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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the role of muscarinic acetylcholine receptors in the hypoxia/hypoglycemia (ischemia)-induced functional deficit in hippocampal neurons, we examined the effect of cholinergic drugs on ischemia-induced impairments of glucose uptake and CA1 field potentials in hippocampus slices. Muscarinic receptors were subdivided into M1 (high affinity for pirenzepine) and M2 (low affinity for pirenzepine) subtypes. The M1 receptor subtype is coupled to an increase in phosphoinositide hydrolysis and the M2 receptor subtype is associated with inhibition of adenylate cyclase. The greater potency of carbachol in stimulating phosphoinositide hydrolysis resulted in exacerbated ischemia-induced deficits. Treatment with the muscarinic receptor antagonists scopolamine and pirenzepine (M1 receptor-selective antagonist) had a strong dose-dependent protective effect against ischemia-induced deficits. Oxotremorine and McN-A-343, weak stimulators of phosphoinositide hydrolysis and strong inhibitors of adenylate cyclase, had a weak neuroprotective action against ischemia-induced deficits. These results suggest that stimulation of M1 muscarinic receptors coupled with an increase in phosphoinositide hydrolysis may play a facilitatory role in ischemia-induced deficits. Stimulation of M2 muscarinic receptors may play an inhibitory role in ischemia-induced neuronal deficits.
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PMID:Effect of muscarinic cholinergic drugs on ischemia-induced decreases in glucose uptake and CA1 field potentials in rat hippocampus slices. 145 86

Pulmonary tissue can be damaged in different ways, for instance by xenobiotics (paraquat, butylated hydroxytoluene, bleomycin), during inflammation, ischemia reperfusion, or exposure to mineral dust or to normobaric pure oxygen levels. Reactive oxygen species are partly responsible for the observed pulmonary tissue damage. Several mechanisms leading to toxicity are described in this review. The reactive oxygen species induce bronchoconstriction, elevate mucus secretion, and cause microvascular leakage, which leads to edema formation. Reactive oxygen species even induce an autonomic imbalance between muscarinic receptor-mediated contraction and the beta-adrenergic-mediated relaxation of the pulmonary smooth muscle. Vitamin E and selenium have a regulatory role in this balance between these two receptor responses. The autonomic imbalance might be involved in the development of bronchial hyperresponsiveness, occurring in lung inflammation. Finally, several antioxidants are discussed which may be beneficial as therapeutics in several lung diseases.
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PMID:Oxygen radicals in lung pathology. 170 30

The neuroprotective effects of riluzole, a novel antiglutamate, has been demonstrated in a model of ischemia induced in female Mongolian gerbils by transient bilateral carotid occlusion. Riluzole was administered at a dose of 4 mg/kg, i.p., just before, 4 hr after, and for the 14 d following the transient bilateral carotid occlusion (10 min). The functional sequelae of ischemic damage were assessed using a memory test (passive avoidance) and the extent of neuronal damage by histological examination and quantitative autoradiography of muscarinic cholinergic receptors in the hippocampus. The performance of the ischemic gerbils in the memory test was about half that of control animals. This memory deficit was completely reversed in animals treated with riluzole. This protective effect of riluzole was confirmed by histological and autoradiographic studies. The neuronal degeneration of CA1 pyramidal cells in the hippocampus observed in the ischemic group was not seen in the riluzole-treated animals, which resembled the control group. This neuronal degeneration in the CA1 area was confirmed by a quantitative measurement of muscarinic receptors: The binding was decreased by a third in the lacunosum moleculare, the stratum oriens, and the stratum radiatum. By contrast in riluzole-treated gerbils, this decrease was reversed by 50%. Finally, a clear-cut correlation was found between the deficit in the memory test and the decrease in muscarinic receptor binding in the CA1 fields. These results are compatible with the idea that glutamic acid may be involved in the neuronal degeneration of the hippocampus following ischemia, and could be foreseeable.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Riluzole, a novel antiglutamate, prevents memory loss and hippocampal neuronal damage in ischemic gerbils. 258 51

Fasted Wistar rats were given a mild level of traumatic brain injury (TBI) and then subjected to 6 min of transient forebrain ischemia 24 h posttrauma. One group was given simultaneous 1 mg/kg scopolamine and 4 mg/kg phencyclidine intraperitoneally (IP) 15 min before trauma and another group an equal volume of plasmalyte A solution. After 7 days of postinjury survival, placebo-treated rats demonstrated increased posttraumatic vulnerability to secondary ischemic CA1 neuronal death even 24 h after trauma. This finding confirmed that increased posttraumatic ischemic vulnerability persists for at least 24 h even following mild trauma. Combined muscarinic receptor and N-methyl-D-aspartate (NMDA) receptor coupled ion channel blockade given and present during the mild TBI statistically attenuated this enhanced secondary ischemic CA1 neuronal death and thus posttraumatic increased ischemic vulnerability. Placebo-treated rats had 335.3 +/- 93.6 CA1 neurons/10(6) microns 2 and drug-treated rats had 844.8 +/- 184.9 CA1 neurons/10(6) microns 2. This result suggests that muscarinic and/or NMDA receptor-mediated events confined to TBI and the early posttraumatic period are in part responsible for the phenomenon of increased posttraumatic ischemic vulnerability.
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PMID:Combined pretrauma scopolamine and phencyclidine attenuate posttraumatic increased sensitivity to delayed secondary ischemia. 285 56

The dose-response characteristics for the effect of ATP upon cardiac function and vascular tone have been investigated in the isolated perfused rat heart. Vasodilation was observed with low ATP concentrations (0.01-0.1 mM) whereas severe vasoconstriction occurred with high concentrations (1.0-10.0 mM). At all doses studied, heart rate and pressure-rate product were reduced in a dose-dependent manner, with 10 mM ATP almost complete cardiac arrest was observed. Analysis of epicardial electrograms revealed that ATP induced arrhythmias, prolonged the P-R interval and induced partial blockade of S-A nodal activity and A-V conduction. Investigating possible mechanisms for the vascular and contractile effects of ATP, it was possible to exclude the calcium chelating properties of ATP and the effects of coincident ischemia arising as a consequence of ATP-induced vasoconstriction. Pharmacological studies revealed the ATP-induced vasoconstriction to be unresponsive to a range of coronary vasodilators and also allowed exclusion of prostaglandins, catecholamines and adrenergic receptors in the mediation of ATP effects. Investigations with acetylcholine revealed remarkably similar effects upon both contractile and vascular activity but studies with atropine suggested that the muscarinic receptor was not involved. Studies with theophylline allowed a dissociation of the vascular and contractile effects of ATP and indicated a possible involvement of the adenosine receptor in the cellular response to both high and low concentrations of ATP.
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PMID:Vascular and contractile responses to extracellular ATP: studies in the isolated rat heart. 299 28

The influence of transient forebrain ischemia on adenosine A1 and muscarinic cholinergic receptors in the gerbil brain 1-27 days after recirculation was studied. The topographical distribution and the alteration in the adenosine A1 and muscarinic receptor sites were analyzed by means of quantitative receptor autoradiography using [3H]cyclohexyladenosine ([3H]CHA) and [3H]quinuclidinyl benzilate ([3H]QNB), respectively. In most regions examined, the temporal profiles of the alteration of the receptor density were in accordance with the histopathological findings. [3H]CHA binding activity decreased suddenly after neuronal damage, while [3H]QNB grain density showed a gradual decrease in the dorsolateral caudate-putamen and in the CA1 subfield of the hippocampus. In the caudate-putamen, [3H]CHA and [3H]QNB binding activity in the dorsal aspect was markedly reduced 1-27 days after ischemia. [3H]CHA binding activity in the ventromedial region of the caudate-putamen also decreased 1-3 days after ischemia, though neuronal damage was restricted to the dorsolateral aspect. Neuronal death in CA1 was preceded by the decrease in [3H]QNB binding activity in the stratum radiatum 1 and 2 days after ischemia. Marked decrease in [3H]QNB and [3H]CHA binding activity was noted in the CA1 subfield 3-27 days after recirculation. Three to 27 days after ischemia, the A1 binding activities in the CA3 subfield of the hippocampus and in the dentate gyrus were reduced despite the normal appearance of these areas throughout the reperfusion period. Muscarinic binding sites in the CA3 subfield were also reduced 27 days after ischemia. Despite minimal neuronal damage in the lateral septal nucleus and in the substantia nigra, the A1 binding activity in these regions was reduced by 70% and 50%, respectively. These results provide further evidence that the muscarinic receptors in the dorsolateral region of the caudate-putamen are localized postsynaptically on small and medium-sized neurons and that those in the CA1 subfield of the hippocampus are localized on the CA1 pyramidal cells.
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PMID:Quantitative autoradiographic analysis of muscarinic cholinergic and adenosine A1 binding sites after transient forebrain ischemia in the gerbil. 360 99

Brief episodes of ischemia paradoxically protect or "precondition" the heart and reduce infarct size caused by a subsequent, more sustained, coronary artery occlusion, perhaps by stimulation of adenosine receptors coupled to muscarinic receptors via the inhibitory G protein. However, brief ischemia is not a desirable form of therapy. Using the anesthetized canine model, we therefore sought to determine if small intravenous (i.v.) doses of the muscarinic agonist acetylcholine would provide a therapeutically feasible means to mimic preconditioning. Four groups of dogs underwent a 40-minute intervention period, followed by 1 hour of coronary occlusion and 5 hours of reperfusion: 8 received two i.v. doses of acetylcholine (0.01 mg each) at 40 minutes and 5 minutes before the sustained occlusion; 8 received equipotent doses of nitroglycerin (0.05 mg; a vasodilator that does not act via the M2 muscarinic receptor); 7 received conventional ischemic preconditioning (four 5-minute episodes of coronary occlusion, each interrupted by 5 minutes of reperfusion); and 8 controls received no intervention. Coronary blood flow and hemodynamic parameters were monitored throughout the protocol, regional myocardial blood flow was measured during the sustained occlusion by injection of radiolabeled microspheres, and infarct size was assessed by tetrazolium staining. All four groups were equally ischemic during coronary occlusion. However, infarct size was reduced significantly in both the preconditioned and acetylcholine-treated dogs when compared with controls (6% +/- 2% [p < 0.01 vs controls], 10% +/- 2% [p < 0.05 vs controls], and 19% +/- 3% of the myocardium at risk).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low-dose i.v. acetylcholine acts as a "preconditioning-mimetic" in the canine model. 757 32

Ischemic preconditioning (PC) has been shown to limit ischemia- and reperfusion-induced arrhythmias. We wished to determine whether the antiarrhythmic effect of PC would be affected by inhibition of the L-arginine nitric oxide (NO) pathway in anesthetized rats. Ischemia and reperfusion were produced by occlusion and release of a snare around the left coronary artery in all rats. The effect of PC (three cycles of 2-min coronary artery occlusion and 5-min reperfusion) on development of reperfusion-induced arrhythmias after 5-min coronary artery occlusion was studied in 12 rats. In 24 other rats, the specific NO synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA 10 mg/kg, n = 12) or the muscarinic receptor antagonist-NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME 10 mg/kg, n = 12), was administered intravenously (i.v.) before PC. In control groups, solvent (n = 15), L-NAME (10 mg/kg i.v., n = 12), L-NMMA (10 mg/kg i.v., n = 12), or L-arginine (L-Arg 100 mg/kg i.v., n = 12) was administered to rats 5 min before coronary artery occlusion without PC. PC significantly reduced the incidence of ventricular premature beats (VPBs) from 100% in the non-PC solvent group to 17%, decreased the incidence of ventricular tachycardia (VT) from 93 to 8%, and abolished the incidence of reversible and irreversible ventricular fibrillation (RVF and IVF: 87 and 47% in the non-PC solvent group, respectively). L-NAME and L-NMMA did not significantly affect the protective effect of PC on reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does the antiarrhythmic effect of ischemic preconditioning in rats involve the L-arginine nitric oxide pathway? 759 18

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

We addressed the mechanism for reduced pial vascular reactivity to muscarinic stimulation by evaluating pial vessel responses to receptor-dependent [10(-5) M acetylcholine (ACh)] and independent (10(-5) M A-23187) agonists and the endothelium-independent nitric oxide (NO) donor [10(-5) M nitroprusside (NP)]. Cerebral blood flow (CBF, microspheres) and pial arteriolar diameters (intravital microscopy) were measured in halothane-anesthetized cats. Cats (n = 13) were treated with 12 min of near-complete global cerebral ischemia, whereas control animals (n = 9) were identically instrumented but were not submitted to ischemia. Postischemic hypoperfusion was evident in most animals at 60 min of reperfusion, accompanied by attenuated pial arterial dilation to topical ACh (baseline dilation 23 +/- 4% vs. postischemia 11 +/- 3%) and A-23187 (16 +/- 4 vs. 0 +/- 3% dilation). Dilation to NP was unaffected. CBF response to intravenous administration of the muscarinic receptor agonist oxotremorine was also decreased throughout the forebrain (162 +/- 12 vs. 116 +/- 6% increase in flow) in these cats. These data suggest that endothelium-dependent vasodilation with topical muscarinic agonists is impaired during hypoperfusion, but vascular smooth muscle responsivity to NO remains intact. We conclude that the defect in the signal transduction pathway is not limited to the receptor and may involve an abnormality with NO synthesis or its destruction within endothelium.
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PMID:Effect of postischemic hypoperfusion on vasodilatory mechanisms in cats. 797 32


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