dihydropyridines and Arrhythmias--Cardiac

GROUPS OF CALCIUM CHANNEL BLOCKERS: The calcium channel blockers comprise a heterogeneous group of drugs. From both pharmacological and clinical points of view, they can be divided into three groups: the dihydropyridines, the phenylalkylamines and the benzothiazepines. REASONS FOR DIFFERENCES: There are important clinical and functional differences between the three groups. This may be explained by the fact that these families bind at different sites to the calcium channel. In this review, the major differences between the three groups are discussed, with an emphasis on verapamil.

Topics: Antihypertensive Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Sympathetic Nervous System; Verapamil

The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.. We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.. In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

Topics: Angina Pectoris; Arrhythmias, Cardiac; Calcium Channel Blockers; Confidence Intervals; Coronary Disease; Depression, Chemical; Dihydropyridines; Dose-Response Relationship, Drug; Hemorrhage; Humans; Hypotension; Myocardial Contraction; Myocardial Ischemia; Nifedipine; Odds Ratio; Renin-Angiotensin System; Sympathetic Nervous System; Time Factors

Topics: Aged; Angina Pectoris; Arrhythmias, Cardiac; Dihydropyridines; Electrocardiography; Exercise Test; Humans; Magnetic Resonance Imaging; Male; Myocardial Ischemia; Treatment Outcome; Ventricular Dysfunction

We previously established that furnidipine (FUR) and oxy dihydropyridines prevent rats mortality by strong reduction of the lethal arrhythmias in reperfusion. Therefore we decided to study the influence of three main metabolites (M-2, M-3, M-8) of FUR on ischemia-and reperfusion- induced arrhythmias and hemodynamic parameters in rat model to examine their independent activity. The metabolites (M-2, M-3, M-8) were given orally 20 mg/kg (24 and 1 h before ischemia). Mortality was significantly diminished in M-2 and M-3 treated groups with M-3 preventing animal mortality entirely. All three examined substances significantly reduced the duration and incidence of ventricular fibrillation (VF) with M-3, once again, completely preventing VF. Moreover, only M-3 significantly decreased the duration of ventricular tachycardia but had no influence on their incidence. Through the occlusion and reperfusion periods, M-2 and M-3 were markedly less hypotensive than M-8 and did not influence on heart rate. We conclude that two tested metabolites of FUR, M-3 and M-2 exhibited the most pronounced anti-arrhythmic effect being at the same time the most normotensive and therefore caused the most beneficial effects.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dihydropyridines; Male; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley

Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure.. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice.. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Heart; Heart Failure; Mice, Knockout; Mice, Transgenic; Nitrendipine; Repressor Proteins; Time Factors; Ventricular Function, Left

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels, N-Type; Death, Sudden, Cardiac; Dihydropyridines; Heart; Heart Failure

L-type calcium (Ca(2+)) currents conducted by voltage-gated Ca(2+) channel CaV1.2 initiate excitation-contraction coupling in cardiomyocytes. Upon activation of β-adrenergic receptors, phosphorylation of CaV1.2 channels by cAMP-dependent protein kinase (PKA) increases channel activity, thereby allowing more Ca(2+) entry into the cell, which leads to more forceful contraction. In vitro reconstitution studies and in vivo proteomics analysis have revealed that Ser-1700 is a key site of phosphorylation mediating this effect, but the functional role of this amino acid residue in regulation in vivo has remained uncertain. Here we have studied the regulation of calcium current and cell contraction of cardiomyocytes in vitro and cardiac function and homeostasis in vivo in a mouse line expressing the mutation Ser-1700-Ala in the CaV1.2 channel. We found that preventing phosphorylation at this site decreased the basal L-type CaV1.2 current in both neonatal and adult cardiomyocytes. In addition, the incremental increase elicited by isoproterenol was abolished in neonatal cardiomyocytes and was substantially reduced in young adult myocytes. In contrast, cellular contractility was only moderately reduced compared with wild type, suggesting a greater reserve of contractile function and/or recruitment of compensatory mechanisms. Mutant mice develop cardiac hypertrophy by the age of 3-4 mo, and maximal stress-induced exercise tolerance is reduced, indicating impaired physiological regulation in the fight-or-flight response. Our results demonstrate that phosphorylation at Ser-1700 alone is essential to maintain basal Ca(2+) current and regulation by β-adrenergic activation. As a consequence, blocking PKA phosphorylation at this site impairs cardiovascular physiology in vivo, leading to reduced exercise capacity in the fight-or-flight response and development of cardiac hypertrophy.

Topics: Adaptation, Physiological; Adrenergic beta-Agonists; Amino Acid Substitution; Animals; Arrhythmias, Cardiac; Barium; Calcium; Calcium Channels, L-Type; Cardiomyopathy, Hypertrophic; Casein Kinase II; Dihydropyridines; Exercise Tolerance; Heart Failure; Ion Transport; Isoproterenol; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Molecular; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Phosphorylation; Phosphoserine; Point Mutation; Protein Conformation; Protein Processing, Post-Translational; Receptors, Adrenergic, beta; Signal Transduction; Transfection

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 μg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Topics: Administration, Intravenous; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Dihydropyridines; Heart; Hemodynamics; Male; Nifedipine; Nimodipine; Nisoldipine; Nitrendipine; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

Dihydropyridines are known not only to have antiarrhythmic effects but also to exert a significant cardiac depressive influence. We previously showed that M-2, an active and final metabolite of furnidipine, had cardioprotective effects without the marked cardiac depression seen with this dihydropyridine. We studied the influence of M-2 infusion (10(-7) M) on hemodynamics during low-flow and regional ischemia in the rat working heart. We examined the protection conferred by M-2 infusion (10(-7) M) against effects of veratridine-induced intracellular calcium overload in the Langendorff heart. Additionally, we performed an in vivo study to explore the effects of oral administration of M-2 at different times and doses, in the ischemia- and reperfusion-induced arrhythmias model. M-2 improved coronary flow during low-flow and regional ischemia while favorably maintaining aortic pressure parameters. M-2 provided outstanding protection against deleterious effects of calcium overloading by significantly preventing rise in left ventricular diastolic pressure and decrease in coronary flow. M-2 reduced mortality and incidence and duration of severe arrhythmias while exhibiting differential influence on blood pressure, which depended on dose and time of administration and could suggest its clinical indication. The results of our entire study establish a beneficial cardioprotective role of M-2, which exhibited pleiotropic effects on the ischemic heart by imparting protection in various ways. This combined with good tolerance, long duration of action, low toxicity, and relatively large therapeutic window makes M-2 a promising candidate as a precursor for a new chemical class of cardioprotective drugs.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Heart; Male; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley

Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.. We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.. T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Topics: Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Female; Mibefradil; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Nitrendipine; Nitrophenols; Organophosphorus Compounds; Patch-Clamp Techniques

Cardiac effects of 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), a novel multidrug resistance (MDR) inhibitor, in Langendorff-perfused rat heart have been investigated and compared to that of nifedipine. Nifedipine decreased concentration-dependently (IC50=8.89+/-1.09x10(-8) M) left ventricular pressure leaving unaltered coronary perfusion pressure, whereas DP7 did not affect both parameters. Nifedipine did not modify both QRS and QT intervals of electrocardiogram (ECG). Second-degree atrioventricular block or ventricular rhythm occurred in presence of nifedipine, however, in 4 out of 6 hearts. DP7, up to 30 microM, failed to alter ECG parameters. In conclusion, DP7, may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of cardiac effects.

Topics: Animals; Antineoplastic Agents; Arrhythmias, Cardiac; ATP Binding Cassette Transporter, Subfamily B; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Electrocardiography; Heart; Heart Conduction System; In Vitro Techniques; Male; Nifedipine; Perfusion; Rats; Rats, Sprague-Dawley; Ventricular Function, Left; Ventricular Pressure

Protective effects of acute oral or intravenous doses of furnidipine against ischemia and re-perfusion-induced arrhythmias and creatine kinase release were studied in a rat model for cardiac ischemia and re-perfusion. Transient cardiac ischemia was induced by occluding the left coronary descending artery of anaesthetized rats for 7 min, and re-perfusion period studied was 15 min. Pre-treatment period for oral doses (1, 5 or 10 mg/kg) was 1 h, whereas that for the intravenous ones (1.25, 2.5, 5 or 10 microg/kg) was 10 min. After both routes of administration, significant protective effects of furnidipine on creatine kinase release were observed after the two lowest doses only. In contrast, its higher dosages were more effective in preventing re-perfusion-induced mortality, arrhythmias and hypotensive episodes, and for transiently lowering arterial blood pressure before initiation of ischemia. These observations suggest potential uses of furnidipine for preventing re-perfusion triggered lethal arrhythmias. Efforts to evaluate therapeutic potential of low dose furnidipine as a cardio-protective agent seem warrantable.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Ventricles; Injections, Intravenous; Male; Myocardial Reperfusion Injury; Protective Agents; Rats; Rats, Sprague-Dawley; Survival Rate

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.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Benzopyrans; Blood Gas Analysis; Coronary Disease; Decanoic Acids; Dihydropyridines; Drug Combinations; Hemodynamics; Hydroxy Acids; Male; Myocardial Ischemia; Nicorandil; Potassium Channels; Rabbits; Reperfusion Injury; Survival Rate

Briefly after withdrawal of the (T-type) calcium channel blocker mibefradil from the market, four cases of life-threatening interaction of mibefradil with dihydropyridines were reported. We investigated in vitro whether mibefradil interacts with a dihydropyridine, as described for other non-dihydropyridine compounds. Rat working hearts were used to examine functional interactions between amlodipine and mibefradil. Gallopamil and another T-type-channel blocker, ethosuximide, were included for comparison. Effects of mibefradil, (+)- and (-)-gallopamil on [3H](+)-isradipine binding were studied in membranes from tsA201-cells transfected with alpha(1c)-, alpha(2)delta-, and beta(1a)- or beta(2a)-calcium channel subunits. Mibefradil increased negative inotropic effect of amlodipine, but not of gallopamil. Gallopamil and ethosuximide showed no influence on contractile effects of amlodipine. Furthermore, mibefradil concentration-dependently caused bradycardic rhythm disturbance. The same type of arrhythmia was observed combining low concentrations of mibefradil with amlodipine, or with gallopamil, respectively. Amlodipine alone, or the combination of gallopamil or ethosuximide with amlodipine did not cause any arrhythmia. Binding studies showed a concentration-dependent positive allosteric interaction between [3H](+)-isradipine and mibefradil, but not with [3H](+)-isradipine and gallopamil enantiomers. Molecular and functional evidence points to an interaction between a dihydropyridine and mibefradil. Mibefradil caused rhythm disturbances and potentiation of negative inotropy when combined with amlodipine.

Topics: Amlodipine; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Line; Cell Membrane; Dihydropyridines; Drug Interactions; Ethosuximide; Female; Gallopamil; Humans; In Vitro Techniques; Isradipine; Male; Mibefradil; Myocardial Contraction; Perfusion; Radioligand Assay; Rats; Rats, Wistar; Ventricular Pressure

During ischaemia and reperfusion increased cytosolic Ca2+ is one of the important causes for ischaemic-reperfusion myocardial injury. In the present study we compared effects of preferentially L-type Ca2+ antagonists nitrendipine (NT) and lacidipine (LP), and of mibefradil (MB) a Ca2+ antagonist with higher affinity to T- than to L-type channels on myocardial function during reperfusion. Coronary flow (CF), heart rate (HR), left ventricular pressure (LVP), lactate dehydrogenase (LDH) release rate and ECG were registered during 40 min of reperfusion following 30 min of global zero flow ischaemia in Langendorff's isolated rat hearts. Either NT (100 nmol/L) or LP (10 nmol/L) or MB (100 nmol/L) was added to Krebs-Henseleit solution 10 min before ischaemia till the end of experiments. All three drugs influenced CF, HR and LVP. All of them decreased LDH release rate (P < 0.05, in microkat/g x min) when compared with control hearts (53.2 +/- 5.1): MB (19.4 +/- 4.3) > LP (30.7 +/- 6.6) > NT (43.3 +/- 2.8). NT reduced the duration of continuous arrhythmias at the beginning of reperfusion (to 59.1 +/- 6.1% of ischaemic controls) as well as the number of single arrhythmic events arising during the whole period of reperfusion (to 26.1 +/- 6.0% of ischaemic controls). MB diminished only single arrhythmic events during reperfusion to 39.1 +/- 17.3% of ischaemic controls. LP did not affect the onset of arrhythmias. Results of our experiments indicate a relatively greater importance of T-type than of L-type Ca2+ channels in the arising of postischaemic myocardial damage.

Topics: Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Coronary Circulation; Dihydropyridines; Female; Heart; Hemodynamics; In Vitro Techniques; Male; Mibefradil; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitrendipine; Pressure; Rats; Rats, Wistar; Reference Values; Ventricular Function, Left

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Agonists; Cardiotonic Agents; Coronary Vessels; Digitalis Glycosides; Dihydropyridines; Dogs; Epinephrine; Female; Heart Ventricles; Hemodynamics; Male; Pyrazines; Pyridazines; Quinolines; Stereoisomerism; Vasoconstrictor Agents; Ventricular Fibrillation

1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; ATP-Binding Cassette Transporters; Benzopyrans; Dihydropyridines; Electrophysiology; Female; Glyburide; Guinea Pigs; Heart Conduction System; Hypoglycemic Agents; In Vitro Techniques; KATP Channels; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying

Clinical and experimental studies demonstrate that calcium (Ca2+) overload in myocardial cells is an important factor in the genesis of various serious arrhythmias. Calcium antagonists block voltage-dependent channels and thus reduce entry of Ca2+ into heart cells. Because of their specificity for atrioventricular nodal cells, verapamil and diltiazem are used clinically to treat supraventricular arrhythmias involving transmission in the atrioventricular node. These two drugs and the dihydropyridine (DHP) calcium antagonists have been shown to prevent ventricular ischemic and reperfusion arrhythmias in the laboratory. Despite these data indicating that calcium antagonists are antiarrhythmic, a recent controversy has raised the possibility that certain calcium antagonists are unsafe to use, especially for patients with coronary heart disease. Proarrhythmia has been proposed to be a mechanism contributing to potentially adverse outcomes. Although excessive concentrations of verapamil and diltiazem may cause sino-atrial nodal asystole and varying degrees of atrioventricular block, there is little direct evidence that this contributes to significant proarrhythmia, for example, ventricular tachyarrhythmias. Nonetheless, although it appears paradoxical that agents which block the entry of Ca2+ into heart cells may be considered arrhythmogenic, there are circumstances under which dosage with certain calcium antagonists potentially leads to myocardial Ca2+ overload. For example, bouts of neurohormonal activation brought about by calcium antagonist-induced abrupt reductions in blood pressure may be accompanied each time by significant beta-adrenergic-enhanced influx of Ca2+ through the L-type cardiac calcium channels. This elevates the intracellular Ca2+ concentration and disturbs Ca2+ regulation, especially in diseased hearts whose intracellular Ca2+ regulation has already been compromised, and might induce alterations in cardiac electrical activity. In the present article, interactions among cardiac calcium channels, classes of calcium antagonists, and specific formulations of certain antagonists are considered with respect to directly induced ventricular arrhythmogenesis. Indirect potentially proarrhythmic actions of the calcium antagonists are also discussed. We outline some of the many questions that remain to be answered with respect to the actions of DHP on the heart including that of whether beta-adrenergic stimulation modifies the degree of cardiac Ca2+ ch

Topics: Arrhythmias, Cardiac; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Heart; Humans; Myocardial Ischemia; Prospective Studies; Risk Factors

Protective effects of cysteine (Cys), N-acetylcysteine (NAC), cysteamine (MEA), cystamine (CSSC) and aminopropylmethylisothiourea (APMT) on ischemia/reperfusion induced arrhythmias were studied in isolated Langendorff perfused rat hearts. The arrhythmias were caused by ligation of the anterior descending branch of the left coronary artery for 10 min and reperfused for 5 min. The drugs were dissolved in saline (NS) and perfused through a peristaltic pump system at 0.1, 0.6 or 3.6 mumol/min (n = 10), starting from 10 min before ligation up to 5 min after reperfusion. The control hearts were perfused with NS. The results showed that Cys, NAC and MEA pursued at 0.6-3.6 mumol/min significantly reduced the incidence of ventricular fibrillation (VF), which were 80-90% in control and 0-20% in 3 treated groups, with P less than 0.01-0.001. The duration of ventricular tachycardia (VT) + VF was 3.0 +/- 1.6 min in control and were 0.2 +/- 0.2, 0.2 +/- 0.1 and 1.2 +/- 2.1 min in Cys, NAC and MEA groups, respectively (with P less than 0.01-0.001). Coronary flow (CF) were remarkably reduced to about 50% during ligation in NS, but remained at normal levels in three treated groups. There were no significant protective effects on arrhythmias in CSSC and APMT perfused hearts. CF of CSSC and APMT groups were even less than those of control. The structure-activity analysis suggested that the SH group may play a crucial role in the protective effect of SH compounds on ischemia/reperfusion induced arrhythmias. The mechanism of protection was briefly discussed in this paper.

Topics: Acetylcysteine; Animals; Arrhythmias, Cardiac; Coronary Circulation; Cysteamine; Cysteine; Dihydropyridines; Dimaprit; Female; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Thiourea

Topics: Adult; Arrhythmias, Cardiac; Dihydropyridines; Drug Evaluation; Eligibility Determination; Humans; Male; Reference Values; Vagus Nerve