Effect of a novel thromboxane A2 synthetase inhibitor on ischemia-induced mitochondrial dysfunction in canine hearts

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of antiarrhythmic agents classified as class III group on ischaemia-induced myocardial damage in canine hearts

1. The cardioprotective effects of antiarrhythmic agents classified as class III, amiodarone, sotalol and E-4031, were investigated in anaesthetized dogs. 2. The left anterior descending coronary artery was occluded for 2 h. 3. Heart mitochondria were prepared from both the ischaemic and non-ischaemic areas, and their function was estimated polarographically. 4. Activities of the lysosomal enzymes, N-acetyl-beta-glucosaminidase and beta-glucuronidase, were measured in each fraction. 5. Two hour occlusion induced ventricular arrhythmias, and amiodarone, sotalol and E-4031 greatly suppressed the development of arrhythmias. 6. Amiodarone, sotalol and E-4031 significantly protected mitochondria against ischaemia, and prevented ischaemia-induced leakage of lysosomal enzymes. 7. Antiarrhythmic agents classified as class III show cardioprotective effects, which might participate in their antiarrhythmic effect.     

Mitochondrial K ATP channel activation is important in the antiarrhythmic and cardioprotective effects of non-hypotensive doses of nicorandil and cromakalim during ischemia/reperfusion: a study in an intact anesthetized rabbit model.

The roles of cardiomyocyte sarcolemmal ATP-sensitive K(+) (K(ATP)) and mitochondrial K(ATP) channels in the cardioprotection and antiarrhythmic activity induced by K(ATP) channel openers remain obscure, though the mitochondrial K(ATP) channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers (nicorandil and cromakalim), a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate (5-HD)) and a specific sarcolemmal K(ATP) channel blocker (HMR 1883; (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits.The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n=80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30min. In Group II (n=184), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery.Both in Groups I and II, early intravenous infusion of nicorandil (100 micro g/kg bolus+10 micro g/kg/min), cromakalim (0.2 micro g/kg/min), HMR 1883 (3mg/kg)/nicorandil and HMR 1883 (3mg/kg)/cromakalim just prior to and during ischemia increased survival rate (75%, 67%, 86% and 75% versus 60% in the control subgroup in Group I; 75%, 75%, 75% and 67% versus 50% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or cromakalim at the onset and during reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and cromakalim were abolished by pretreating the rabbits with 5-HD (5mg/kg, i.v. bolus), a selective mitochondrial K(ATP) channel blocker but not by HMR 1883 (3mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and cromakalim.We, therefore, conclude that intervention by intravenous administration of nicorandil and cromakalim (through the selective activation of mitochondrial K(ATP) channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion. The mitochondrial K(ATP) channel may be a potential site of cardioprotection and antiarrhythmic activity.     

Effects of administration of nicorandil or bimakalim prior to and during ischemia or reperfusion on survival rate, ischemia/reperfusion-induced arrhythmias and infarct size in anesthetized rabbits

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and bimakalim), and a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left fourth intercostal space and after pericardiotomy the heart was exposed. In Part I, occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Part II, arrhythmias were induced by reperfusion following a 20-min ligation of the left main coronary artery. In Part I, early intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just prior to and during ischemia increased survival rate (75% and 67% vs. 60% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. In Part II also, early intervention by intravenous infusion of nicorandil (100 microg/kg bolus + 10 microg/kg per min) or bimakalim (3 microg/kg bolus + 0.1 microg/kg per min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or bimakalim at the onset and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and bimakalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker. In conclusion, intervention by intravenous administration of nicorandil and bimakalim (through the activation of mitochondrial KATP channels), increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion.     

Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.     

Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model

Recent evidence suggests that the mitochondrial K(ATP) channels may be involved as a subcellular mediator in cardioprotection afforded by ischemic and pharmacological preconditioning by K(ATP) activators. The present study investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers, nicorandil (NIC) and pinacidil (PIN), and specific blockers of mitochondrial (5-hydroxydecanoate) and sarcolemmal (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methyl-thiourea, HMR 1883) K(ATP) channels prior to and during coronary occlusion and post-ischemic reperfusion on survival rate, ischemia- and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized rabbits. In Group I, myocardial ischemia-induced arrhythmias were provoked by tightening a ligature over the left main coronary artery for 30 min. In Group II, arrhythmias were induced by reperfusion following a 20 min ligation of the same artery. Both in Group I and Group II, early iv administration of NIC (0.47 mg/kg), PIN (0.1 mg/kg), HMR 1883 (3 mg/kg)/NIC and HMR 1883/PIN just prior to and during ischemia increased survival rate (75%, 86%, 75% and 75%, respectively, vs. 55% in the control in Group I; 75%, 75%, 75% and 67%, respectively, vs. 50% in the control in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late iv administration of NIC or PIN just prior to reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects were abolished by pretreating rabbits with 5-hydroxy-decanoate (5 mg/kg, iv bolus). In the present study, higher levels of malondialdehyde and lower levels of reduced glutathione and superoxide dismutase in necrotic zone of myocardium in all subgroups in Group II suggest little anti-free radical property of NIC and PIN. Therefore, it may be assumed that mitochondrial K(ATP) channel opening leads to mitochondrial generation and release of ROS providing for IPC and antiarrhythmic activity. The mitochondrial rather than sarcolemmal K(ATP) channel may represent a potential site of cardioprotection and antiarrhythmic activity.     

Selective mitochondrial K(ATP) channel activation results in antiarrhythmic effect during experimental myocardial ischemia/reperfusion in anesthetized rabbits

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K+ channel (K(ATP)) openers (nicorandil and aprikalim), and a specific mitochondrial K(ATP) channel blocker (5-hydroxydecanoate) prior to and during coronary occlusion as well as prior to and during post-ischemic reperfusion on survival rate, ischemia/reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. Arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery with a releaseable silk ligature. Early intervention by intravenous infusion of nicorandil (100 microg/kg bolus+10 microg/kg/min) or aprikalim (10 microg/kg bolus+0.1 microg/kg/min) just before and during ischemia increased survival rate (86% and 75% vs. 55% in the control group), significantly decreased the incidence and severity of life-threatening arrhythmias and myocardial infarct size. The antiarrhythmic and cardioprotective effects of both nicorandil and aprikalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus). In conclusion, intervention by intravenous administration of nicorandil and aprikalim (through the selective activation of mitochondrial K(ATP) channels) increased survival rate and exhibited antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits when administered prior to and during coronary occlusion.     

Pharmacological preconditioning by levosimendan is mediated by inducible nitric oxide synthase and mitochondrial KATP channel activation in the in vivo anesthetized rabbit heart model

BACKGROUND: Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Levosimendan (LEV) is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. OBJECTIVES AND METHODS: The aim of this investigation was to test whether the administration of LEV has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a manner similar to ischemic preconditioning (IPC) in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n=122) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. RESULTS: Pretreatment with either 1 cycle of IPC, LEV (0.1 micromol/kg, i.v.), or IPC+LEV prior to the period of coronary occlusion offers significant infarct size reduction (21.6+/-1.6%, 22.1+/-2.2%, and 21.4+/-1.4%, respectively vs 38.7+/-3.6% in saline control group; P<0.01) and antiarrhythmic effects. IPC, LEV and IPC+LEV treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13%, 13% and 13%, respectively vs 100% in saline control group; P<0.005) and other arrhythmias (25%, 25% and 13%, respectively vs 100% in saline control group; P<0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD, N(omega)-nitro-L-arginine methyl ester (L-NAME, a nonspecific NOS inhibitor) and the specific iNOS inhibitor 1400 W [N-(-3-(aminomethyl)benzyl) acetamidine] abolished the beneficial effects of IPC, and LEV on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via both the selective activation of cardiomyocyte mitochondrial K(ATP) channels and NO. One cycle of IPC and LEV pretreatment significantly preserved the level of ATP in the 30 min ischemic heart and 120 min reperfused heart. CONCLUSIONS: The present study demonstrates similarities between acute LEV treatment and IPC of the rabbit myocardium in terms of survival, cardioprotection, antiarrhythmic activity, and metabolic status.     

Similarities between ischemic preconditioning and 17beta-estradiol mediated cardiomyocyte KATP channel activation leading to cardioprotective and antiarrhythmic effects during ischemia/reperfusion in the intact rabbit heart

The aims of our present work were to assess whether treatment with either ischemic preconditioning (IPC) or 17beta-estradiol or both combined produce proarrhythmic or antiarrhythmic effects, and whether opening of the sarcolemmal or mitochondrial KATP channels is relatable to this effect; to assess biochemically the effects of IPC and/or 17beta-estradiol on oxidant stress and antioxidant defenses in the myocardium; to examine the effects of nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME) pretreatment in rabbits treated with either IPC or 17beta-estradiol (because 17beta-estradiol evoked NO release has been implicated in KATP activation and IPC); and examine the effects of ischemic preconditioning and 17beta-estradiol on myocardial energy metabolism during ischemia and reperfusion in a well-standardized model of reperfusion arrhythmias in anesthetized adult male New Zealand White rabbits (n = 124) subjected to 30 minutes occlusion of the left coronary artery followed by 120 minutes of reperfusion. Pretreatment with either 17beta-estradiol (10 microg/kg, i.v.) or one cycle of ischemic preconditioning prior to the period of coronary occlusion offers significant infarct size reduction (18.6 +/- 2.2% and 19.4 +/- 1.9%, respectively versus 40.1 +/- 3.9% in saline control and 39.2 +/- 3.2% in vehicle control groups; P < 0.01) and antiarrhythmic effects. Both 17beta-estradiol and ischemic preconditioning treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13% and 13%, respectively versus 100% in saline control and 100% in vehicle control groups; P < 0.001) and other arrhythmias (25% and 25%, respectively versus 100% in saline control and 100% in vehicle control groups; P < 0.001), and were quite effective in increasing the number of animals that survived without developing any arrhythmia during ischemia and reperfusion. 5-hydroxydecanoate(5-HD; 5 mg/kg, i.v.) alone offered no cardioprotective and antiarrhythmic activities. Pretreatment with 5-HD but not HMR 1883 (3 mg/kg, i.v.) abolished the beneficial effects of 17beta-estradiol and ischemia preconditioning on reperfusion-induced arrhythmias and cardioprotection suggesting that such effects have been achieved via the selective activation of cardiomyocyte mitochondrial KATP channels rather than sarcolemmal KATP channels. The reduced reperfusion arrhythmic incidence and durations induced by estrogen was not significantly altered by ICI 182 720 (2.5 mg/kg, i.v.). The lack of effect of ICI 182 720 on antiarrhythmic and infarct-limiting effects of 17beta-estradiol and ischemic preconditioning suggest that these favorable effects are rapid, direct, and non-genomic effects. This study demonstrates similarities between 17beta-estradiol and ischemic preconditioning of the rabbit myocardium in terms of cardioprotection, antiarrhythmic, and metabolic activities. Ischemic preconditioning and 17beta-estradiol appear to share a final common effector; the mitochondrial KATP channel.     

Beneficial effect of nipradilol (K-351) on acute myocardial ischemia. Study of the relationship between regional myocardial blood flow and energy metabolism

To examine the effects of nipradilol on ischemic myocardium, experiments were performed on regional myocardial blood flow (MBF) and energy metabolism in anesthetized, open-chest dogs. Nipradilol at a dose of 0.3 mg/kg was i.v.-administered 10 min after coronary ligation. MBFs at various sites, including ischemic and non-ischemic areas, were determined by the hydrogen gas clearance method. The levels of ATP and creatine phosphate (CP) at the site of MBF determination were measured 60 min after ligation, and mitochondrial function (RCI, QO2) in the ischemic and non-ischemic areas was determined. Following nipradilol administration, aortic pressure and heart rate were significantly lowered. In ischemic areas with MBF below 40 ml/min/100 g, nipradilol had no influence on MBF. However, the tissue level of ATP in nipradilol treated hearts was significantly higher as compared with untreated hearts. In the area of mild ischemia with MBF of 40-60 ml/min/100 g, nipradilol preserved the tissue ATP and CP levels in spite of a decrease in MBF. Moreover, an inhibition of the decrease in mitochondrial respiratory function was observed in ischemic areas with MBF below 20 ml/min/100 g. Thus, nipradilol administered following ischemia preserved ATP content and mitochondrial function in the ischemic myocardium with reduction of heart rate and aortic pressure. This suggests that nipradilol exerts a cardioprotective effect in acute ischemia. It seems that the cardioprotective effect is due to a decrease in myocardial oxygen demand and preservation of mitochondrial function.     

Cibenzoline. A review of its pharmacological properties and therapeutic potential in arrhythmias.

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.     

Pretreatment with a single bolus injection of polyoxyethylene-modified superoxide dismutase prevents reperfusion induced arrhythmias in the anesthetized rat

Effects of a newly introduced polyoxyethylene-modified superoxide dismutase (SOD-POE) on reperfusion induced arrhythmias were examined in the pentobarbital anesthetized rat. Reperfusion induced arrhythmias were elicited by occlusion of the left anterior descending coronary artery (LAD) for 15 min and subsequent release. The LAD occlusion was performed by compressing the artery using a suction cup of 2 mm in diameter placed on the LAD to which negative pressure was applied. The LAD occlusion and release was repeated at an interval of 30 min. SOD-POE or human SOD (h-SOD) (1000 U/kg) was injected intravenously 15 min prior to the occlusion at the second trial of the occlusion. In the control group, various types of arrhythmias including ventricular fibrillation (Vf), ventricular tachycardia (VT), premature ventricular contraction (PVC) and premature atrial contraction (PAC) were elicited immediately after release of the occlusion. In the SOD-POE-treated group, Vf and VT were completely prevented and the numbers of PVC and PAC significantly decreased, while pretreatment with h-SOD did not prevent the occurrence of reperfusion induced arrhythmias. The protective effects of SOD-POE lasted for more than 90-120 min. The plasma half life for SOD-POE was 10.8 hr, while that for h-SOD was 8.6 min. Results indicate that intravenous administration of SOD-POE would provide a new means of preventing reperfusion induced arrhythmias occurring in clinical situations.     

Crossover comparison of cibenzoline and quinidine in ambulatory patients with chronic ventricular arrhythmias

This study was designed to compare the efficacy and safety of cibenzoline and quinidine in ambulatory patients with ventricular arrhythmias. Following washout of previous antiarrhythmic treatment, a 48-h ambulatory electrocardiographic (ECG) recording was obtained. Twenty-seven patients were screened, of whom 20 met the entry criteria of greater than or equal to 30 ventricular premature beats (VPBs)/h. Cibenzoline was started at 130 mg every 12 h and was increased to 160 mg every 12 h if necessary. Quinidine was started at 300 mg every 6 h and was increased to 400 mg every 6 h if necessary. Treatment was assessed by 24-h ambulatory ECG recording. Efficacy was defined as greater than 75% reduction in single VPBs, greater than 90% reduction in paired VPBs, and total abolition of ventricular tachycardia events. A 7-day washout with repeat 24-h ambulatory ECG recording to document return of ventricular arrhythmias was required prior to crossover. Efficacy was documented in 9 of 20 (45%) patients receiving cibenzoline and in 9 of 20 (45%) patients receiving quinidine. Response to cibenzoline 130 mg every 12 h was documented in 8 of 20 (40%) patients and in 1 of 11 (9%) patients receiving cibenzoline 160 mg every 12 h. Response to quinidine 300 mg every 6 h was documented in 8 of 20 (40%) patients and in 2 of 6 (33%) patients receiving 400 mg every 6 h. Dose-limiting side effects occurred in 1 of 20 (5%) patients receiving cibenzoline and in 7 of 20 (35%) patients receiving quinidine. Cibenzoline and quinidine are equal in efficacy, but cibenzoline is significantly better tolerated.     

Inhibition of the Na(+)/H(+) exchanger attenuates phase 1b ischemic arrhythmias and reperfusion-induced ventricular fibrillation

The sodium-hydrogen exchanger-isotype 1 (NHE-1) plays a critical role in myocardial ischemia-reperfusion injury. While studies employing less selective sodium-hydrogen inhibitors have demonstrated antiarrhythmic activity, only one study has examined the in vivo efficacy of selective NHE-1 inhibition in a canine model of ischemia-reperfusion-induced arrhythmia. In the present study, the antiarrhythmic activity of Benzamide, N-(aminoiminomethyl)-4-?4-(2-furanylcarbonyl)-1-piperazinyl -3-(methy lsulfonyl), methanesulfonate (BIIB 513), a novel NHE-1 inhibitor, was examined. An in vivo canine model of myocardial ischemia-reperfusion injury in which 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion was employed. BIIB 513 was infused either prior to ischemia or prior to reperfusion. Arrhythmias were quantified by single lead electrocardiogram. Infarct size, determined by triphenyltetrazolium staining, was expressed as a percent of the area-at-risk. In vivo, NHE-1 inhibition did not affect phase 1a arrhythmias, which occur within the first 10 min of occlusion, however, BIIB 513 significantly reduced the incidence of ischemia-induced phase 1b arrhythmias which occur between 10 and 30 min following occlusion and the incidence of reperfusion-induced ventricular fibrillation. Furthermore, NHE-1 inhibition significantly reduced infarct size, when the drug was administered either prior to ischemia or prior to reperfusion. NHE-1 inhibition selectively reduces both ischemia-induced phase 1b arrhythmias and reperfusion-induced ventricular fibrillation, and also markedly reduces myocardial infarct size when the drug is administered prior to ischemia or prior to reperfusion.     

Ischemia- and reperfusion-induced arrhythmias: beneficial actions of nifedipine

The effects of nifedipine against ischemia- and reperfusion-induced arrhythmias were investigated using anesthetized rats with transient coronary artery occlusion. Nifedipine (5 micrograms/kg i.v.) administered 10 min prior to occlusion significantly decreased the incidence of arrhythmias occurring during 20-min coronary occlusion. The incidence and duration of reperfusion-induced ventricular fibrillation and subsequent mortality following 5-min coronary occlusion were also significantly reduced by this intervention. However, administration of nifedipine 1 min prior to reperfusion afforded no protection against reperfusion arrhythmias. To investigate whether nifedipine possesses a true antiarrhythmic action or merely extends the ischemic duration prior to reperfusion resulting in maximal rhythm disturbances, reperfusion was initiated after 3, 5, 7, 10, 20, and 30 min of ischemia. Nifedipine reduced the incidence of reperfusion-induced ventricular fibrillation after all ischemic intervals, with no change in the time of peak vulnerability to reperfusion arrhythmias. Measurements of coronary flow with 153Gadolinium microspheres indicated that flow within ischemic tissue relative to that in normal tissue was significantly increased by nifedipine. Thus, administration of nifedipine prior to occlusion affords a protective effect against ischemia- and reperfusion-induced arrhythmias, and this action is not due to extension of the ischemic duration prior to reperfusion resulting in maximal rhythm disturbances.     

Electrophysiologic effects of bretylium tosylate on the canine heart during coronary artery occlusion and reperfusion

The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized dogs. Three groups of animals were studied: Group I (n = 8) served as saline controls, Group II (n = 7) received bretylium tosylate (10 mg/kg i.v.) 60 min prior to coronary artery occlusion, and Group III (n = 5) received bretylium tosylate (30 mg/kg i.v.) in three divided doses over the 24 h prior to coronary artery occlusion. In Groups II and III the effective refractory period of the nonischemic myocardium was not altered by bretylium before or during the occlusion period, nor was it influenced by bretylium during the subsequent reperfusion period. In Group I the effective refractory period of the ischemic myocardium decreased 24 +/- 3.0% after coronary occlusion and increased 12 +/- 3% above the preocclusion level on reperfusion. In Group II the effective refractory period of the ischemic myocardium decreased 28 +/- 3.2% after coronary occlusion but did not overshoot preischemic levels on reperfusion. In Group III the effective refractory period decreased 15 +/- 3.8% following coronary occlusion and did not overshoot preocclusion levels during reperfusion. The ventricular activation times of the normal and ischemic myocardium were not affected by bretylium tosylate during occlusion or reperfusion in Group II or III. Significant reperfusion arrhythmias were observed only in Groups I and II. These data suggest that bretylium tosylate exerts its antiarrhythmic actions in ischemic myocardium by reducing the dispersion of cardiac refractoriness produced by coronary artery occlusion and, consequently, abolishing the abrupt change in cardiac refractoriness that follows coronary artery reperfusion. These antiarrhythmic actions of bretylium are pronounced in the chronically treated group, suggesting an electrophysiologic basis of the delayed antiarrhythmic actions of bretylium.     

Effects of SUN-1165, N-(2,6-dimethylphenyl)-8-pyrrolizidine acetamide hydrochloride hemihydrate, a new class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the refractory period in canine myocardial infarction.

Effects of SUN-1165, a class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the effective refractory period (ERP) were examined in a canine model of myocardial infarction and compared with those of lidocaine. The antiarrhythmic effects were examined on the arrhythmias developed 24 h after left anterior descending coronary artery (LAD) ligation and ventricular premature stimulation-induced arrhythmias 5-7 days after LAD ligation. Effects on intraventricular conduction and ERP were also examined in animals 5-7 days after LAD ligation. The intraventricular conduction time (CT) was determined by excitation induced by a ventricular stimulation at various coupling intervals from 200 to 1,000 ms. SUN-1165 (1 and 3 mg/kg) showed a marked reduction in the frequency of ventricular ectopic beats 24 h after LAD ligation and was more potent than lidocaine. SUN-1165 (1 and 3 mg/kg) prolonged CT in the infarcted zones over a wide range of the coupling intervals and produced block of severely delayed conduction. In contrast, lidocaine prolonged CT only at short coupling intervals. Ventricular premature stimulation produced ventricular arrhythmias, which were prevented by pretreatment with SUN-1165 (3 mg/kg). ERP was prolonged by SUN-1165 (3 mg/kg). In conclusion, SUN-1165 showed antiarrhythmic effects in a canine model of myocardial infarction. A selective depression of delayed conduction in the infarcted zone and a prolongation of ERP probably contribute to this antiarrhythmic effect.     

Biotransformation of cibenzoline to 2-(2,2-diphenylcyclopropyl)-1H-imidazole

A microsomal metabolite of cibenzoline, 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole butanedioate, was identified by n.m.r. as the 4,5-dehydro analogue, 2-(2,2-diphenylcyclopropyl)-1H-imidazole. Three dogs dosed orally with 13.8 mg/kg 14C-cibenzoline base excreted 1.8-3.5% of the dose as this metabolite in the urine. Mean plasma concentrations of cibenzoline reached a peak of 1.5 micrograms/ml at 2 h while mean concentrations of the metabolite of 0.4-0.5 micrograms/ml were found between 2 and 7 h. The metabolite was synthesized and found to decrease the frequency of ventricular premature depolarizations in conscious dogs having a two-stage occlusion of the left anterior descending coronary artery performed 48 h before. It did not inhibit ventricular arrhythmia in rats induced by i.v. infusion of aconitine. Thus, in contrast to cibenzoline, the metabolite does not appear to be a true antiarrhythmic agent.     

Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings

Previously, it was shown that antiarrhythmic peptides and our lead substance AAP10 enhance electrical intercellular communication via gap junctions. Now, we wanted to elucidate whether AAP10 acts preferably in the ischemic area and the molecular mechanism of this peptide. Seventeen rabbit hearts were isolated, perfused according to Langendorff, and submitted to 30-min local ischemia by LAD occlusion with/without AAP10 (50 nM). Electrophysiology was assessed by 256 channel epicardial mapping. Finally, the ischemic zone, border zone, and non-ischemic zone were excised, and the cardiac gap junction protein connexin43 (Cx43), its phosphorylation state, and the distribution at the polar and lateral membrane of cardiomyocytes were determined by Western blot and immunofluorescence. Ischemia led to a decrease in activation recovery interval (ARI) homogeneity, which could be completely prevented by AAP10. Moreover, ischemia-induced activation wave slowing in the ischemic border zone was antagonized by AAP10. In ischemic center and border zone, but not in the non-ischemic area, (phospho-Cx43/dephospho-Cx43)-ratio decreased. This was also significantly antagonized by AAP10. Serine 368 was identified as one phosphorylation site for the activity of AAP10. In the non-ischemic area, AAP10 had no influence on Cx43 phosphorylation state. Interestingly, ischemia led to a loss of Cx43 from the cell poles and lateral sides in the ischemic area and border zone. AAP10 completely prevented the ischemia-induced decrease in polar Cx43 presence. In the ischemic area, AAP10 prevents from ischemia-induced Cx43 dephosphorylation and loss of Cx43 from the gap junction at cell poles and in parallel prevents the decrease in ARI homogeneity and attenuates ischemia-induced slowing of activation wave propagation. The AAP10 action seems confined to the ischemic area. Supported by a grant from the Deutsche Forschungsgemeinschaft DFG.     

Myocardial tolerance to arrhythmogenic exposure and pharmacological activation of K(ATP)-channels in rats

The cardioselective KATP channel activator BMS 180448 (3 mg/kg) administered intravenously 15 min before the coronary artery occlusion (10 min) decreased the incidence of ischemic and reperfusion arrhythmias in rats. A similar antiarrhythmic effect was observed when BMS 180448 was infused 2 min before reperfusion. Pretreatment with BMS 180448 also prevented the occurrence of CsCl induced arrhythmias, but but did not affect the incidence of epinephrine induced arrhythmias. On the contrary, BMS 180448 potentiated the arrhythmogenic action of CaCl2. The mechanism of the antiarrhythmic activity of BMS 180448 is discussed.