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A H Weston - One of the best experts on this subject based on the ideXlab platform.
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the contribution of rb permeable potassium channels to the relaxant and membrane hyperpolarizing actions of Cromakalim rp49356 and diazoxide in bovine tracheal smooth muscle
British Journal of Pharmacology, 1991Co-Authors: J Longmore, K M Bray, A H WestonAbstract:1. Cromakalim (1 and 10 microM), RP49356 (5 and 50 microM) and diazoxide (100 and 300 microM) produced full relaxation of smooth muscle strips pre-contracted with 25 mM KCl. These agents caused membrane hyperpolarization and increased 42K and 86Rb efflux. The time taken to achieve the maximum change in each of these parameters (tmax) was less for the higher concentration levels of Cromakalim, RP49356 and diazoxide than for the lower concentration levels. 2. Calculation of permeability (P) changes showed that cormakalim (1 and 10 microM) produced a greater rise in PK than PRb, although the PRb:PK ratio was similar at both concentration levels. Similarly RP49356 produced a greater change in PK than PRb. However, in contrast to Cromakalim, this difference was more marked at the higher concentration (50 microM) and was reflected by a differential effect of the two concentrations of RP49356 on the PRb:PK ratio. Diazoxide (100 and 300 microM) produced similar changes in PK and PRb. 3. For Cromakalim (1 and 10 microM) the tmax for the electrical and mechanical effects and also the profile of change in these parameters corresponded to changes in both PK and PRb. For RP49356 (5 microM), changes in tension and membrane potential were related to both changes in PK and PRb, whereas at 50 microM these responses more closely corresponded to changes in PK. For diazoxide (100 and 300 microM) the electrical and mechanical effects corresponded to changes in both PK and PRb. 4. The results show that changes in 42K and 86Rb efflux induced by Cromakalim, RP49356 and diazoxide are good indicators of changes in membrane PK and PRb evoked by these agents. Furthermore, it is concluded that the K channels involved in the mechanical and electrical effects of Cromakalim are represented by the opening of a single population through which Rb can pass less easily than K, whilst the K channels associated with actions of diazoxide are equally permeable to both K and Rb. In contrast, the relaxant and membrane hyperpolarizing actions of RP49356 may involve the opening of more than one group of K channels which differ in their permeability to Rb.
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actions of Cromakalim on ionic currents recorded from single smooth muscle cells of the rat portal vein
Journal of Pharmacology and Experimental Therapeutics, 1990Co-Authors: Kohji Okabe, K. Nakao, Kenji Kitamura, H. Kuriyama, Shunichi Kajioka, A H WestonAbstract:The effects of Cromakalim (BRL34915), a novel K channel opener, on ionic currents in dispersed smooth muscle cells of the rat portal vein were investigated. Application of Cromakalim (greater than 3 microM) generated an outward current, the reversal potential of which (-79 mV) was almost the same as the theoretical K equilibrium potential (-80 mV) under the experimental conditions used. When the Ca in the physiological salt solution (PSS) was replaced with Mn, the Cromakalim-induced outward current was inhibited markedly. When 4 mM ethylene glycol bis(beta-aminoethyl ether(N,N'-N,N'-tetraacetic acid (EGTA) was added to the pipette solution (bath solution, Ca-free PSS + Mn), Cromakalim inhibited the outward current evoked by command pulses. Using a pipette solution containing high Cs with 4 mM EGTA and a bath PSS containing 2.5 mM Ca with 1 microM tetrodotoxin, the Ca inward current was isolated. Cromakalim (greater than 3 microM) inhibited the Ca inward current in a voltage- dependent manner. Cromakalim (30 microM) inhibited the Ca inward current to 0.6 times the control. The decay of the inward Ca current comprised fast and slow components. Cromakalim inhibited the latter component and shifted the voltage-dependent inactivation curve of this current to the left (more hyperpolarized direction) in a parallel manner and delayed recovery from inactivation as estimated using a double pulse protocol. By using a pipette solution containing high Cs with 4 mM EGTA and Ca-free PSS containing 2.5 mM Mn in the bath, Na inward currents, blocked by tetrodotoxin (IC50 = 10 nM), were evoked by depolarizing pulses. Cromakalim (up to 30 microM) had no effect on the Na inward current.(ABSTRACT TRUNCATED AT 250 WORDS)
Gary J. Grover - One of the best experts on this subject based on the ideXlab platform.
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Comparative cardioprotective effects of Cromakalim and diltiazem in ischemic hypertrophied rat hearts
2016Co-Authors: Gary J. Grover, Steven Dzwonczyk, M. Monticello, Gary J, Thomas MAbstract:Monticello. Comparative cardioprotective effects of cromaka-lim and diltiazem in ischemic hypertrophied rat hearts. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H174-H182, 1996.-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 hyperten-sive 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 uM Cromakalim or 0.1-1.0 uM diltiazem). SHR had heart weight-to-body weight ratios 40-50 % greater than age-matched SD or WKY. Both diltiazem and cromakali
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cardioprotection with the katp opener Cromakalim is not correlated with ischemic myocardial action potential duration
Journal of Cardiovascular Pharmacology, 1995Co-Authors: Gary J. Grover, Charles S Parham, Albert J Dalonzo, Raymond B. DarbenzioAbstract:: We endeavored to determine if the enhanced shortening of the myocardial action potential duration (APD) during ischemia can be dissociated from the cardioprotective effects of the adenosine triphosphate (ATP) sensitive potassium channel (KATP) opener Cromakalim. To establish if there is a relationship between APD shortening and the cardioprotective effect of Cromakalim, we determined the effect of a dose of the delayed rectifier (IKr) blocker dofetilide (which abolishes the APD shortening effect of Cromakalim) on the cardioprotective activity of Cromakalim. Cromakalim was infused at a previously determined cardioprotective dose (10 micrograms/kg + 0.3 micrograms/kg/min infusion i.c.), and we determined the effect of 1 mg/kg (followed by a 0.01 mg/kg/min i.v. infusion) dofetilide alone and in combination with Cromakalim on APD shortening and infarct size (90-min coronary occlusion and 5-h reperfusion) in anesthetized dogs. Dofetilide completely abolished the APD shortening effects of Cromakalim during ischemia such that APD was similar to preischemic values. Cromakalim only shortened the APD during ischemia, although this effect was attenuated late into ischemia. Cromakalim significantly reduced infarct size (40% reduction from vehicle group value), whereas dofetilide alone had no effect. Dofetilide, at a dose that prevented the Cromakalim-induced shortening of APD in ischemic tissue, did not attenuate the cardioprotective effects of Cromakalim. No differences in collateral blood flow for any of the groups were observed. Dofetilide did cause a slight bradycardia, but this effect is unlikely to affect the interpretation of the results. These data suggest that APD shortening observed with the KATP opener Cromakalim is not correlated with its cardioprotective effects.
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The cardioprotective and electrophysiological effects of Cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: Gary J. Grover, Paul G. Sleph, Albert J. D'alonzo, Steven Dzwonczyk, Thomas A. Hess, Raymond B. DarbenzioAbstract: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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Effects of intracoronary Cromakalim on postischaemic contractile function and action potential duration.
Cardiovascular Research, 1992Co-Authors: Albert J. D'alonzo, Raymond B. Darbenzio, Charles S Parham, Gary J. GroverAbstract:Objective: The effects of intracoronary Cromakalim (1 μg·kg−1·min−1) on postischaemic contractile function and monophasic action potential duration at the 95% repolarisation level (APD95) were assessed in a canine model of stunned myocardium. Methods: Animals (n=24) were anaesthetised, subjected to a left thoracotomy, and the left anterior descending coronary artery was isolated. Measurements of segmental shortening and monophasic action potential were taken before drug, after drug, during a 15 min occlusion, and at times following reperfusion. Results: Cromakalim significantly improved reperfusion recovery of function. Both preischaemic and postischaemic myocardial blood flows were increased with Cromakalim, although there was no significant change in collateral blood flow during ischaemia relative to vehicle. In the absence of ischaemia, Cromakalim reduced APD95 by 8%. There was no change in APD95 with vehicle alone. During coronary occlusion, Cromakalim significantly reduced APD95 by 27% as compared with 8% in the vehicle group. APD95 values returned to preocclusion levels within minutes of reperfusion and remained there throughout reperfusion (30 min). Glyburide (3.0 mg·kg−1 intravenously), a blocker of ATP sensitive potassium channels, abolished the APD95 effects of Cromakalim. One out of six animals given glyburide survived through reperfusion. In contrast, four out of five of the glyburide+Cromakalim treated animals survived through reperfusion. Conclusions: Cardioprotection with Cromakalim is likely to be mediated through activation of ATP sensitive potassium channels, measured as a decrease in action potential duration. Shortening of action potential duration with Cromakalim was shown to be augmented in the presence of ischaemia. It is suggested that a possible interrelationship between cardioprotection and action potential duration shortening may exist such that the cardioprotective effects of Cromakalim may be selective for ischaemic conditions. Cardiovascular Research 1992; 26 :1046-1053
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cardioprotective effects of the potassium channel opener Cromakalim stereoselectivity and effects on myocardial adenine nucleotides
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Gary J. Grover, Paul G. Sleph, Steven Dzwonczyk, Saima Ahmed, Jane W Newburger, S C Taylor, K S AtwalAbstract:We determined if the cardioprotective effects of the potassium channel opener Cromakalim are stereoselective and if it can preserve adenine nucleotides in ischemic myocardium. We subjected isolated isovolumically beating rat hearts to 25 min of global ischemia and reperfusion with and without pretreatment by Cromakalim or its enantiomers. All of these compounds significantly increased preischemic coronary flow with the (3S,4R)-(-)-enantiomer being more potent (EC25 = 0.52 microM) compared to Cromakalim (EC25 = 1.04 microM) and the (3R,4S)-(+)-enantiomer (EC25 greater than 100 microM). The (-)-enantiomer was also significantly more potent in reducing ischemic/reperfusion damage compared to Cromakalim and its (+)-enantiomer. Reperfusion contractile function was improved significantly and lactate dehydrogenase release was reduced by these compounds. Time to contracture was also increased significantly by the (-)-enantiomer (EC25 = 2.27 microM), Cromakalim (EC25 = 4.89 microM) and the (+)-enantiomer (EC25 greater than 100 microM). We determined if Cromakalim, in a concentration which does not depress cardiac function (10 microM), can preserve high energy phosphates during ischemia in isolated rat hearts. Cromakalim significantly preserved ATP at 15 to 25 min of ischemia. Adenylate energy charge was also significantly improved by Cromakalim at 20 to 25 min into an ischemic episode. Thus, the cardioprotective effects of Cromakalim are stereoselective and may be due partly to preservation of myocardial energy reserves. It is significant that Cromakalim can preserve adenine nucleotides despite its lack of negative inotropic effects.
Paul G. Sleph - One of the best experts on this subject based on the ideXlab platform.
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The cardioprotective and electrophysiological effects of Cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: Gary J. Grover, Paul G. Sleph, Albert J. D'alonzo, Steven Dzwonczyk, Thomas A. Hess, Raymond B. DarbenzioAbstract: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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cardioprotective effects of the potassium channel opener Cromakalim stereoselectivity and effects on myocardial adenine nucleotides
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Gary J. Grover, Paul G. Sleph, Steven Dzwonczyk, Saima Ahmed, Jane W Newburger, S C Taylor, K S AtwalAbstract:We determined if the cardioprotective effects of the potassium channel opener Cromakalim are stereoselective and if it can preserve adenine nucleotides in ischemic myocardium. We subjected isolated isovolumically beating rat hearts to 25 min of global ischemia and reperfusion with and without pretreatment by Cromakalim or its enantiomers. All of these compounds significantly increased preischemic coronary flow with the (3S,4R)-(-)-enantiomer being more potent (EC25 = 0.52 microM) compared to Cromakalim (EC25 = 1.04 microM) and the (3R,4S)-(+)-enantiomer (EC25 greater than 100 microM). The (-)-enantiomer was also significantly more potent in reducing ischemic/reperfusion damage compared to Cromakalim and its (+)-enantiomer. Reperfusion contractile function was improved significantly and lactate dehydrogenase release was reduced by these compounds. Time to contracture was also increased significantly by the (-)-enantiomer (EC25 = 2.27 microM), Cromakalim (EC25 = 4.89 microM) and the (+)-enantiomer (EC25 greater than 100 microM). We determined if Cromakalim, in a concentration which does not depress cardiac function (10 microM), can preserve high energy phosphates during ischemia in isolated rat hearts. Cromakalim significantly preserved ATP at 15 to 25 min of ischemia. Adenylate energy charge was also significantly improved by Cromakalim at 20 to 25 min into an ischemic episode. Thus, the cardioprotective effects of Cromakalim are stereoselective and may be due partly to preservation of myocardial energy reserves. It is significant that Cromakalim can preserve adenine nucleotides despite its lack of negative inotropic effects.
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Specific block of the anti-ischemic actions of Cromakalim by sodium 5-hydroxydecanoate.
Circulation Research, 1991Co-Authors: John R. Mccullough, Paul G. Sleph, S Dzwonczyk, Diane E. Normandin, Mary Lee Conder, Gary J. GroverAbstract:The potassium channel activators Cromakalim and pinacidil were recently shown to have anti-ischemic properties in isolated globally ischemic rat hearts. The effects of two reported blockers of ATP-sensitive potassium channels, glibenclamide (glyburide) and sodium 5-hydroxydecanoate, on the anti-ischemic efficacy of Cromakalim were determined in this model. Buffer-perfused rat hearts were subjected to 25 minutes of ischemia followed by 30 minutes of reperfusion. Pretreatment of these hearts with 60 microM Cromakalim significantly decreased indexes of contractile function but caused a significant improvement of postreperfusion function and a significant decrease in release of lactate dehydroxygenase and in end-diastolic pressure. Pretreatment with glibenclamide at concentrations that reversed the preischemic effects of Cromakalim (0.05 and 1.0 microM) also significantly reversed its postischemic protective effects. Sodium 5-hydroxydecanoate (100 and 300 microM) had no effect on the preischemic (negative inotropic) effects of Cromakalim but completely reversed its cardioprotective effects. Sodium 5-hydroxydecanoate did not reverse the cardioprotective effects of the calcium entry blocker diltiazem. In phenylephrine-contracted rat aorta, glibenclamide (0.1-10 microM) inhibited Cromakalim-induced relaxation, whereas sodium 5-hydroxydecanoate (10-1,000 microM) had no effect. Similarly, the ability of Cromakalim to shorten cardiac action potential duration in guinea pig papillary muscle and to increase outward whole-cell potassium currents in isolated myocytes was inhibited by glibenclamide, whereas sodium 5-hydroxydecanoate was without effect. Thus, both glibenclamide and sodium 5-hydroxydecanoate inhibited the effects of Cromakalim after reperfusion; however, sodium 5-hydroxydecanoate, unlike glibenclamide, had no effect in nonischemic preparations. These results suggest that sodium 5-hydroxydecanoate is an ischemia-selective inhibitor of ATP-sensitive potassium channels.
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the protective effects of Cromakalim and pinacidil on reperfusion function and infarct size in isolated perfused rat hearts and anesthetized dogs
Cardiovascular Drugs and Therapy, 1990Co-Authors: Gary J. Grover, Charles S Parham, Steven Dzwonczyk, Paul G. SlephAbstract:The direct myocardial protective effects of intracoronary infusions of Cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 μg/kg/min) or pinacidil (0.09 μg/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25±5%) compared with vehicle controls (55±7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in Cromakalim-treated animals, particularly in the subepicardial region. When the same dose of Cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of Cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 μM Cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, Cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both Cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.
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Pharmacologic profile of Cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs.
Journal of Cardiovascular Pharmacology, 1990Co-Authors: Gary J. Grover, Paul G. Sleph, Steven DzwonczykAbstract: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.
Steven Dzwonczyk - One of the best experts on this subject based on the ideXlab platform.
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Comparative cardioprotective effects of Cromakalim and diltiazem in ischemic hypertrophied rat hearts
2016Co-Authors: Gary J. Grover, Steven Dzwonczyk, M. Monticello, Gary J, Thomas MAbstract:Monticello. Comparative cardioprotective effects of cromaka-lim and diltiazem in ischemic hypertrophied rat hearts. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H174-H182, 1996.-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 hyperten-sive 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 uM Cromakalim or 0.1-1.0 uM diltiazem). SHR had heart weight-to-body weight ratios 40-50 % greater than age-matched SD or WKY. Both diltiazem and cromakali
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The cardioprotective and electrophysiological effects of Cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism.
The Journal of pharmacology and experimental therapeutics, 1994Co-Authors: Gary J. Grover, Paul G. Sleph, Albert J. D'alonzo, Steven Dzwonczyk, Thomas A. Hess, Raymond B. DarbenzioAbstract: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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cardioprotective effects of the potassium channel opener Cromakalim stereoselectivity and effects on myocardial adenine nucleotides
Journal of Pharmacology and Experimental Therapeutics, 1991Co-Authors: Gary J. Grover, Paul G. Sleph, Steven Dzwonczyk, Saima Ahmed, Jane W Newburger, S C Taylor, K S AtwalAbstract:We determined if the cardioprotective effects of the potassium channel opener Cromakalim are stereoselective and if it can preserve adenine nucleotides in ischemic myocardium. We subjected isolated isovolumically beating rat hearts to 25 min of global ischemia and reperfusion with and without pretreatment by Cromakalim or its enantiomers. All of these compounds significantly increased preischemic coronary flow with the (3S,4R)-(-)-enantiomer being more potent (EC25 = 0.52 microM) compared to Cromakalim (EC25 = 1.04 microM) and the (3R,4S)-(+)-enantiomer (EC25 greater than 100 microM). The (-)-enantiomer was also significantly more potent in reducing ischemic/reperfusion damage compared to Cromakalim and its (+)-enantiomer. Reperfusion contractile function was improved significantly and lactate dehydrogenase release was reduced by these compounds. Time to contracture was also increased significantly by the (-)-enantiomer (EC25 = 2.27 microM), Cromakalim (EC25 = 4.89 microM) and the (+)-enantiomer (EC25 greater than 100 microM). We determined if Cromakalim, in a concentration which does not depress cardiac function (10 microM), can preserve high energy phosphates during ischemia in isolated rat hearts. Cromakalim significantly preserved ATP at 15 to 25 min of ischemia. Adenylate energy charge was also significantly improved by Cromakalim at 20 to 25 min into an ischemic episode. Thus, the cardioprotective effects of Cromakalim are stereoselective and may be due partly to preservation of myocardial energy reserves. It is significant that Cromakalim can preserve adenine nucleotides despite its lack of negative inotropic effects.
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the protective effects of Cromakalim and pinacidil on reperfusion function and infarct size in isolated perfused rat hearts and anesthetized dogs
Cardiovascular Drugs and Therapy, 1990Co-Authors: Gary J. Grover, Charles S Parham, Steven Dzwonczyk, Paul G. SlephAbstract:The direct myocardial protective effects of intracoronary infusions of Cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 μg/kg/min) or pinacidil (0.09 μg/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25±5%) compared with vehicle controls (55±7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in Cromakalim-treated animals, particularly in the subepicardial region. When the same dose of Cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of Cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 μM Cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, Cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both Cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.
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Pharmacologic profile of Cromakalim in the treatment of myocardial ischemia in isolated rat hearts and anesthetized dogs.
Journal of Cardiovascular Pharmacology, 1990Co-Authors: Gary J. Grover, Paul G. Sleph, Steven DzwonczykAbstract: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.
J Longmore - One of the best experts on this subject based on the ideXlab platform.
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the contribution of rb permeable potassium channels to the relaxant and membrane hyperpolarizing actions of Cromakalim rp49356 and diazoxide in bovine tracheal smooth muscle
British Journal of Pharmacology, 1991Co-Authors: J Longmore, K M Bray, A H WestonAbstract:1. Cromakalim (1 and 10 microM), RP49356 (5 and 50 microM) and diazoxide (100 and 300 microM) produced full relaxation of smooth muscle strips pre-contracted with 25 mM KCl. These agents caused membrane hyperpolarization and increased 42K and 86Rb efflux. The time taken to achieve the maximum change in each of these parameters (tmax) was less for the higher concentration levels of Cromakalim, RP49356 and diazoxide than for the lower concentration levels. 2. Calculation of permeability (P) changes showed that cormakalim (1 and 10 microM) produced a greater rise in PK than PRb, although the PRb:PK ratio was similar at both concentration levels. Similarly RP49356 produced a greater change in PK than PRb. However, in contrast to Cromakalim, this difference was more marked at the higher concentration (50 microM) and was reflected by a differential effect of the two concentrations of RP49356 on the PRb:PK ratio. Diazoxide (100 and 300 microM) produced similar changes in PK and PRb. 3. For Cromakalim (1 and 10 microM) the tmax for the electrical and mechanical effects and also the profile of change in these parameters corresponded to changes in both PK and PRb. For RP49356 (5 microM), changes in tension and membrane potential were related to both changes in PK and PRb, whereas at 50 microM these responses more closely corresponded to changes in PK. For diazoxide (100 and 300 microM) the electrical and mechanical effects corresponded to changes in both PK and PRb. 4. The results show that changes in 42K and 86Rb efflux induced by Cromakalim, RP49356 and diazoxide are good indicators of changes in membrane PK and PRb evoked by these agents. Furthermore, it is concluded that the K channels involved in the mechanical and electrical effects of Cromakalim are represented by the opening of a single population through which Rb can pass less easily than K, whilst the K channels associated with actions of diazoxide are equally permeable to both K and Rb. In contrast, the relaxant and membrane hyperpolarizing actions of RP49356 may involve the opening of more than one group of K channels which differ in their permeability to Rb.
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Differences between the effects of Cromakalim and nifedipine on agonist-induced responses in rabbit aorta
British Journal of Pharmacology, 1991Co-Authors: K M Bray, J Longmore, Susan Duty, Arthur H. Weston, D. T. Newgreen, Gillian Edwards, T.j. BrownAbstract:Abstract 1. The effects of Cromakalim on endothelium-denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine. 2. Pre-incubation with Cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)-induced responses. 3. Cromakalim (0.3-10 microM), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of Cromakalim were antagonized by raising extracellular [K+] or by glibenclamide. 4. Nifedipine inhibited contractions produced by KCl (40 mM) whereas Cromakalim had no effect. 5. In Ca2(+)-free physiological salt solution (PSS), Cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA-releasable Ca2+ stores, whereas nifedipine was ineffective. 6. In tissues preloaded with 42K+ Cromakalim (0.3-10 microM) produced a concentration-dependent increase in the 42K+ efflux rate coefficient. NA (0.3 microM) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 microM). 7. When microelectrodes were used, Cromakalim (1-10 microM) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of Cromakalim (less than 1 microM) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential. 9. It is concluded that the ability of Cromakalim to relax NA-induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine-sensitive Ca2+ channels. Instead, Cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.
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The action of diazoxide and minoxidil sulphate on rat blood vessels: a comparison with Cromakalim.
British Journal of Pharmacology, 1990Co-Authors: D. T. Newgreen, J Longmore, K M Bray, Susan Duty, Arthur H. Weston, A. D. Mcharg, B. S. Brown, P. B. Kay, Gillian Edwards, J. S. SouthertonAbstract:1. The actions of diazoxide and minoxidil sulphate have been compared with those of Cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to Cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only Cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of Cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst Cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like Cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.