Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac repolarisation depends mainly on the cellular extrusion of positive electrical charge related to the potassium ion through different channels. There are many potassium channels which are responsible for repolarisation in different cardiac tissues. Prolongation or shortening of the repolarisation period may be both antiarrhythmic and proarrhythmic depending on the given experimental conditions. Different potassium channels may be opened or blocked by clinically prescribed drugs. Activators of the iK(ATP) channels may exert antiarrhythmic effects by inhibiting activity induced by prolonged repolarisation. Experimentally, they may exert a proarrhythmic effect by predisposing to arrhythmias during myocardial ischemia. However, these effects have not been clearly demonstrated clinically. Potassium channel blockers may have an antiarrhythmic effect by reducing the variability of repolarisation, by prolonging the atrial and ventricular refractory periods and by their antifibrillatory actions. Nevertheless, they may have proarrhythmic effects resulting in triggered activation under particular conditions of bradycardia and/or ischemia. Examples of these effects have been reported in man. The understanding of the relationship between potassium channels and arrhythmias is particularly complex because of the multiple factors regulating the duration of repolarisation and the effects of drugs on this duration. These factors include the activity of the autonomic nervous system, the heart rate, ischemia and acidosis and the differences in response to endocardial and epicardial tissues.
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PMID:[Potassium channels and arrhythmia]. 130 98

We determined whether any of the antiischemic effects of nicorandil were due to direct cardioprotective effects such as potassium channel activation or to its peripheral hemodynamic effects. Nicorandil was administered either intravenously (i.v.) or directly into the ischemic coronary artery (i.c.) and compared with i.c. cromakalim (a potassium channel activator previously shown to improve reperfusion function directly in rat hearts) or vehicle for their ability to improve postischemic contractile function as measured by ultrasonic crystals in anesthetized dogs or in isolated perfused rat hearts. In a model of 25-min global ischemia and reperfusion in isolated perfused rat hearts, nicorandil (10-100 microM) did not improve reperfusion function or decrease LDH release, although 300 microM nicorandil did protect the hearts. Cromakalim (7 microM) significantly improved reperfusion function and reduced lactate dehydrogenase (LDH) release. In the dog studies, the left anterior descending coronary artery (LAD) was occluded for 15 min and was reperfused for 3 h. Nicorandil improved reperfusion function only when administered i.v., although i.c. cromakalim was efficacious in improving function. Neither nicorandil nor cromakalim improved collateral flow, although cromakalim significantly improved preischemic and reperfusion blood flows, particularly in the subepicardial region. Although i.c. treatment with cromakalim and nicorandil did not result in significant changes in peripheral hemodynamic status, i.v. nicorandil reduced both preload and afterload. Thus, at the dose used, nicorandil does not appear to have direct myocardial protective effects and the beneficial effects of nicorandil do not appear to be related to potassium channel activation in the myocardium. Potassium channel activation by cromakalim does result in direct cardioprotective effects whereas nicorandil appears to be dependent on peripheral actions for its efficacy.
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PMID:Nicorandil improves postischemic contractile function independently of direct myocardial effects. 169 28

Potassium channel activators have been shown to protect ischemic myocardium. We studied the ability of the novel potassium channel activator, RP 52891, to also reduce ischemic damage in isolated globally ischemic rat hearts. RP 52891 (1-100 microM) was given before the hearts were subjected to 25 min of ischemia and 30 min of reperfusion. Before ischemia, RP 52891 reduced contractile function only at the highest concentration (100 microM). Significant reductions in ischemic damage were observed at 3 microM and higher concentrations. RP 52891 improved reperfusion contractile function and reduced lactate dehydrogenase release. Contracture was significantly reduced by RP 52891 during reperfusion. The protective effects of RP 52891 were completely reversed by glyburide and sodium 5-hydroxydecanoate, both blockers of ATP-sensitive potassium channels. Thus, RP 52891 has direct cardioprotective efficacy, which may be related to activation of ATP-sensitive potassium channels.
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PMID:Reduction of ischemic damage in isolated rat hearts by the potassium channel opener, RP 52891. 212 45

During acute myocardial ischemia, passage of potassium ions across the sarcolemma to the extracellular space is a well-established phenomenon. A recent hypothesis is that the ATP-dependent potassium channel plays a role in contributing to the potassium loss. As the potassium loss starts while the overall level of ATP is still relatively high, and as the channel is inhibited by rather low concentrations of ATP, the question arises as to how the channel is opened. Among the proposals are that, in addition to the total concentration of ATP, there is modulation of the regulation by its breakdown products, such as ADP and adenosine. Alternatively, or in addition, breakdown products of anaerobic glycolysis, such as lactate and protons, may also play a role. Extracellular acidosis may help to activate the channel, and internal lactate accumulation may have a similar effect. In certain circumstances there is evidence that ATP produced by glycolysis plays a significant role in the control of potassium channel activity. The concept of subsarcolemmal ATP is another explanation for the activation of the channel at relatively high ATP concentrations. Potassium channel closing drugs, such as glibenclamide, may prolong the action potential duration (shortened by ischemia) and thereby decrease the incidence of early ventricular arrhythmias. This same category of drugs may reduce early potassium loss from the ischemic tissue, thereby lessening the potentially protective effect of the external accumulation of potassium on the ischemic zone, the so-called local cardioplegic effect. Conversely, drugs of the potassium channel activating group are likely to have opposite effects on these arrhythmias and on myocardial protection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of ischemia by regulation of the ATP-sensitive potassium channel. 825 20

Potassium channel opener's (KCOs) were originally thought of as nonselective smooth muscle relaxants. However, recent investigations in animal models of both peripheral vascular disease (PVD) and asthma have revealed interesting effects of these drugs as unexpectedly low doses. Hemodynamically, KCOs are interesting in PVD since they have little effect on blood supply to normally perfused skeletal muscle, but enhance perfusion to chronically ligated ischemic tissue. In animal PVD models, SDZ PCO-400 and cromakalim have been shown to improve recovery of muscle energy stores from ischemia or to preserve performance under conditions of ischemic contracture. Beneficial effects in rat PVD models were manifest at doses below those affecting systemic blood pressure and may be attributable to a selective dilatation of collateral vessels. With regard to the airways, the apparent efficacy of KCOs as antiasthmatic drugs seems not to be attributable solely to their bronchodilator activity. Although KCOs elicit no antiinflammatory effect in animal models, studies with SDZ PCO-400 in guinea pigs sensitized to antigen or treated with immune complexes have revealed that expression of airway hyperreactivity is significantly inhibited at drug doses exhibiting only modest bronchodilator activity. At least part of this action can be attributed to inhibition at the level of neural innervation of the airways, possibly through attenuation of nonadrenergic noncholinergic (NANC) transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic potential of potassium channel openers in peripheral vascular disease and asthma. 825 25

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to the betablocker esmolol and atenolol in patients with coronary artery disease. Tedisamil induced a dose-dependent decrease in both heart rate and the index of myocardial oxygen consumption associated with an improvement in ST segment depression. Tedisamil as well as esmolol and atenolol showed almost equipotent antiischemic effects at the doses administered. Compared with gallopamil, both tedisamil and esmolol were superior in their effects on myocardial oxygen consumption and ST segment depression, whereas plasma lactate concentrations were more reduced by tedisamil and gallopamil.
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PMID:Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists. 1082 53

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K( ATP) channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.
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PMID:Dose-related shortening of ventricular tachycardia cycle length after administration of the KATP channel opener bimakalim in a 4-day-old chronic infarct anesthetized pig model. 1958 23