Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042510 (ventricular fibrillation)
 10,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ro 40-5967 is a new calcium channel antagonist that binds at the same membrane sites as verapamil, yet has minimal negative inotropic effects. The effects of Ro 40-5967 on the susceptibility to ventricular fibrillation were investigated and compared to diltiazem. Ventricular fibrillation (VF) was induced in 40 mongrel dogs with healed myocardial infarctions by a 2-min coronary occlusion during exercise. Twenty-four animals were found to be susceptible to VF and were given the treatments described below. Pretreatment with Ro 40-5967 (n = 17, 1000 micrograms/kg i.v.) significantly (P < 0.001) reduced the incidence of VF (13 of 17 protected) during the exercise plus ischemia test. Diltiazem (n = 8, 1000 micrograms/kg) completely suppressed VF. Lower doses of diltiazem and Ro 40-5967 did not prevent VF. The hemodynamic effects of Ro 40-5967 were also compared to diltiazem and verapamil. Diltiazem and verapamil, but not Ro 40-5967, increased P-R interval in a dose-dependent manner. Even when reflex tachycardia was controlled by beta-adrenoceptor blockade, Ro 40-5967 still exerted only minimal effects on P-R interval. Verapamil, but neither Ro 40-5967 nor diltiazem, provoked a dose-dependent negative inotropic response. All three drugs elicited large increases in coronary blood flow. These data support the hypothesis that calcium entry may play a critical role in the development of malignant arrhythmias during ischemia. Further, Ro 40-5967 can protect against ventricular fibrillation without significant negative inotropic or dromotropic effects.
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PMID:Ro 40-5967, a novel calcium channel antagonist, protects against ventricular fibrillation. 149 May 22

1. We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin-1 (ET-1) in anaesthetized dogs. 2. ET-1, 1, 3 and 10 ng kg-1 i.c., produced dose-related increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET-1, 30, 100 and 300 ng kg-1 i.c., produced dose-related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose-related falls in cardiac output, mean arterial pressure, +dP/dt and -dP/dt and increases in left ventricular end-diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ng kg-1, ET-1 produced a 22% reduction in heart rate. 3. Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 +/- 2 min after 300 ng kg-1 ET-1. 4. The administration of diltiazem (15 micrograms kg-1 min-1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET-1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET-1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg-1 ET-1 by 60% but not the response to 30 or 300 ng kg-1 ET-1. Two out of five diltiazem-treated dogs died of ventricular fibrillation with a mean time to death of 20 min following treatment with ET-1 (300 kg- 1). 5. ET-1 is a very potent coronary vasodilator. At slightly higher doses ET-1 is also a coronary vasoconstrictor. ET-1 also appears to have direct cardiotoxicity independent of myocardial ischaemia. The vasoconstrictor activity and direct cardiotoxicity are only weakly inhibited by diltiazem.
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PMID:The effect of diltiazem on the coronary haemodynamic and cardiac functional effects produced by intracoronary administration of endothelin-1 in the anaesthetized dog. 218 13

The ability of diltiazem to prevent early ischemia and reperfusion-induced arrhythmias was investigated in conscious rats with coronary artery occlusion. During a 30-min period of occlusion of the left coronary artery, 100% of placebo-treated animals exhibited ventricular tachycardia, 65% exhibited ventricular fibrillation and the mean total number of premature ventricular complexes was 1076 +/- 254. Diltiazem (0.5 or 2.0 mg/kg body weight, given intravenously 10 mins prior to coronary occlusion), reduced the incidence of ventricular tachycardia to 62% (P less than 0.01) and 54% (P less than 0.001), respectively and the incidence of ventricular fibrillation to 31% (P = NS) and 15% (P less than 0.01), respectively. The total number of premature ventricular complexes was also reduced to 248 +/- 78 (P = NS) and 156 +/- 55 (P less than 0.02). The development of ST segment elevation, induced by coronary artery occlusion, was delayed in both drug-treated groups. Similarly, diltiazem, at the same doses, reduced the incidence of ventricular fibrillation induced by reperfusion after 5 mins of coronary artery occlusion from 100% to 50% (P less than 0.01) and 25% (P less than 0.001) and mortality from 87% to 42% (P less than 0.02) and 25% (P less than 0.01), respectively. The anti-arrhythmic effects of diltiazem were not related to changes in heart rate and all groups showed similar occluded zone sizes, as measured by a fluorescent microsphere technique. Thus, diltiazem affords substantial protection against both early ischemia-induced ventricular arrhythmias and reperfusion-induced arrhythmias and this action may be associated with the beneficial effects on ischemia-induced ST segment elevation.
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PMID:'Early' ischemia and reperfusion-induced arrhythmias: antiarrhythmic effects of diltiazem in the conscious rat. 335 53

The effects of the calcium entry blockers diltiazem, KB-944 [diethyl 4-(benzothiazol-2-yl)benzylphosphonate] and bepridil on the vulnerability of ischemically injured myocardium toward fibrillation were determined in urethane-anesthetized dogs 4 to 7 days after anterior myocardial infarction. Diltiazem (3.0-30.0 micrograms/kg/min X 30 min), KB-944 (0.3-3.0 mg/kg) and bepridil (1.0-10.0 mg/kg) were administered i.v. to produce equivalent increases in atrioventricular nodal effective and functional refractory periods as a measure of slow calcium channel blockade. At dosages producing equivalent increases in atrioventricular nodal refractoriness, diltiazem and KB-944 failed to increase the electrical current threshold required to produce ventricular fibrillation, whereas bepridil elevated the fibrillation threshold from 4.2 +/- 0.5 mA predrug to 14.7 +/- 2.2 mA postdrug (P less than .01). Increases in atrial (128 +/- 6-185 +/- 29 msec, P less than .01) and ventricular (156 +/- 4-175 +/- 6 msec, P less than .05) refractory periods accompanied the increase in fibrillation threshold with bepridil. These findings suggest that calcium entry blockade per se does not reduce ventricular vulnerability toward fibrillation in the setting of recent myocardial infarction.
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PMID:The effects of calcium entry blockade on the vulnerability of infarcted canine myocardium toward ventricular fibrillation. 349 May 65

The effects of diltiazem on ventricular arrhythmias and ventricular vulnerability for fibrillation, both in the very beginning of myocardial ischemia and in the early stage of myocardial necrosis, were evaluated in 13 mongrel dogs. In part I of the study, repeated coronary occlusions were performed. Time course and extent of ventricular ectopy were continuously recorded, and changes in ventricular fibrillation threshold were assessed, both after coronary artery occlusion and release. In part II, a permanent coronary artery occlusion was performed, and the changes in frequency of ventricular arrhythmias were assessed. Diltiazem displayed strong antiarrhythmic and antifibrillatory effects on early ventricular occlusion arrhythmias. The drop in ventricular fibrillation threshold 5 min after coronary occlusion was significantly attenuated. Following the release of coronary artery obstruction, diltiazem failed to reduce the frequency of ventricular fibrillation immediately after the onset of reperfusion. However, during the early postreperfusion period, the drug was able to accelerate significantly the increase in the ventricular fibrillation threshold. Late phase ventricular arrhythmias were not influenced by the drug even when high doses were applied. The different antiarrhythmic actions of diltiazem on early and late phase ventricular arrhythmias can be assumed to be due to differences in the arrhythmogenesis at the very onset of myocardial ischemia compared to the stage of myocardial necrosis.
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PMID:Antiarrhythmic and antifibrillatory action of diltiazem on early and late phase ventricular arrhythmias following coronary artery occlusion and on reperfusion ventricular arrhythmias. 373 71

The potential role of calcium entry blockers in the prevention of life-threatening arrhythmias associated with acute myocardial ischemia and reperfusion is still controversial. In 98 anesthetized cats, the effect of diltiazem was examined in two experimental models. In protocol I, ventricular tachycardia or fibrillation was consistently induced by the interaction between a 2 minute coronary artery occlusion and a 30 second left stellate ganglion stimulation. After three trials under control conditions, if the same pattern of arrhythmia was induced, the drug under study was administered and three additional trials were performed. In 16 animals the administration of saline solution did not modify the pattern of arrhythmias. In contrast, diltiazem (0.1 mg/kg body weight plus 0.2 mg/kg per h) abolished both ventricular tachycardia and fibrillation that had occurred in 64 and 36%, respectively, of the cats in the control state. In protocol II, a 20 minute coronary artery occlusion was released in three groups; one served as the control group, one received diltiazem 15 minutes before occlusion and one received diltiazem 3 minutes before reperfusion. The incidence of reperfusion ventricular fibrillation was 62% (16 of 26) in the control group. It was significantly (p less than 0.05) reduced by diltiazem administered before the occlusion to 25% (4 of 16), whereas it was not affected when diltiazem was administered just before reperfusion (7 [47%] of 15). These results indicate that diltiazem exerts a striking protective effect against the malignant arrhythmias induced by the combination of acute myocardial ischemia and sympathetic hyperactivity. Diltiazem was also effective in reducing the incidence of life-threatening reperfusion arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy of diltiazem in two experimental feline models of sudden cardiac death. 374 14

The effect of diltiazem was studied in a new model of myocardial ischaemia in which in addition to a critical constriction of the left circumflex branch (LCX), the left anterior descending coronary artery (LAD) was suddenly occluded. This model is probably more relevant to the clinical situation in which multivessel coronary artery disease is common. In this model diltiazem exerted a beneficial effect, manifested by an increase in myocardial blood flow (MBF) within the stenosed area of the LCX; by a marked reduction of the enhanced preload (LVEDP); by a diminution of the inhomogeneity of electrical activation and by a decrease in ST-segment elevation. Diltiazem also caused a significant reduction both in the number of extrasystoles and in the incidence of ventricular fibrillation. Increased MBF within the stenosed area was associated with enhanced blood flow to the ischaemic myocardium, i.e. diltiazem directed flow to the ischaemic zone by improvement of the collateral circulation. The beneficial electrophysiological changes caused by diltiazem are probably at least partly due to the drug-induced improvement of myocardial blood supply to the ischaemic area.
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PMID:Importance of myocardial blood flow changes in the protective action of diltiazem in a new model of myocardial ischaemia. 405 33

Calcium channel blockade appears to be at least as effective as beta-blockade in the treatment of anginal syndromes, but whether a similar protective effect is afforded against sudden death is unknown. In order to compare experimental antifibrillatory effects of calcium channel blockade (diltiazem), beta-adrenoceptor blockade (timolol), and nitroglycerin, we measured ventricular fibrillation (VF) thresholds in anesthetized, open-chest dogs before and after 3 min of coronary ischemia before and after i.v. administration of each of these drugs or saline. In control studies, VF occurred after delivery of 11.8 +/- 5.3 mA (X +/- SD) in the nonischemic state and 9.4 +/- 4.6 mA during ischemia (n = 25). During saline administration, no significant change in VF threshold occurred during ischemia, and a minimal increase over time occurred in the nonischemic state. Diltiazem (0.04-0.08 mg/kg/min; n = 10) increased VF thresholds under both ischemic (by 7.7 mA, p less than .01) and nonischemic (by 5.5-5.8 mA, p less than .05) conditions. Timolol (0.03 mg/kg; n = 8) caused substantially greater increases in VFT during nonischemia and ischemia: 11.2 +/- 2.8 mA to 51.6 +/- 38.5 mA (nonischemia) and 8.4 +/- 3.8 mA to 28.7 +/- 16.4 mA (ischemia), both p less than 0.02. VF thresholds were not changed after nitroglycerin (n = 8). Differing experimental effects of these drugs emphasize the need for clinical studies to establish the relative potential of calcium channel blockade and nitroglycerin to reduce mortality in ischemic heart disease.
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PMID:Experimental antifibrillatory effects of calcium channel blockade with diltiazem: comparison with beta-blockade and nitroglycerin. 620 80

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.
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PMID:Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog. 669 97

The antidysrhythmic and antifibrillatory actions of the calcium entry blocker diltiazem were examined in three experimental canine models: 1) ventricular fibrillation thresholds in the anesthetized dog; 2) programmed electrical stimulation in the conscious dog during the subacute phase of myocardial infarction; and 3) a conscious canine model of sudden coronary death wherein ventricular fibrillation was produced by acute myocardial ischemia in the presence of previous anterior myocardial infarction. Diltiazem administration failed to alter ventricular fibrillation thresholds determined under normal physiologic conditions and during acute occlusion of the distal left anterior descending coronary artery. Diltiazem did not prevent ventricular tachyarrhythmias produced by programmed electrical stimulation in the subacute phase of myocardial infarction. The coupling intervals of premature beats producing ventricular tachycardia and the cycle length of the ventricular tachycardias were unchanged by diltiazem administration. In a conscious canine model of sudden coronary death, left circumflex coronary artery thrombosis was produced in the presence of previous anterior myocardial infarction. Acute myocardial ischemia as evidenced by ST-segment changes in saline-treated animals (145 +/- 26 min) was followed by the development of premature ventricular beats (150 +/- 27 min) and ventricular tachycardia (154 +/- 26 min). Ventricular fibrillation occurred in 9 of 10 animals at 156 +/- 28 min. Diltiazem administration did not affect the time to development of ST-segment changes (196 +/- 38 min), premature ventricular beats (202 +/- 37 min) or ventricular tachycardia (209 +/- 37 min). Although the development of ventricular fibrillation was not prevented by diltiazem (9 of 10 animals developed ventricular fibrillation), the time to onset of the fatal arrhythmia was delayed significantly (P less than .01). These data fail to suggest a protective action for the calcium entry blocker diltiazem.
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PMID:Effects of diltiazem upon experimental ventricular dysrhythmias. 683 74


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