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)

We have previously reported that cromakalim and U-89232 reduce infarct size in a rabbit model of myocardial ischemia. Because U-89232 appeared to lack activity in the vasculature, we tested its reversibility with glibenclamide. Twenty-eight ketamine-xylazine anesthetized open-chest, New Zealand White rabbits were instrumented for regional coronary occlusion and reperfusion. Study animals received either cromakalim, U-89232 or vehicle. In some animals, glibenclamide was administered. All animals were then subjected to ischemia (30 min) and reperfusion (120 min), and necrosis was determined using tetrazolium. With comparable hemodynamics and myocardium at risk, infarct size in control animals was 35.5 +/- 4.6% of risk region, and was not different from glibenclamide-treated animals (37.7 +/- 5.8%). Cromakalim alone has been shown to be protective, however when combined with glibenclamide necrosis amounted to 35.1 +/- 3.8% of the risk region (p = NS vs. control). In contrast, U-89232 was protective in the presence of glibenclamide (17.2 +/- 4.9% of the risk region). We conclude that U-89232 produces myoprotection independent of K-ATP channel inhibition, indicating that this compound possesses novel anti-ischemic characteristics.
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PMID:Cardioprotection with U-89232 is not reversible with glibenclamide: evidence of a novel anti-ischemic agent derived from cromakalim. 797 26

Recently, a new class of drugs has been developed with unique properties with regard to cardiovascular pharmacology: K(+)-channel openers. The increased K+ efflux from smooth muscle cells induced by these drugs is accompanied by a reduced intracellular availability of free Ca++, which in turn induces vascular relaxation. This property is currently being exploited to achieve peripheral and coronary artery dilatation in patients with ischemic heart disease. Cromakalim, pinacidil, and nicorandil, are the most extensively investigated agents in this class. Nicorandil, in addition to its K(+)-channel opener property, also shows a nitrate-like activity on guanylate cyclase of vascular smooth muscle cells. Clinical trials demonstrate that chronic administration of nicorandil can significantly increase exercise tolerance in patients with coronary artery disease. In experimental studies, this drug has also shown protective effects against myocardial injury induced by ischemia and reperfusion, by mechanisms partly independent of its vasodilating properties. These results suggest that K(+)-channel openers may have a relevant place in the pharmacological treatment of patients with ischemic heart disease.
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PMID:[Anti-angina activity of potassium-channel activators]. 802 48

The effects of the potassium channel openers (KCO), cromakalim or pinacidil, were evaluated in an anesthetized porcine model of pacing- and ischemia-induced ventricular fibrillation (VF). Hearts were paced at 180 bpm and the left anterior descending coronary artery was occluded until VF was induced. Reproducible times to VF (in seconds) were obtained allowing at least 20 min recovery following defibrillation. Cromakalim (0.3 mg/kg) or pinacidil (3 mg/kg) produced equivalent drops in mean arterial blood pressure. At these doses, cromakalim reduced monophasic action potential duration measured at 90% repolarization (APD90). Although time to VF in the cromakalim group was significantly greater than the vehicle treated group, it was not significantly different from its predrug value. In contrast, pinacidil reduced APD90, and significantly increased time to VF from 134 +/- 5 to 322 +/- 62 s (p < 0.05). Neither cromakalim nor pinacidil affected whole-cell calcium currents recorded in guinea pig myocytes. During ischemia, cromakalim or pinacidil further reduced APD90; however, pinacidil had a two-fold greater effect than did cromakalim. The Class III antiarrhythmic agent, dofetilide, prolonged APD90, but did not increase time to VF. In conclusion, the increased time to VF observed with pinacidil coincides with its ability to shorten APD, and is consistent with activation of ATP-sensitive K+ channels (K+ ATP). It is suggested that indirect reduction of calcium influx through K+ ATP activation and APD shortening is sufficient to increase time to VF in this model. However, the inability of dofetilide to be effective suggests that this model would not be useful to test for Class III antiarrhythmic agents.
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PMID:Effects of cromakalim or pinacidil on pacing- and ischemia-induced ventricular fibrillation in the anesthetized pig. 807 40

Recent published studies indicate that the cyclooxygenase inhibitor meclofenamate can abolish preconditioning. Unpublished preliminary data from this laboratory suggest that meclofenamate may be blocking cardiac ATP-sensitive potassium channels (KATP channels), which may also mediate preconditioning. The purpose of the present study was to determine whether meclofenamate is a cardiac KATP channel blocker and it can abolish the anti-ischemic activity of the KATP channel opener cromakalim. This concept was tested initially in an isolated rat heart model of 25 min of ischemia and 30 min of reperfusion. Meclofenamate, in a concentration (5 microM) that did not cause proischemic effects alone, abolished the protective effect of cromakalim, as measured by recovery of contractile function, lactate dehydrogenase release and contracture formation. The preischemic coronary dilating activity of cromakalim was not attenuated by meclofenamate. The cyclooxygenase inhibitors indomethacin and SQ 29,109 had no effect on the cardioprotection afforded by cromakalim. Concentration-response curves for the ability of cromakalim to increase time to contracture during ischemia in rat hearts were generated alone or in the presence of 5 or 10 microM meclofenamate. Cromakalim increased the time to contracture with an EC25 of approximately 3 microM. Meclofenamate appeared to block this effect in a manner that was not surmountable by 100 microM cromakalim. Studies in guinea pig hearts showed that meclofenamate had no effect on action potential duration or effective refractory period when given alone. Meclofenamate attenuated the action potential duration shortening effects of cromakalim in this model. Thus, meclofenamate blocked the cardioprotective effects of cromakalim and this effect was not related to cyclooxygenase inhibition. Meclofenamate appears to be a cardiac KATP channel blocker.
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PMID:The cardioprotective and electrophysiological effects of cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism. 818 22

Cromakalim is a member of the new antihypertensive drug family possessing an action that involves an increased K efflux in vascular and cardiac muscle. We studied the contribution of opening of ATP-sensitive K channel to the development of reperfusion-induced arrhythmias and myocardial ion shifts, particularly that of Na, K, Ca and Mg in isolated rat hearts. After 30 min of global ischemia, cromakalim (1 to 30 microM) failed to reduce reperfusion arrhythmias. On the postischemic-reperfused myocardium in a subset of hearts unresponsive to reperfusion-induced arrhythmias (duration of ischemia was reduced to 25 min), cromakalim treatment was associated with a higher incidence of reperfusion ventricular fibrillation (VF) and ventricular tachycardia (VT) as compared to the controls (100% VF and 100% VT in treated vs. 41% VF and 50% VT in controls, P < .05). Proarrhythmic effects of cromakalim were also reflected in a maldistribution of myocardial ions. At concentrations of 3, 10 and 30 microM of glibenclamide, a K channel blocker, a significant reduction in the incidence of reperfusion-induced VF and VT was observed, and an attenuation in the maldistribution of myocardial ion contents induced by ischemia/reperfusion was found. The reduction in myocardial contractility was detected at relatively high concentrations (10 and 30 microM) in both cromakalim- and glibenclamide-treated groups. The proarrhythmic effect of cromakalim (30 microM) was abolished by 3 microM of glibenclamide, suggesting that the increased tendency to develop reperfusion arrhythmias is associated with the cromakalim-induced K efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potassium channel openers and blockers: do they possess proarrhythmic or antiarrhythmic activity in ischemic and reperfused rat hearts? 826 98

Examination was made of cardioprotective effect related to the ATP-sensitive K+ (KATP) channel on isolated globally ischemic reperfused rat hearts using cromakalim, a putative ATP-sensitive K+ channel opener. The hearts were subjected to 20 min Langendorff perfusion with Krebs Henseleit Bicarbonate Buffer (KHBB) (70 cmH2O, 37 degrees C), followed by 30 min ischemia at 36 degrees C, and 30 min reperfusion with KHBB, with (cromakalim group) or without (control group) pretreatment by 10 microM cromakalim added to KHBB for 5 min prior to ischemia. Before ischemia, no significant change in heart rate (HR), left ventricular developed pressure (LVDP) or coronary flow (CF) by 10 microM cromakalim could be detected. The two groups were the same in CF during reperfusion, but recovery of HR and LVDP significantly improved in the cromakalim group. Creatine kinase (CK) leakage in the cromakalim group was significantly less than in the control group during reperfusion. Cromakalim is thus shown to reduce the myocardial injury during ischemia and reperfusion. Intracellular Ca2+ content of the cromakalim group appeared lower than that of the control group at 30 min of reperfusion. At 5-30 min of reperfusion, in the cromakalim group, intracellular Ca2+ storage was prevented, leading to a good recovery of cardiac function, while in the control group, intracellular Ca2+ increased and recovery of cardiac function was poor. After pretreatment with 10 microM cromakalim, intracellular K+ content of the cromakalim group was significantly lower than in the control group before ischemia. At 5 min of reperfusion, intracellular K+ content of the cromakalim group was slightly less than that of the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cardioprotective effect of cromakalim, a K+ channel opener, on isolated globally ischemic and reperfused rat hearts]. 847 73

The incidence of reperfusion ventricular fibrillation (VF) and tachycardia (VT), heart function and the maldistribution of cardiac cations were studied in isolated ischemic/reperfused hearts obtained from streptozotocin-induced diabetic rats. Effects of an ATP-sensitive potassium (KATP) channel opener, cromakalim, and a KATP channel blocker, glibenclamide, also were studied. After 2 and 8 weeks of diabetes, hearts were isolated and subjected to 30 min of ischemia followed by reperfusion. After 2 weeks of diabetes, the incidence of VF and VT was reduced from their nondiabetic control values of 100 and 100 to 42% (P < .05) and 50% (P < .05), respectively. The reduction in VF and VT was not observed with progressive diabetes and after 8 weeks cardiac failure developed. In the 8-week diabetics, the development of cardiac failure was reflected in the aggravation of heart function (26, 16 and 17% reductions in aortic flow, left ventricular developed pressure and first derivative of developed pressure, respectively), and ion shifts (56 and 71% accumulation in cellular Na+ and Ca++, respectively, and 15% loss in cell K+) before the induction of ischemia. After ischemia/reperfusion, these changes were pronounced in diabetic groups. Cromakalim aggravated and glibenclamide attenuated the incidence of arrhythmias, contractile function and ion shifts induced by ischemia/reperfusion in diabetic hearts. The data show that the use of KATP channel openers as anti-ischemic agents may be of particular concern in the population of postinfarction diabetic patients who are known to be at high risk of sudden coronary death.
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PMID:Diabetes and ATP-sensitive potassium channel openers and blockers in isolated ischemic/reperfused hearts. 853 Oct 71

ATP-sensitive potassium channel (KATP) openers directly protect ischemic myocardium, which may make them useful for treating patients undergoing cardiopulmonary bypass, but whether high-potassium-containing cardioplegic solutions would inhibit their protective effects is not clear. We determined whether additional protection greater than that provided by cardioplegia could be found for KATP openers. We studied the effect of 10 microM cromakalim or BMS-180448 pretreatment (10 min before cardioplegia) on severity of ischemia in isolated rat hearts given normothermic or cold St. Thomas' cardioplegic solution (16 mM K+). After cardioplegic arrest, the hearts were subjected to 30-min (normothermic) or 150-min (hypothermic) global ischemia, each followed by 30-min reperfusion. The cardioplegic solutions significantly protected the hearts, as measured by increased time to onset of contracture, enhanced recovery of function, and reduced lactate dehydrogenase (LDH) release. Cromakalim and BMS-180448 both further significantly increased time to contracture in both normothermic and hypothermic arrested hearts; this was accompanied by enhanced recovery of reperfusion contractile function and reduced cumulative LDH release. This additional protective effect of the K ATP openers was abolished by glyburide. Because administration of the K ATP openers only with the cardioplegic solution (1 min before global ischemia) was not efficacious, >1-min pretreatment apparently is necessary. K ATP openers provide additional protection to that afforded by cold or normothermic potassium cardioplegia in rat heart, although the timing of treatment may be crucial.
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PMID:Protective effect of K(ATP) openers in ischemic rat hearts treated with a potassium cardioplegic solution. 863 83

Previous studies have indicated that alterations in cardiac ATP-sensitive potassium channels (KATP) can occur with cardiac hypertrophy. The goal of this study was to determine the effect of cardiac hypertrophy in spontaneously hypertensive rats (SHR) on the response to the cardioprotective agents diltiazem and cromakalim. Isolated rat hearts from 14-wk-old SHR, normotensive heterozygote Wistar-Kyoto (WKY), and Sprague-Dawley (SD) strains were subjected to 25 min of global ischemia and 30 min of reperfusion in the presence of vehicle (3-30 microM cromakalim or 0.1-1.0 microM diltiazem). SHR had heart weight-to-body weight ratios 40-50% greater than age-matched SD or WKY. Both diltiazem and cromakalim increased reperfusion contractile function in a concentration-dependent manner in SD rats as previously reported. Cromakalim and diltiazem caused similar improvements in reperfusion function in WKY rats and SHR. Cumulative lactate dehydrogenase (LDH) release during reperfusion was similar for vehicle-treated SD, WKY, or SHR hearts. LDH release was significantly attenuated by cromakalim and dilitiazem at all concentrations tested in SD and WKY hearts, whereas LDH release was not attenuated in SHR hearts by any concentration of cromakalim or diltiazem tested. Morphological assessment of hearts by light microscopy indicated that the severity and distribution of myocardial lesions were not affected by cromakalim in SHR hearts, compared with vehicle-treated SHR, supporting the LDH data. These results suggest that in SHR hearts, cromakalim and dilitiazan may exert much of their cardioprotective effects on the population of myocytes that are not irreversibly damaged.
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PMID:Comparative cardioprotective effects of cromakalim and diltiazem in ischemic hypertrophied rat hearts. 876 49

The effect of the timing of treatment with the ATP-regulated potassium channel agonist BMS-180448 was evaluated in isolated rat heart and ferret models of ischemia and reperfusion. In rat hearts, 10 microM BMS-180448, given before and after global ischemia as well as only during reflow, improved reperfusion contractile function and attenuated lactic dehydrogenase release, although reperfusion-only treatment was less effective. Cromakalim (10 microM) and bimakalim (10 microM) treatment before and after global ischemia afforded a degree of protection similar to that of BMS-180448, although they were not cardioprotective when given only during reperfusion. Pre- and post-treatment cardioprotection were abolished by glyburide. Ischemia/reperfusion significantly increased cytosolic calcium concentration ([Ca++]i) and BMS-180448 given only during reperfusion attenuated this change. In anesthetized ferrets, BMS-180448 (2 mg/kg) or vehicle was infused i.v. during a 40-min interval beginning 1) 10 min before coronary occlusion, 2) at the 45th min of ischemia or 3) at the 5th min of reperfusion. Preocclusion administration of BMS-180448 was associated with a 35% reduction in infarct damage from that recorded in vehicle-treated control ferrets. Drug administered at the midpoint of ischemia reduced infarct size approximately 44%, whereas delaying BMS-180448 infusion until the 5th min of reperfusion reduced, but still provided a significant (17%) level of salvage. The favorable effects of BMS-180448 in the ferret were not associated with changes in either collateral blood flow or peripheral hemodynamics. Thus BMS-180448 shows some protective effects when given only during reperfusion. Cromakalim and bimakalim did not exert similar actions and the difference may be secondary to the faster penetration of BMS-180448.
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PMID:Effect of timing of treatment of the glyburide-reversible cardioprotective activity of BMS-180448. 910 76


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