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

Single or multiple brief periods of ischemia (preconditioning) have been shown to protect the myocardium from infarction after a subsequent more prolonged ischemic insult. To test the hypothesis that preconditioning is the result of opening ATP-sensitive potassium (KATP) channels, a selective KATP channel antagonist, glibenclamide, was administered before or immediately after preconditioning in barbital-anesthetized open-chest dogs subjected to 60 minutes of left circumflex coronary artery (LCX) occlusion followed by 5 hours of reperfusion. Preconditioning was elicited by 5 minutes of LCX occlusion followed by 10 minutes of reperfusion before the 60-minute occlusion period. Glibenclamide (0.3 mg/kg i.v.) or vehicle was given 10 minutes before the initial ischemic insult in each of four groups. In a fifth group, glibenclamide was administered immediately after preconditioning. In a final series (group 6), a selective potassium channel opener, RP 52891 (10 micrograms/kg bolus and 0.1 micrograms/mg/min i.v.) was started 10 minutes before occlusion and continued throughout reperfusion. Transmural myocardial blood flow was measured at 30 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk. There were no significant differences in hemodynamics, collateral blood flow, or area at risk between groups. The ratio of infarct size to area at risk in the control group (28 +/- 6%) was not different from the group pretreated with glibenclamide in the absence of preconditioning (31 +/- 6%). Preconditioning produced a marked reduction (p less than 0.002) in infarct size (28 +/- 6% to 6 +/- 2%), whereas glibenclamide administered before or immediately after preconditioning completely abolished the protective effect (28 +/- 6% and 30 +/- 8%, respectively). RP 52891 also produced a significant (p less than 0.03) reduction (28 +/- 6% to 13 +/- 3%) in infarct size. These results suggest that myocardial preconditioning in the canine heart is mediated by activation of KATP channels and that these channels may serve an endogenous myocardial protective role.
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PMID:Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. 131 Apr 43

Possible anti- and proarrhythmic effects of glyburide, an ATP-sensitive K+ channel blocker, were assessed in an isolated tissue model of reperfusion. Transmembrane electrical activity was recorded from endo- and epicardium of isolated segments of guinea pig right ventricular free walls, or two sites on papillary muscles with microelectrodes. An electrocardiogram was recorded by two electrodes placed at opposite ends of the tissue bath. Regular stimulation was delivered to endocardium. Tissues were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode's solution. Rapid sustained or nonsustained ventricular tachycardia, bigeminy or trigeminy with characteristics of transmural re-entry occurred early in reperfusion in 50% of free walls. Triggered arrhythmias with characteristics of oscillatory afterpotentials (delayed afterdepolarizations) occurred in 20%. Arrhythmias were accompanied by prolongation of transmural conduction times and abbreviation of endocardial effective refractory periods and action potential durations. Glyburide (3 or 30 microM) significantly attenuated abbreviation of action potential durations and effective refractory periods during ischemic conditions and early reperfusion. Neither endocardial nor transmural conduction times were modified by glyburide; however, glyburide significantly decreased the incidence of transmural conduction block during ischemic conditions. Glyburide abolished reperfusion arrhythmias with characteristics of re-entry, but potentiated oscillatory afterpotentials in papillary muscles and triggered arrhythmias with characteristics of oscillatory afterpotentials in free walls. Identical effects were seen with glyburide present in ischemic solution, or in both ischemic and reperfusion solutions, but no effect was observed with glyburide present only in reperfusion. Our study demonstrates possible cellular mechanisms underlying simultaneous pro- and antiarrhythmic drug effects exerted on late premature beats and rapid arrhythmias and closely coupled premature beats.
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PMID:Differential effects of glyburide on premature beats and ventricular tachycardia in an isolated tissue model of ischemia and reperfusion. 138 28

Our aim was to elucidate the site and mechanism responsible for reactive hyperemia in coronary circulation. In in vivo beating canine hearts, microvessels of the left anterior descending coronary artery (LAD) were observed through a microscope equipped with a floating objective. Flow velocity of the LAD was measured with a suction-type Doppler probe. The LAD was occluded for 20 or 30 seconds and then released, and reactive hyperemia was observed before and after 8-phenyltheophylline (7.5 mg/kg i.v.) or glibenclamide (200 micrograms/kg into the LAD) infusion. During the occlusion, only arterial microvessels smaller than 100 microns in diameter dilated. Dilation of those vessels was partially attenuated by 8-phenyltheophylline and completely abolished with glibenclamide. In the early phase of reactive hyperemia, all arterial microvessels dilated, and the magnitude of peak dilation was greater in vessels smaller than 100 microns compared with those larger than 100 microns. Vasodilation during reactive hyperemia ceased within 60 seconds in vessels smaller than 100 microns but was sustained for more than 120 seconds in those larger than 100 microns. 8-Phenyltheophylline did not change peak dilation of arterial microvessels but reduced dilation after the peak. Glibenclamide remarkably attenuated dilation of all arterial microvessels in the whole phase of reactive hyperemia. These results indicate that all arterial microvessels are responsible for reactive hyperemia after coronary artery occlusions of 20-30 seconds, but there is greater participation of vessels smaller than 100 microns in the early phase of reactive hyperemia. Dilation of vessels larger than 100 microns assumes an important role in the later phase. ATP-sensitive K+ channels mediate dilation of arterial microvessels both in brief ischemia and reactive hyperemia.
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PMID:Microvascular sites and mechanisms responsible for reactive hyperemia in the coronary circulation of the beating canine heart. 151 63

The effect of glyburide on coronary reactive hyperemia and dilator responses to adenosine was evaluated in isolated perfused guinea pig hearts and anesthetized dogs. In isolated guinea pig hearts, changes in flow due to increasing concentrations of adenosine were measured, followed by 2 min of global ischemia to produce reactive hyperemia. This procedure was repeated after glyburide treatment. A similar study was performed in anesthetized open chest dogs. In isolated guinea pig hearts, 1 microM glyburide reduced reactive hyperemia with a peak flow reduction of 30.7% and debt repayment reduction of 78.0%, relative to vehicle-treated hearts. The adenosine dose-response curve in these hearts was shifted 20-fold to the right by 1 microM glyburide. Glyburide (3 mg/kg + 0.01 mg/kg/min) in dogs inhibited both the peak flow (from 154 +/- 26 to 105 +/- 22 ml/min) and the percentage of debt repayment (from 756 +/- 243 to 336 +/- 88%) of reactive hyperemia. Additionally, the canine intracoronary adenosine response curve was shifted rightward 100-fold by glyburide. Thus, there is a glyburide-sensitive component influencing the magnitude of both the adenosine and the reactive hyperemia response, suggesting that some of this response involves ATP-sensitive potassium channels.
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PMID:Coronary reactive hyperemia and adenosine-induced vasodilation are mediated partially by a glyburide-sensitive mechanism. 157 Mar 62

Glibenclamide, a known selective inhibitor of ATP-sensitive potassium channels, was infused into the coronary vasculature of anesthetized dogs and of isolated perfused rabbit hearts to assess the role of this channel in the maintenance of basal coronary resistance. Infusion of glibenclamide at a concentration of 55-80 microM in the dogs resulted in a twofold steady-state increase in coronary resistance with resultant tissue ischemia. Infusion of 1 microM glibenclamide in the isolated hearts resulted in a 67% increase in coronary resistance with resultant tissue ischemia. The ischemic changes were reversible upon removal of the drug. These findings indicate that the ATP-sensitive K+ channel plays a significant role in the maintenance of basal coronary resistance in vivo. Higher concentrations of glibenclamide (80-100 microM) in the in vivo dog heart consistently gave rise to an oscillating pattern of coronary flow. These oscillations were either eliminated or decreased in amplitude and frequency by the infusion of 8-phenyltheophylline, a specific competitive inhibitor of adenosine receptors. 31P-nuclear magnetic resonance spectroscopy performed at the peaks and troughs of these oscillations revealed oscillation of the phosphorylation potential at the same frequency. Thus adenosine release caused by tissue ischemia appears to play a major role in creating the oscillating pattern of coronary blood flow, that occurs during the inhibition of ATP-sensitive K+ channels by glibenclamide.
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PMID:ATP-sensitive potassium channel is essential to maintain basal coronary vascular tone in vivo. 159 Mar 61

The detailed antiischemic pharmacology of the potassium channel activator cromakalim was determined in isolated globally ischemic rat hearts and a canine model of coronary occlusion and reperfusion. Cromakalim significantly improved reperfusion function in rat hearts starting at a concentration of 1 microM; this effect peaked at 7 microM. No cardiodepressant effects were observed in nonischemic tissue with cromakalim until a concentration of 100 microM was achieved, and this effect was reversed by glyburide. The antiischemic effect of 7 microM cromakalim was also completely reversed by glyburide and the novel ATP-sensitive potassium channel blocker sodium 5-hydroxydecanoate (5-HD). Glyburide did not reverse the antiischemic effects of 1 microM diltiazem. Cromakalim not only improved reperfusion contractile function in rat hearts, but improved the functional reserve and efficiency of O2 utilization. In anesthetized dogs, intracoronary cromakalim (0.1 micrograms/kg/min given throughout ischemia and reperfusion) significantly reduced infarct size in hearts subjected to 90-min coronary occlusion and 5-h reperfusion. Along with this reduced infarct size, the frequency of ectopic beats and the proportion of animals fibrillating during reperfusion were significantly reduced by cromakalim. In isolated globally ischemic and reperfused rat hearts, cromakalim was significantly profibrillatory. Thus, cromakalim is significantly cardioprotective, and may have the propensity for profibrillatory activity, although this is not true under all conditions.
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PMID:Pharmacologic profile of cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs. 170 76

Glibenclamide, a hypoglycemic sulfonylurea, is a blocker of the adenosine triphosphatase-modulated potassium ion channels. The opening of these channels in the myocardial cells, induced by acute myocardial hypoxia, can be responsible for ischemic ventricular arrhythmias. To evaluate the antiarrhythmic effects of this drug 19 non-insulin-dependent diabetic patients were selected. They had coronary artery disease and evidence on Holter monitoring of ventricular premature complexes or nonsustained ventricular tachycardia, or both, induced by transient myocardial ischemia. In all patients, 24-hour electrocardiographic monitoring was performed to evaluate the number and duration of myocardial ischemic events, the frequency of ventricular premature complexes and nonsustained ventricular tachycardia per minute of ischemia and the percentage of ventricular premature complexes versus total ischemic beats. Selected patients were classified in 2 groups: group A (9 patients) received metformin (placebo) and group B (10 patients) was treated with glibenclamide. On the fourteenth day patients underwent 24-hour control monitoring. Then a crossover between the 2 groups was made and a new Holter monitoring sequence was performed at the end of the second phase. Results indicate that glibenclamide significantly (p less than 0.001) reduced both the frequency of ventricular premature complexes and the episodes of nonsustained ventricular tachycardia during transient myocardial ischemia, but did not change the number and duration of acute myocardial ischemic attacks and did not reduce the spontaneous ventricular arrhythmias. Thus, glibenclamide appears to have an antiarrhythmic effect in preventing ventricular arrhythmias induced by transient myocardial ischemia.
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PMID:Effectiveness of glibenclamide on myocardial ischemic ventricular arrhythmias in non-insulin-dependent diabetes mellitus. 170 21

Glibenclamide (Gli) 0.3, 1, 3 mg.kg-1 and tolbutamide (Tol) 3, 10, 30 mg.kg-1 iv 10 min before ischemia or ouabain infusion prevented ventricular fibrillation induced by ischemia in rat and arrhythmias induced by ouabain in guinea pig. Gli 10 mumol.L-1 and Tol 1 mmol.L-1 increased APD and ERP in rat ventricular muscle. Gli 0.1, 1, 10 mumol.L-1 and Tol 0.01, 0.1, 1 mmol.L-1 prevented and reversed the shortening of APD and ERP induced by hypoxia in guinea pig ventricular muscle. These effects of Gli and Tol were dose-dependent. The results confirmed that Gli and Tol were effective on arrhythmias induced by ischemia and ouabain by blocking ATP-sensitive potassium channel.
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PMID:Effects of glibenclamide and tolbutamide on ischemia- and ouabain-induced arrhythmias and membrane potentials of ventricular myocardium from rat and guinea pig. 181 92

We examined influences of a blocker (glibenclamide) and an opener (nicorandil) of the ATP-sensitive potassium (KATP) channel on extracellular K concentration [( K+]e), as well as the myocardial function and metabolites during global ischemia and reperfusion in Langendorff-perfused rat heart preparation. In control hearts, [K+]e began to rise 20 s after the onset of ischemia up to an initial peak (8.3 +/- 0.3 mM) at 2.5 +/- 0.7 min, then fell to 6.0 +/- 0.8 mM after 8.2 +/- 0.7 min, and then rose progressively to 14.6 +/- 0.8 mM at the end of 30 min of ischemia. Glibenclamide (50 microM) reduced the initial peak of [K+]e to 7.2 +/- 0.3 mM (P less than 0.01), and nicorandil (200 microM) increased it to 9.4 +/- 0.6 mM (P less than 0.01). There were no significant differences in [K+]e values among all groups at the end of ischemia. During ischemia, nicorandil decreased the time to mechanical arrest from 1.9 +/- 0.1 min to 1.5 +/- 0.1 min, whereas it was increased by glibenclamide to 2.7 +/- 0.4 min. In control hearts, the time to onset of ischemic contracture was 14.7 +/- 1.8 min. Nicorandil delayed onset of contracture and glibenclamide accelerated it. Thus we have confirmed that some part of the early increase in [K+]e during ischemia is attributable to K+ efflux through the KATP channel in our model, and opening of the KATP channel may contribute to a rapid reduction of the contractility of the ischemic myocardium that subsequently protects the myocardium against further ischemic injury.
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PMID:Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in isolated perfused rat hearts. 183 11

Nicorandil and cromakalim relaxed rat aortic rings denuded of endothelium and precontracted with a low concentration of KCl (25 mM). Glibenclamide (1 microM) strongly antagonized only the effects of cromakalim while those of nicorandil were inhibited by methylene blue, an inhibitor of the soluble form of guanylate cyclase. High concentrations of nicorandil also produced vasorelaxation in aortic preparations contracted with 55 mM KCl, whereas cromakalim did not. In pentobarbital-anesthetized rats a 20-min i.v. infusion of cromakalim (5 micrograms/kg/min) or nicorandil (100 micrograms/kg/min) similarly decreased the mean carotid artery blood pressure. These effects, as well as the antihypertensive activity of nicorandil (5.0 mg/kg p.o.) and cromakalim (0.25 mg/kg p.o.) in spontaneously hypertensive rats were markedly inhibited by glibenclamide (20 mg/kg i.v.). Finally, glibenclamide (4 mg/kg i.v.) displaced to the right the control dose-coronary vasodilatory response curve to nicorandil injected into the left circumflex coronary artery of pentobarbital-anesthetized dogs. In conclusion, these results indicate that in a rat conductive vessel (aorta) nicorandil acts exclusively like nitrates, that is, it stimulates guanylate cyclase, and in resistance vessels (in the intact rat or dog coronary vascular bed) it opens K+ channels, as does cromakalim. Thus, nicorandil can be expected to have a broader spectrum of antianginal activity than drugs with a single mechanism of action. Additionally, as mentioned in the discussion section, substantial evidence exists that K+ channel opening can also afford marked cardioprotection against ischemia.
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PMID:K+ channel opening mediates the vasorelaxant effects of nicorandil in the intact vascular system. 183 48


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