hypoxia did not alter total aqueous radioactivity when compared to normoxia, but there was a significant increase in IP2. However, there was decreased PI turnover in chronically stimulated (30-60 min) hypoxic cells when compared to normoxic cells. Hypoxia had no effect on radioactivity in the IP3 fraction with either 0, 5, or 60 min of alpha 1AR stimulation, but there was a significant increase in [1,4,5]-IP3 in hypoxic cells with 30 s alpha 1AR stimulation. With hypoxia, there was no difference in radioactivity in the phosphatidylinositols with either 0 or 5 min stimulation when compared to normoxia. However, after 60 min of alpha 1AR stimulation, hypoxia resulted in increased PI and PIP, when compared to normoxic cells, but PIP2 radioactivity was unchanged. There was no effect of pertussis toxin on either the acute or chronic phase of PI turnover, negating involvement of Gi or G(o). These data suggest that alpha 1AR stimulation in neonatal rat cardiac myocytes is biphasic, and that hypoxia produces a slower monophasic response during extended alpha 1-agonist exposure as would be found with ischemia.
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PMID:Alterations in alpha 1-adrenergic receptor-mediated phosphatidylinositol turnover in hypoxic cardiac myocytes. 826 53

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

Activation of the adenosine A1(A1) receptor, Gi protein, and ATP-sensitive K+ (KATP)-channel system has been shown to play an important role in the cardioprotective effects of ischemic preconditioning in dogs. The present study was undertaken to elucidate the possible involvement of this system in hypoxic preconditioning, which ameliorates injury induced by prolonged ischemia and subsequent reperfusion in perfused rat hearts. Ten minutes of hypoxic preconditioning resulted in an appreciable improvement of post-ischemic cardiac contractile recovery. This was associated with a significant reduction in the release of creatine kinase (CK) from reperfused hearts. Hypoxic preconditioning shortened the time to ischemic contracture onset and prevented a further rise in left ventricular end-diastolic pressure (LVEDP) during reperfusion. Neither the selective A1 receptor antagonist, 8-cyclopentyltheophylline (CPT) nor the KATP channel blocker, glibenclamide, altered the beneficial effects of hypoxic preconditioning. In vivo pretreatment with an inhibitor of Gi protein, pertussis toxin (PTX), also did not diminish the preconditioning effect. The results suggest that, although hypoxic preperfusion ameliorates post-ischemic contractile dysfunction, neither the activation of the A1 receptor, nor the opening of the KATP-channel, nor transduction through Gi protein are involved in the post-ischemic functional recovery of hypoxic preconditioning in the perfused rat heart.
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PMID:Hypoxic preconditioning in isolated rat hearts: non-involvement of activation of adenosine A1 receptor, Gi protein, and ATP-sensitive K+ channel. 865 66

Platelet-activating factor (PAF) may be a neuromodulator involved in neural cell differentiation, cerebral inflammation, and ischemia. The PAF receptor is a member of the G protein-coupled receptor superfamily. In the present study, we sought to define the specific G protein(s) that mediate PAF-stimulated phosphoinositide (PI) metabolism in an immortalized hippocampal cell line, HN33.11. PAF increased the production of 3H-labeled inositol phosphates (IPs) with EC50 values of 1.2-1.5 nM. The effect of PAF on 3H-IPs formation was completely blocked by the PAF antagonist BN 50739 at a concentration of 300 nM. Pertussis toxin pretreatment attenuated PAF-stimulated 3H-IPs production by 20-30% (p < 0.05). Consistent with a role for Gi1/2 in this response, antiserum against G alpha i1/2 blocked the response to a similar degree. Pretreatment of permeabilized cells with G alpha q/11 antiserum attenuated the response by 70% (p < 0.05), suggesting a role for Gq/11 in mediating the PAF response in this cell line. Stimulation with PAF increased [alpha-32P]-GTP binding to both G alpha q and G alpha i1/2 proteins. Moreover, specific [3H]PAF binding sites coprecipitated with G alpha q and G alpha i1/2 proteins. The results suggest that PAF-stimulated PI metabolism in HN33.11 cells is mediated by both Gq and Gi1/2 proteins.
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PMID:Guanine nucleotide regulatory proteins, Gq and Gi1/2, mediate platelet-activating factor-stimulated phosphoinositide metabolism in immortalized hippocampal cells. 885 30

The acute impairment of endothelium-dependent relaxations after ischemia and acute reperfusion injury has been studied extensively. However, less is known about the chronic status of the coronary endothelium following progressive reperfusion. Experiments were designed to characterize, after 60 min of ischemia followed by progressive reperfusion, the coronary endothelial function under acute and chronic conditions. Heartworm-free mongrel dogs were used. A percutaneous balloon catheter was inflated to occlude the left anterior descending coronary artery for 60 min, followed by progressive deflation. After 60 min or 4 weeks of reperfusion, the coronary arteries were dissected free, cut into rings, suspended in organ chambers, and exposed to endothelium-dependent and endothelium-independent agonists, both in the presence and absence of pertussis toxin. Left circumflex coronary arteries (from the same dogs) that had not been subjected to occlusion and reperfusion were studied in parallel as controls. The acute endothelium-dependent relaxations to serotonin, thrombin, and adenosine/diphosphate were impaired significantly following ischemia-reperfusion injury. Four weeks after ischemia-reperfusion injury, the endothelium-dependent relaxations to these substances were normal compared with those of controls. The endothelium-dependent relaxations to acetylcholine, bradykinin, and the calcium ionophore A23187 were unaffected either acutely or chronically. An early impairment of endothelium-dependent relaxations after ischemia-reperfusion injury occurs in response to serotonin, thrombin, and adenosine diphosphate. This early impairment is transient and is not evident 4 weeks after reperfusion. In contrast to the regenerated endothelium following balloon deendothelialization, the chronic endothelial pertussis toxin-sensitive G-protein function is not impaired selectively after ischemia-reperfusion injury, provided the reperfusion occurs gradually.
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PMID:Recovery of endothelium-dependent relaxations four weeks after ischemia and progressive reperfusion in canine coronary arteries. 890 80


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