hmr-1098 and Myocardial-Infarction

Previous studies in our laboratory suggest that an acute inhibition of glycogen synthase kinase 3 (GSK3) by SB-216763 (SB21) is cardioprotective when administered just before reperfusion. However, it is unknown whether the GSK inhibitor SB21 administered 24 h before ischemia is cardioprotective and whether the mechanism involves ATP-sensitive potassium (K(ATP)) channels and the mitochondrial permeability transition pore (MPTP). Male Sprague-Dawley rats were administered the GSK inhibitor SB21 (0.6 mg/kg) or vehicle 24 h before ischemia. Subsequently, the rats were acutely anesthetized with Inactin and underwent 30 min of ischemia and 2 h of reperfusion followed by infarct size determination. Subsets of rats received either the sarcolemmal K(ATP) channel blocker HMR-1098 (6 mg/kg), the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5-HD; 10 mg/kg), or the MPTP opener atractyloside (5 mg/kg) either 5 min before SB21 administration or 5 min before reperfusion 24 h later. The infarct size was reduced in SB21 compared with vehicle (44 +/- 2% vs. 61 +/- 2%, respectively; P < 0.01). 5-HD administered either before SB21 treatment or 5 min before reperfusion the following day abrogated SB21-induced protection (54 +/- 4% and 61 +/- 2%, respectively). HMR-1098 did not affect the SB21-induced infarct size reduction when administered before the SB21 treatment (43 +/- 1%); however, HMR-1098 partially abrogated the SB21-induced infarct size reduction when administered just before reperfusion 24 h later (52 +/- 1%). The MPTP opening either before SB21 administration or 5 min before reperfusion abrogated the infarct size reduction produced by SB21 (61 +/- 2% and 62 +/- 2%, respectively). Hence, GSK inhibition reduces infarct size when given 24 h before the administration via the opening K(ATP) channels and MPTP closure.

Topics: Animals; Atractyloside; Benzamides; Blood Gas Analysis; Blood Pressure; Cardiotonic Agents; Glycogen Synthase Kinase 3; Heart Rate; Indoles; KATP Channels; Male; Maleimides; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardial Ischemia; Potassium Channel Blockers; Rats; Rats, Sprague-Dawley

Both glycogen synthase kinase 3beta (GSK3beta) and the ATP-dependant potassium channel (K(ATP)) mediate opioid-induced cardioprotection (OIC). However, whether direct K(ATP) channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3beta inhibition is unknown. Therefore, we investigated the role of K(ATP) channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and K(ATP) channels in cardioprotection.Male Sprague-Dawley rats underwent 30 minutes ischemia with 2 hours of reperfusion and infarct size was determined. Rats given the nonselective opioid agonist, morphine (0.3 mg/kg), or the selective delta opioid agonist, BW373U86 (1.0 mg/kg), 5 minutes prior to reperfusion reduced infarct size (40.3+/-1.6*, 39.7+/-1.9* versus 60.0+/-1.1%, respectively, * P<0.001%). This protection was abrogated with prior administration of the putative sarcolemmal K(ATP) antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial K(ATP) antagonist, 5-HD (10 mg/kg). The putative sK(ATP) channel opener, P-1075 (1microg/kg) or the putative mK(ATP) channel opener, BMS-191095 (1 mg/kg) given 5 minutes prior to reperfusion also reduced infarct size (41.8+/-2.4*, 43.4+/-1.4*) and protection was abrogated by prior administration of the PI3k inhibitor wortmannin (60.0+/-1.7, 64.0+/-2.6%, respectively, * P<0.001). Cardioprotection afforded by the GSK inhibitor SB216763 (0.6 mg/kg) given 5 minutes prior to reperfusion was also partially blocked by either HMR or 5-HD and completely blocked when HMR and 5-HD were given in combination (40.8+/-1.6*, 50.4+/-1.6;; 49.4+/-1.7;, 61.6+/-1.6%, respectively, * or ; P<0.001). These data indicate that both the sK(ATP) and mK(ATP) channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via K(ATP) channel opening.

Topics: Analgesics, Opioid; Androstadienes; Animals; Benzamides; Benzopyrans; Blood Pressure; Cardiotonic Agents; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Guanidines; Heart Rate; Imidazoles; Indoles; Ion Channel Gating; Male; Maleimides; Morphine; Myocardial Infarction; Myocardial Reperfusion Injury; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Potassium Channel Blockers; Potassium Channels; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sarcolemma; Signal Transduction; Time Factors; Wortmannin

Prophylactic treatment with D-myo-inositol 1,4,5-trisphosphate hexasodium [D-myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying D-myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal K(ATP) channels) in the infarct-sparing effect of D-myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with D-myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, D-myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+ (K(ATP)) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both D-myo-Ins(1,4,5)P3- and PC-treated hearts versus controls. D-myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, K(ATP) channels. Moreover, the benefits of D-myo-Ins(1,4,5)P3 were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: D-myo-Ins(1,4,5)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective epsilon-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial K(ATP) channels participate in the reduction of infarct size afforded by prophylactic administration of D-myo-Ins(1,4,5)P3.

Topics: Alkaloids; Animals; Benzamides; Benzophenanthridines; Cardiotonic Agents; Chromones; Decanoic Acids; Enzyme Inhibitors; Hydroxy Acids; In Vitro Techniques; Inositol 1,4,5-Trisphosphate; Ischemic Preconditioning, Myocardial; Mitochondria, Heart; Morpholines; Myocardial Infarction; Myocardium; Phenanthridines; Phosphatidylinositol 3-Kinases; Potassium Channels; Protein Kinase C-epsilon; Rabbits; Stereoisomerism

This study was conducted to examine the relationship between myocardial ATP-sensitive potassium (K(ATP)) channels and sex differences in myocardial infarct size after in vitro ischemia-reperfusion (I/R). Hearts from adult male and female Sprague-Dawley rats were excised and exposed to an I/R protocol (1 h of ischemia, followed by 2 h of reperfusion) on a modified Langendorff apparatus. Hearts from female rats showed significantly smaller infarct sizes than hearts from males (23 +/- 4 vs. 40 +/- 5% of the zone at risk, respectively; P < 0.05). Administration of HMR-1098, a sarcolemmal K(ATP) channel blocker, abolished the sex difference in infarct size (42 +/- 4 vs. 45 +/- 5% of the zone at risk in hearts from female and male rats, respectively; P = not significant). Further experiments showed that blocking the K(ATP) channels in ischemia, and not reperfusion, was sufficient to increase infarct size in female rats. These data demonstrate that sarcolemmal K(ATP) channels are centrally involved in mechanisms that underlie sex differences in the susceptibility of the intact heart to I/R injury.

Topics: Animals; ATP-Binding Cassette Transporters; Benzamides; Female; In Vitro Techniques; KATP Channels; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Sarcolemma; Sex Characteristics

Previous work from our laboratory has shown that the sarcolemmal K(ATP) channel (sK(ATP)) is required as a trigger for delayed cardioprotection upon exogenous opioid administration. We also established that the mitochondrial K(ATP) (mK(ATP)) channel is not required for triggering delayed delta-opioid-induced infarct size reduction. Because mechanistic differences have been found among delta-opioids and that due to ischemic preconditioning (IPC), we determined whether the triggering mechanism of delayed IPC-induced infarct size reduction involves either the sK(ATP) or mK(ATP). Male Sprague-Dawley rats received either sham surgery or IPC (3- to 5-min cycles of ischemia and reperfusion) 24 h before being subjected to 30 min of ischemia and 2 h of reperfusion. Infarct size was determined and expressed as a percentage of the area at risk, with significance compared with sham reported at P

Topics: Adenosine Triphosphate; Animals; Benzamides; Decanoic Acids; Hemodynamics; Hydroxy Acids; Ischemic Preconditioning, Myocardial; Male; Mitochondria, Heart; Myocardial Infarction; Myocardium; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Sarcolemma; Time Factors

This study was conducted to examine the role of myocardial ATP-sensitive potassium (K(ATP)) channels in exercise-induced protection from ischaemia-reperfusion (I-R) injury. Female rats were either sedentary (Sed) or exercised for 12 weeks (Tr). Hearts were excised and underwent a 1-2 h regional I-R protocol. Prior to ischaemia, hearts were subjected to pharmacological blockade of the sarcolemmal K(ATP) channel with HMR 1098 (SedHMR and TrHMR), mitochondrial blockade with 5-hydroxydecanoic acid (5HD; Sed5HD and Tr5HD), or perfused with buffer containing no drug (Sed and Tr). Infarct size was significantly smaller in hearts from Tr animals (35.4 +/- 2.3 versus 44.7 +/- 3.0% of the zone at risk for Tr and Sed, respectively). Mitochondrial K(ATP) blockade did not abolish the training-induced infarct size reduction (30.0 +/- 3.4 versus 38.0 +/- 2.6 in Tr5HD and Sed5HD, respectively); however, sarcolemmal K(ATP) blockade completely eradicated the training-induced cardioprotection. Infarct size was 71.2 +/- 3.3 and 64.0 +/- 2.4% of the zone at risk for TrHMR and Sed HMR. The role of sarcolemmal K(ATP) channels in Tr-induced protection was also supported by significant increases in both subunits of the sarcolemmal K(ATP) channel following training. LV developed pressure was better preserved in hearts from Tr animals, and was not influenced by addition of HMR 1098. 5HD decreased pressure development regardless of training status, from 15 min of ischaemia through the duration of the protocol. This mechanical dysfunction was likely to be due to a 5HD-induced increase in myocardial Ca2+ content following I-R. The major findings of the present study are: (1) unlike all other known forms of delayed cardioprotection, infarct sparing following chronic exercise was not abolished by 5HD; (2) pharmacological blockade of the sarcolemmal K(ATP) channel nullified the cardioprotective benefits of exercise training; and (3) increased expression of sarcolemmal K(ATP) channels was observed following chronic training.

Topics: Animals; ATP-Binding Cassette Transporters; Benzamides; Calcium; Decanoic Acids; Female; Heart; Hydroxy Acids; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Physical Conditioning, Animal; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Protein Isoforms; Rats; Rats, Sprague-Dawley; Receptors, Drug; Sarcolemma; Sulfonylurea Receptors; Ventricular Dysfunction, Left

The blockade of myocardial K(ATP) channels may be antiarrhythmic for ischemic arrhythmias. A new sulfonylthiourea, HMR1098 (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenylsulfonyl]-3-methylthiourea, sodium salt), was demonstrated to be a cardioselective K(ATP)-channel antagonist and to suppress arrhythmias during acute ischemia. We investigated effects of HMR1098 on the arrhythmias induced by programmed electrical stimulation (PES) in a canine old myocardial infarction model. HMR1098 (3 mg/kg, i.v.) significantly improved the scores of PES-induced ventricular arrhythmias, without changing the blood glucose concentrations. A classical sulfonylurea, glibenclamide (1 mg/kg, i.v.), had no significant effects on these arrhythmias, but reduced the blood glucose and increased the plasma insulin concentrations.

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Benzamides; Disease Models, Animal; Dogs; Electric Stimulation; Female; Glyburide; Male; Myocardial Infarction; Potassium Channel Blockers; Potassium Channels; Sarcolemma

Recently it has been postulated that mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels rather than sarcolemmal K(ATP) (sarcK(ATP)) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcK(ATP) channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcK(ATP) current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoK(ATP) channel function was preserved in KO ventricular cells. In anesthetized mice, IPC reduced the infarct size in WT but not KO mice. Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts. Treatment with HMR1098, a sarcK(ATP) channel blocker, but not 5-hydroxydecanoate, a mitoK(ATP) channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts. These findings suggest that sarcKATP channels figures prominently in modulating ischemia/reperfusion injury in the mouse. The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcK(ATP) channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.

Topics: Animals; Benzamides; Decanoic Acids; Hydroxy Acids; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Potassium Channels, Inwardly Rectifying; Sarcolemma

We have demonstrated the effects of estrogen on modulation of ATP-sensitive K(+) channels; however, the subcellular location of these channels is unknown. The purpose of the present study was to investigate the role of the sarcolemmal and mitochondrial ATP-sensitive K(+) channels in a canine model of myocardial infarction after stimulation with 17 beta-estradiol. Anesthetized dogs were subjected to 60 min of the left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Infarct size was markedly reduced in estradiol-treated dogs compared with controls (14 +/- 6 versus 42 +/- 6%, P < 0.0001), indicating the effective dose of estradiol administrated. Pretreatment with the mitochondrial ATP-sensitive K(+) channel antagonist 5-hydroxydecanoate completely abolished estradiol-induced cardioprotection. The sarcolemmal ATP-sensitive K(+) channel antagonist 1-15-12-(5-chloro-o-anisamido)ethyl-methoxyphenyl)sulfonyl-3-methylthiourea (HMR 1098) did not significantly attenuate estradiol-induced infarct size limitation. In addition, estradiol administration significantly reduced the incidence and duration of reperfusion-induced ventricular tachycardia and ventricular fibrillation. Although 5-hydroxydecanoate alone caused no significant effect on the incidence of reperfusion arrhythmias in the presence or absence of estradiol, the administration of HMR 1098 abolished estrogen-induced improvement of reperfusion arrhythmias. Pretreatment with the estrogen-receptor antagonist faslodex (ICI 182,780) did not alter estrogen-induced infarct-limiting and antiarrhythmic effects. These results demonstrate that estrogen is cardioprotective against infarct sizes and fatal reperfusion arrhythmias by different ATP-sensitive K(+) channels for an estrogen receptor-independent mechanism. The infarct size-limiting and antiarrhythmic effects of estrogen were abolished by 5-hydroxydecanoate and HMR 1098, suggesting that the effects may result from activation of the mitochondrial and sarcolemmal ATP-sensitive K(+) channels, respectively.

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Decanoic Acids; Dogs; Electrocardiography; Estradiol; Estrogen Antagonists; Fulvestrant; Hydroxy Acids; Male; Membrane Proteins; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Potassium Channels; Sarcolemma; Ventricular Function, Left

Chronic consumption of small doses of ethanol protects myocardium from ischemic injury. We tested the hypothesis that mitochondrial and sarcolemmal adenosine triphosphate-dependent potassium (K(ATP)) channels mediate these beneficial effects. Dogs (n = 76) were fed with ethanol (1.5 g/kg) or water mixed with dry food bid for 6 or 12 wk, fasted overnight before experimentation, and instrumented for measurement of hemodynamics. Dogs received intracoronary saline (vehicle), 5-hydroxydecanoate (a mitochondrial K(ATP) channel antagonist; 6.75 mg/kg over 45 min), or HMR-1098 (a sarcolemmal K(ATP) channel antagonist; 45 microg/kg over 45 min) and were subjected to a 60 min coronary artery occlusion followed by 3 h of reperfusion. A final group of dogs was pretreated with ethanol and chow for 6 wk before occlusion and reperfusion. Myocardial infarct size and transmural coronary collateral blood flow were measured with triphenyltetrazolium chloride staining and radioactive microspheres, respectively. The area at risk of infarction was similar between groups. A 12-wk pretreatment with ethanol significantly reduced infarct size to 13% +/- 2% (mean +/- SEM; n = 8) of the area at risk compared with control experiments (25% +/- 2%; n = 8), but a 6-wk pretreatment did not (21% +/- 2%; n = 8). 5-hydroxydecanoate and HMR-1098 abolished the protective effects of 12-wk ethanol pretreatment (24% +/- 2% and 29% +/- 3%, respectively; n = 8 for each group) but had no effect in dogs that did not receive ethanol (22% +/- 2% and 23% +/- 4%, respectively; n = 8 for each group). No differences in hemodynamics or transmural coronary collateral blood flow were observed between the groups. The results indicate that mitochondrial and sarcolemmal K(ATP) channels mediate ethanol-induced preconditioning in dogs independent of alterations in systemic hemodynamics or coronary collateral blood flow.. Mitochondrial and sarcolemmal K(ATP) channels mediate ethanol-induced preconditioning independent of alterations in systemic hemodynamics or coronary collateral perfusion in vivo.

Topics: Adenosine Triphosphate; Animals; Benzamides; Coronary Circulation; Decanoic Acids; Dogs; Ethanol; Hemodynamics; Hydroxy Acids; Ischemic Preconditioning, Myocardial; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Potassium Channel Blockers; Potassium Channels; Sarcolemma

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (K(ATP)) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7-10 days of age (n = 5-16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means +/- SD) by 50% (10 +/- 5%) versus untreated controls (20 +/- 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 +/- 4%) versus untreated controls (54 +/- 6%). The mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) completely (55 +/- 3%) and the sarcolemmal K(ATP) channel blocker HMR 1098 partially (62 +/- 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 +/- 5%). We conclude that both mitochondrial and sarcolemmal K(ATP) channels contribute to isoflurane-induced delayed cardioprotection.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Benzamides; Cytoprotection; Decanoic Acids; Dose-Response Relationship, Drug; Heart; Hydroxy Acids; In Vitro Techniques; Isoflurane; Mitochondria; Myocardial Infarction; Myocardial Ischemia; Myocardium; Potassium Channel Blockers; Potassium Channels; Rabbits; Sarcolemma; Time Factors; Ventricular Function, Left

It has been argued that activation of KATP channels in the sarcolemmal membrane of heart muscle cells during ischemia provides an endogenous cardioprotective mechanism. In order to test whether the novel cardioselective KATP channel blocker HMR 1098 affects cardiac function during ischemia, experiments were performed in rat hearts during ischemia and reperfusion. Isolated perfused working rat hearts were subjected to 30 min of low-flow ischemia in which the coronary flow was reduced to 10% of its control value, followed by 30-min reperfusion. In the first set of experiments the hearts were electrically paced at 5 Hz throughout the entire protocol. At the end of the 30-min ischemic period the aortic flow had fallen to 44 +/- 2% (n=8) of its nonischemic value in vehicle-treated hearts, whereas in the presence of 0.3 micromol/l and 3 micromol/l HMR 1098 it had fallen to 29 +/- 7% (n=5, not significant) and 8 +/- 2% (n=12, P<0.05), respectively. Glibenclamide (3 micromol/l) reduced the aortic flow to 9.5 +/- 7% (n=4, P<0.05). In control hearts the QT interval in the electrocardiogram shortened from 63 +/- 6 ms to 36 +/- 4 ms (n=10, P<0.05) within 4-6 min of low-flow ischemia. This shortening was completely prevented by 3 micromol/l HMR 1098 (60 +/- 5 ms before ischemia, 67 +/- 6 ms during ischemia, n=9, not significant). When rat hearts were not paced, the heart rate fell spontaneously during ischemia, and HMR 1,098 (3 micromol/l) caused only a slight, statistically non-significant reduction in aortic flow during the ischemic period. In order to investigate whether HMR 1098 shows cardiodepressant effects in a more pathophysiological model, the left descending coronary artery was occluded for 30 min followed by reperfusion for 60 min in anesthetized rats. Treatment with HMR 1098 (10 mg/kg i.v.) had no statistically significant effects on mean arterial blood pressure and heart rate during the control, ischemia and reperfusion periods. At the end of the reperfusion period, aortic blood flow was slightly reduced by HMR 1098, without reaching statistical significance (two-way analysis of ANOVA, P=0.15). Myocardial infarct size as a percentage of area at risk was not affected by HMR 1098 (vehicle: 75 +/- 3%, HMR 1098: 72 +/- 2%, n=7 in each group). In conclusion, cardiodepressant effects of HMR 1098 were observed only in isolated perfused working rat hearts which were continuously paced during global low-flow ischemia. In the model of anesthetized rats subjected to

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Benzamides; Glyburide; Heart; Hemodynamics; In Vitro Techniques; Male; Models, Animal; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Potassium; Potassium Channel Blockers; Rats; Rats, Wistar; Sulfonamides; Thiourea

Volatile anesthetic-induced preconditioning is mediated by adenosine triphosphate-dependent potassium (KATP) channels; however, the subcellular location of these channels is unknown. The authors tested the hypothesis that desflurane reduces experimental myocardial infarct size by activation of specific sarcolemmal and mitochondrial KATP channels.. Barbiturate-anesthetized dogs (n = 88) were acutely instrumented for measurement of aortic and left ventricular pressures. All dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle (0.9% saline) or the nonselective KATP channel antagonist glyburide (0.1 mg/kg intravenously) in the presence or absence of 1 minimum alveolar concentration desflurane. In four additional groups, dogs received 45-min intracoronary infusions of the selective sarcolemmal (HMR 1098; 1 microg. kg-1. min-1) or mitochondrial (5-hydroxydecanoate [5-HD]; 150 microg. kg-1. min-1) KATP channel antagonists in the presence or absence of desflurane. Myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively.. Desflurane significantly (P < 0.05) decreased infarct size to 10 +/- 2% (mean +/- SEM) of the area at risk as compared with control experiments (25 +/- 3% of area at risk). This beneficial effect of desflurane was abolished by glyburide (25 +/- 2% of area at risk). Glyburide (24 +/- 2%), HMR 1098 (21 +/- 4%), and 5-HD (24 +/- 2% of area at risk) alone had no effects on myocardial infarct size. HMR 1098 and 5-HD abolished the protective effects of desflurane (19 +/- 3% and 22 +/- 2% of area at risk, respectively).. Desflurane reduces myocardial infarct size in vivo, and the results further suggest that both sarcolemmal and mitochondrial KATP channels could be involved.

Topics: Adenosine Triphosphate; Anesthetics, Inhalation; Animals; Benzamides; Decanoic Acids; Desflurane; Dogs; Glyburide; Hemodynamics; Hydroxy Acids; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoflurane; Mitochondria; Myocardial Infarction; Myocardium; Potassium Channel Blockers; Potassium Channels; Regional Blood Flow; Sarcolemma

We examined the role of the sarcolemmal and mitochondrial ATP-sensitive potassium (K(ATP)) channel in a rat model of myocardial infarction after stimulation with the selective delta(1)-opioid receptor agonist TAN-67. Hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was expressed as a percentage of the area at risk. TAN-67 significantly reduced infarct size/area at risk (29.6 +/- 3.3) versus control (63. 1 +/- 2.3). The sarcolemmal-selective K(ATP) channel antagonist HMR 1098, administered 10 min before TAN-67, did not significantly attenuate cardioprotection (26.0 +/- 7.3) at a dose (3 mg/kg) that had no effect in the absence of TAN-67 (56.3 +/- 4.3). Pretreatment with the mitochondrial selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before the 30-min occlusion completely abolished TAN-67-induced cardioprotection (54.3 +/- 2.7), but had no effect in the absence of TAN-67 (62.6 +/- 4.1), suggesting the involvement of the mitochondrial K(ATP) channel. Additionally, we examined the antiarrhythmic effects of TAN-67 in the presence or absence of 5-HD and HMR 1098 during 30 min of ischemia. Control animals had an average arrhythmia score of 10.40 +/- 2.41. TAN-67 significantly reduced the arrhythmia score during 30 min of ischemia (2.38 +/- 0. 85). 5-HD and HMR 1098 in the absence of TAN-67 produced an insignificant decrease in the arrhythmia score (8.80 +/- 2.56 and 4. 20 +/- 1.07, respectively). 5-HD administration before TAN-67 treatment abolished its antiarrhythmic effect (4.71 +/- 1.11). However, HMR 1098 did not abolish TAN-67-induced protection against arrhythmias (1.67 +/- 0.80). These data suggest that delta(1)-opioid receptor stimulation is cardioprotective against myocardial ischemia and sublethal arrhythmias and suggest a role for the mitochondrial K(ATP) channel in mediating these cardioprotective effects.

Topics: Adenosine Triphosphate; Analgesics, Opioid; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Decanoic Acids; Drug Interactions; Heart Rate; Hydroxy Acids; Male; Mitochondria, Heart; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium Channel Blockers; Potassium Channels; Quinolines; Rats; Rats, Wistar; Receptors, Opioid, delta; Sarcolemma; Ventricular Fibrillation

Earlier studies have shown that activation of bradykinin B2 receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B2-receptor triggered pathway of PC is the ATP sensitive potassium (K(ATP)) channel in the mitochondria (mito-K(ATP) channel) or K(ATP) channel in the sarcolemma (sarc-K(ATP) channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 +/- 2.9 (SE) of the untreated controls to 12.0 +/- 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 micromol/L), a selective mito-K(ATP) channel blocker (% IS/AR = 44.2 +/- 6.4). In contrast, a high dose of HMR1098 (20 micromol/L), which is a newly developed sarc-K(ATP) channel selective blocker with IC50 of 0.6 micromol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 +/- 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 +/- 3.8 and 35.1 +/- 6.2, respectively). These results suggest that opening of the mito-K(ATP) channel but not the sarc-K(ATP) channel is involved in infarct size limitation by a mechanism triggered by bradykinin B2 receptor activation.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Benzamides; Bradykinin; Decanoic Acids; Hemodynamics; Hydroxy Acids; Male; Myocardial Infarction; Organ Size; Potassium Channels; Rabbits; Receptor, Bradykinin B2; Receptors, Bradykinin