hmr-1098 and Arrhythmias--Cardiac

The mechanisms responsible for anti-arrhythmic protection during ischemia-reperfusion (IR) in exercised hearts are not fully understood. The purpose of this investigation was to examine whether the ATP-sensitive potassium channels in the mitochondria (mito K(ATP)) and sarcolemma (sarc K(ATP)) provide anti-arrhythmic protection in exercised hearts during IR. Male Sprague-Dawley rats were randomly assigned to cardioprotective treadmill exercise or sedentary conditions before IR (I = 20 min, R = 30 min) in vivo. Subsets of exercised animals received pharmacological inhibitors for mito K(ATP) (5-hydroxydecanoate) or sarc K(ATP) (HMR1098) before IR. Blinded analysis of digital ECG tracings revealed that mito K(ATP) inhibition blunted the anti-arrhythmic effects of exercise, while sarc K(ATP) inhibition did not. Endogenous antioxidant enzyme activities for total, CuZn, and Mn superoxide dismutase, catalase, and glutathione peroxidase from ischemic and perfused ventricular tissue were not mitigated by IR, although oxidative stress was elevated in sedentary and mito K(ATP)-inhibited hearts from exercised animals. These findings suggest that the mito K(ATP) channel provides anti-arrhythmic protection as part of exercise-mediated cardioprotection against IR. Furthermore, these data suggest that the observed anti-arrhythmic protection may be associated with preservation of redox balance in exercised hearts.

Topics: Animals; Arrhythmias, Cardiac; Benzamides; Catalase; Decanoic Acids; Disease Models, Animal; Electrocardiography; Glutathione Peroxidase; Hydroxy Acids; KATP Channels; Male; Mitochondria, Heart; Myocardial Reperfusion Injury; Myocardium; Oxidation-Reduction; Oxidative Stress; Physical Exertion; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Sarcolemma; Superoxide Dismutase

this study was performed to assess the effect of selective sarcolemmal adenosine triphosphate (ATP)-sensitive K(+) channel (K(ATP)) inhibition and the mitochondrial K(ATP) channel activation on ischemia and reperfusion (I/R)-induced arrhythmias in different gender of rats. We compared the effect of a selective sarcolemmal K(ATP) channel blocker HMR 1098, a selective mitochondrial K(ATP) channel opener diazoxide, a nonselective K(ATP) channel opener pinacidil, and the combination of pinacidil with HMR 1098 on the incidence and duration of ventricular arrhythmias in 2 groups: anesthetized males (n = 31) and females (n = 31).. ischemia and reperfusion was produced by occluding the left main coronary artery of Sprague-Dowley rats for 6 minutes followed by re-opening of the artery for 6 minutes.. the arrhythmia score and the duration of arrhythmias were significantly reduced by HMR 1098, diazoxide, and pinacidil in male rats. The combination of the pinacidil with HMR 1098 did not change the antiarrhythmic effect of pinacidil. The duration of arrhythmas was shorter in females than that in the corresponding males. Drug treatments were not effective in decreasing arrhythmias in female groups to the same extent as in the male group. However, the mitochondrial K( ATP) channel activation that is provided by the combination of pinacidil with HMR 1098 significantly decreased the total length of arrhythmias in females.. results of the current study indicate that both mitochondrial K(ATP) channel activation and sarcolemmal K(ATP) channel inhibition exert antiarrhythmic action in male rats. The antiarrhythmic effect of pinacidil is not depend on the sarcolemmal K(ATP) channel opening. These results also indicate that K(ATP) channel modulators show no discernable effect in female rats due to the already low incidence of arrhythmias in females.

Topics: Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Benzamides; Diazoxide; Female; KATP Channels; Male; Myocardial Reperfusion Injury; Pinacidil; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Sarcolemma; Sex Characteristics

Activation of ATP-sensitive K+ channels (K ATP) during ischemia leads to arrhythmias and blockade of these channels exert antiarrhythmic action. In this study, we investigated the effects of HMR1098, a sarcolemmal K ATP channel blocker and 5-hydroxydeconoate (5-HD), a mitochondrial K ATP channel blocker on cardiac function and arrhythmias in isolated rat hearts. The hearts were subjected to 30 min coronary occlusion, followed by 30 min reperfusion. In the preischemic period, both HMR 1098 and 5-HD slightly increased coronary perfusion pressure. Coronary occlusion increased the perfusion pressure and decreased the left ventricular developed pressure (LVDP) in both control and drug-treated hearts. However, inhibition of LVDP was greater and recovery of the perfusion pressure was lower in 30 micromol/l HMR1098 and 100 micromol/l 5-HD-treated hearts compared to control (P < 0.05). HMR1098, at 3 micromol/l, but not at 30 micromol/l, significantly reduced the ratio of bigeminis, couplets and salvos (P < 0.05). Ventricular tachycardia and ventricular fibrillation were not prevented by HMR1098, at both concentrations, and with 5-HD (100 micromol/l). These results suggest that blockade of sarcK ATP and mitoK ATP channels exert weak antiarrhythmic action, but reduce the recovery of coronary perfusion and contractile force, implying that both types of K(ATP) channels have beneficial role in the recovery of ischemic rat myocardium.

Topics: Animals; Arrhythmias, Cardiac; Benzamides; Coronary Circulation; Decanoic Acids; Dose-Response Relationship, Drug; Electrocardiography; Heart; Heart Rate; Hydroxy Acids; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Perfusion; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Sarcolemma; Vascular Resistance; Ventricular Function, 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

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

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