Effects of sotalol, (-)-propranolol and prazosin on reperfusion-induced arrhythmias and increased cardiac norepinephrine release

The pharmacological actions of sotalol, (-)-propranolol and prazosin on norepinephrine (NE) concentration and creatine kinase (CK) activity in the coronary sinus blood of the ischemic heart were studied in open-chest dogs. A 60 min occlusion of the left anterior descending coronary artery was followed by a reperfusion period of 30 min. In saline-treated dogs, a significant increase in coronary sinus NE concentration occurring 30 s after the onset of reperfusion was followed by a rapid decrease to the initial value within 15 min. CK activity increased gradually and continuously starting 5 min after the beginning of reperfusion. A good correlation (r = 0.9, n = 8, P less than 0.05) was obtained in saline-treated dogs when the calculated slope of the time-activity curves for CK release was plotted against the corresponding peak concentration of NE. The increase in coronary sinus NE concentration upon reperfusion was accompanied by an increased arrhythmic ratio. Sotalol (5 mg/kg i.v.) diminished the increase in coronary sinus NE concentration along with a significant decrease in the arrhythmic ratio. The administration of either (-)-propranolol (0.1 mg/kg i.v.) or prazosin (1 mg/kg i.v.) did not significantly affect the increase in coronary sinus NE concentration. The arrhythmic ratio was significantly reduced by prazosin but not by (-)-propranolol. The rise in coronary sinus CK activity was significantly diminished in the presence of either sotalol, (-)-propranolol or prazosin. These results suggest that the occurrence of severe ventricular arrhythmias upon reperfusion may be related to the action of the increased myocardial NE on the cardiac alpha-adrenoceptors. The increased coronary sinus CK activity suggests that increased cardiac sympathetic activation may accelerate or aggravate the myocardial damage. We conclude that the antiarrythmic effect of sotalol may be due at least in part to its inhibitory action on the release of cardiac NE upon reperfusion.     

Electrophysiological actions of amrinone in dogs with cardiac lesions

We examined the actions of amrinone in five models using dogs to determine under what circumstances intravenous amrinone might exert arrhythmogenic or antiarrhythmic properties. In dogs with 24-h post-coronary artery ligation arrhythmias, amrinone, given at incrementally increasing doses of 1.5, 3.0, and 6.0 mg/kg at 30-min intervals, produced significant increases of cardiac contractility without altering the severity of the arrhythmia. In dogs with 2- to 6-day-old ischemic lesions and 90-100% sinus beats, a bolus dose of 3.0 mg/kg amrinone was followed by an increased incidence of abnormal beats (p = 0.013); neither 1.5 nor 6.0 mg/kg caused a significant incidence of arrhythmias. Acute occlusion of the left anterior descending coronary artery followed by reperfusion caused fibrillation in nine of 15 control dogs and two of 14 dogs treated with 2.3 mg/kg amrinone. This difference was significant at the level p less than 0.05. In ouabain-intoxicated dogs, amrinone at 1.0 and 3.0 mg/kg neither worsened nor improved the arrhythmias. In the atrial circus flutter arrhythmia, amrinone increased ventricular heart rate by a significantly greater amount than it increased atrial rate, suggesting that amrinone facilitates atrioventricular conduction.     

Epicardial controlled-release verapamil prevents ventricular tachycardia episodes induced by acute ischemia in a canine model.

Sustained-release preparations composed of verapamil-polymeric controlled-release matrices were characterized in vitro and utilized as epicardial implants in dogs with ischemic ventricular arrhythmias. Anesthetized open-chest dogs were subjected to 5 hourly, 10-min complete occlusions of the left anterior descending coronary artery followed by reperfusion. A controlled-release matrix preparation (20% verapamil, 80% polyurethane), placed on the left ventricular epicardium prior to the third occlusion, resulted in successful inhibition of ventricular tachycardia (VT) during acute ischemia in a dose-dependent manner. The largest matrix size used, 300 mg (20% verapamil), provided a net systemic dose of 0.52 +/- 0.18 mg/kg over 140 min and significantly reduced VT episodes during acute ischemia (fifth occlusion) compared to untreated controls (0.16 +/- 0.04 vs. 1.01 +/- 0.35 episodes/min, respectively; t = 2.62, p = 0.01). In controls, by the fifth occlusion ventricular fibrillation (VF) occurred after 5.41 +/- 0.78 min in 89% of animals. However, after a 300-mg verapamil matrix was placed on the left ventricular ischemic zone, VF occurred in only 45% (chi-squared = 4.1, p = 0.04, vs. controls) of the animals after 7.87 +/- 0.92 min (fifth occlusion). Systemic venous plasma verapamil levels during the 2 h following the 300-mg matrix ischemic zone implantation ranged from 8.4-22.0 ng/ml, while simultaneous regional coronary venous levels were 125.0-387.0 ng/ml. Sonomicrometry studies of left ventricular wall thickening carried out with a series of 300-mg verapamil matrix cardiac implants did not demonstrate any significant myocardial dysfunction. It is concluded that controlled-release verapamil, administered directly to the heart, was effective for preventing VT and VF associated with acute coronary ischemia, and that this route of administration was not associated with any significant deterioration of cardiac function.     

Human atrial natriuretic peptide in aortic and coronary sinus blood during atrial pacing in patients with ischemic heart disease

This study investigated the plasma concentrations of human atrial natriuretic peptide (hANP) of blood samples obtained from the aorta and coronary sinus (CS) in 19 male patients (mean age of 52.8 +/- 2.1 years) with ischemic heart disease before and during atrial pacing. The plasma concentrations of hANP were measured by radioimmunoassay, and the secretion rate of hANP was calculated on the basis of the CS-aorta difference in plasma hANP concentration and the CS flow rate recorded at blood sampling. Before atrial pacing, aortic plasma hANP concentration showed a significant positive correlation with mean pulmonary capillary wedge pressure (r = 0.67, p less than 0.002) or mean pulmonary artery pressure (r = 0.71, p less than 0.001), and a significant negative correlation with left ventricular ejection fraction (r = -0.50, p less than 0.05). During atrial pacing, aortic plasma hANP concentration increased from 67 +/- 13 (SEM) to 151 +/- 33 pg/ml (p less than 0.01), CS plasma hANP concentration from 727 +/- 121 to 1205 +/- 228 pg/ml (p less than 0.01), and the hANP secretion rate from 45.4 +/- 14.8 to 86.8 +/- 28.2 ng/min (p less than 0.05, n = 12). The aortic plasma hANP concentration was significantly correlated with the CS plasma hANP concentration (r = 0.81, p less than 0.001) or the hANP secretion rate (r = 0.70, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of intracoronary lidocaine on ventricular arrhythmia in the infarcted canine heart

The efficacy of intracoronary administration of lidocaine was studied in three groups of dogs with experimental myocardial infarction induced by occlusion of the left anterior descending coronary artery (LAD). Group 1 included 14 anesthetized and group 2, 7 conscious animals to which lidocaine 1.4 micrograms/kg/minute was administered as an intracoronary infusion. Group 3 consisted of 17 anesthetized dogs that received an intracoronary bolus of lidocaine 40 micrograms/kg over 30 seconds. In group 1, lidocaine reduced ventricular arrhythmia by 59 +/- 30% (p less than 0.001), whereas systemic lidocaine achieved a reduction by 61 +/- 37% (p 0.06). In seven dogs, lidocaine blood levels were measured in the great cardiac and femoral veins. At the end of the infusion the drug concentration was 3.4 +/- 2.2 micrograms/ml in the great cardiac and 1.3 +/- 1.1 micrograms/ml in the femoral vein (p less than 0.05). The reduction in ventricular arrhythmia correlated with the great cardiac vein lidocaine concentration (r = 0.70; p less than 0.05), but not with the drug level in the femoral vein (r = 0.06; NS). In group 2, lidocaine was ineffective by both routes of administration. This may have been related to higher sympathetic activity, as suggested by an elevated heart rate in conscious compared to anesthetized animals (186 +/- 6 vs 164 +/- 21 bpm; p 0.0054). In group 3, bolus injections of lidocaine into the LAD reduced ventricular arrhythmia by 66% (p 0.001). We conclude that by perfusing the infarcted zone with lidocaine, a significant antiarrhythmic effect can be achieved with 2% of the systemic dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antifibrillatory actions of d,l-nadolol in a conscious canine model of sudden coronary death

The role of beta-adrenergic receptor blockade in preventing ventricular fibrillation in a conscious canine model of sudden coronary death was examined using d,l-nadolol and the non-beta-adrenergic receptor blocking isomer, d-nadolol. On day 4, after a temporary 90-min occlusion of the left anterior descending coronary artery, an anodal current of 150 microA was applied to the intimal surface of the left circumflex coronary artery. Occlusive or nonocclusive thrombosis of the artery was accompanied by ST-segment changes. In saline-treated animals (n = 15), ST-segment changes were followed by sinus tachycardia and QT-segment prolongation, with development of ventricular premature beats. Ventricular fibrillation developed in 14 animals (93%). Pretreatment with 1 (n = 9) or 8 mg/kg d,l-nadolol (n = 13) did not alter the development of left circumflex coronary artery thrombosis and ischemic ST-segment changes, but decreased the incidence of ventricular fibrillation and increased survival at 24 h (56% and 63%, respectively) (p less than 0.01 versus saline). d,l-Nadolol also attenuated the sinus tachycardia and QT-interval prolongation accompanying acute ischemia. d-Nadolol (1 mg/kg), the non-beta-adrenergic receptor blocking isomer, failed to prevent development of ST-segment changes. Sinus tachycardia and QT-interval prolongation were not prevented, and ventricular fibrillation developed in all eight animals (100%). In animals without previously induced anterior myocardial ischemic injury (n = 10), left circumflex coronary artery thrombosis failed to produce sinus tachycardia and QT-interval prolongation and was associated with a lower incidence of ventricular fibrillation (20%, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Alpha-human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/reperfusion in dogs

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.     

Protective effect of a novel thromboxane antagonist, BAY-U3405, on canine myocardial damage after coronary artery occlusion and reperfusion

The effects of a novel thromboxane antagonist, (3R)-3-(4-fluorophenylsulfonmido)-1,2,3,4-tetrahydro-9-carbazol epropanoic acid (BAY-U3405), on myocardial damage due to ischemia and reperfusion (added to accelerate the initiated injury) were studied in anesthetized dogs. The left anterior descending (LAD) coronary artery was occluded for 6 hours and reperfused for 30 minutes. BAY-U3405, 1 mg/kg, was injected intravenously 15 minutes after LAD occlusion, followed by continuous infusion of 10 mg/kg/hour starting at 30 minutes after occlusion. The drug had no hemodynamic effects. During the experiments 6 of 14 animals died of ventricular fibrillation (VF) in the placebo-vehicle controls (3 during occlusion and 3 during reperfusion); in the drug-treated group 5 of 13 dogs died of VF (all during occlusion none during reperfusion). This difference in total mortality and cause was not statistically significant. Reperfusion arrhythmias were largely suppressed by BAY-U3405: 201 +/- 43 versus 689 +/- 98 irregular beats during 30 minutes (p less than 0.001) in the experimental and control groups, respectively. Coronary collateral flow, obtained from a load-line analysis by measurement of retrograde coronary flow, and collateral index were similar in both groups. Therefore, BAY-U3405 did not alter collateral blood supply to the ischemic myocardium. Infarct size, determined with tetrazolium staining, was reduced by 65% (p less than 0.01) after its administration. These results suggest that thromboxane antagonism by BAY-U3405 may delay infarct expansion and reduce the frequency of ventricular arrhythmias during reperfusion of previously ischemic myocardium.     

Beneficial effects of amiodarone pretreatment on early ischemic ventricular arrhythmias relative to infarct size and regional myocardial blood flow in the conscious dog

The effects of chronic pretreatment with amiodarone on ischemic ventricular arrhythmias were evaluated in fully conscious instrumented dogs. In control dogs (n = 14) with large myocardial infarcts, early (first 30 min) ventricular arrhythmias occurred in a bimodal distribution with peaks at 3-5 min and at 12-25 min, with only the former associated with epicardial conduction delay. Ventricular fibrillation occurred equally frequently during each peak of early ventricular arrhythmias. Amiodarone (30 mg/kg daily) for 3-4 weeks had no significant effect (n = 11) on anatomic infarct size (28 +/- 6 vs. 30 +/- 5% of left ventricular weight) nor on collateral blood flow in the center of the infarct (19 +/- 11 vs. 15 +/- 7 ml/min/100 g of tissue) or on the ratio of endocardial/epicardial perfusion (0.23 +/- 0.19 vs. 0.28 +/- 19). Despite significant lengthening of peak epicardial conduction delay (191 +/- 20 to 239 +/- 81 ms, p less than 0.05), the frequency of early ventricular arrhythmias, especially during the second peak of ectopic activity, were markedly attenuated by amiodarone pretreatment, with the extrasystole-free intervals often being as long as 6 h. The incidence of ventricular fibrillation was 9% in the treated animals compared with 29% in the controls. In the control animals, arrhythmias always supervened when epicardial fractionation was significant, and no ectopy-free interval was present in the first 6 h following coronary occlusion. The data indicate that chronic amiodarone pretreatment exerts a beneficial effect on the frequency and severity of such ventricular tachyarrhythmias, with reduction in the incidence of ventricular fibrillation and ectopic activity in the early phases following coronary occlusion.     

Adrenergic influences on ischemic and reperfusion arrhythmias in a canine model with diminished collateral blood flow

To examine the role of adrenergic influences on genesis of ischemic and reperfusion arrhythmias, the left anterior descending coronary artery (LAD) was cannulated and perfused by a shunt from the left carotid artery in 38 open-chest pentobarbital-anesthetized dogs. Ischemia was produced by shunt occlusion and retrograde diversion of collateral flow from the LAD. The diverted blood was collected and returned to the animal by intravenous (i.v.) injection. The shunt was opened and the ischemic myocardium reperfused after 30 min of ischemia. Microsphere injections in six dogs during shunt occlusion and retrograde bleeding showed that blood flow to the ischemic zone was less than 1.5% of normal zone flow. The remaining 32 dogs were randomized into four treatment groups. Dogs (n = 8) were treated before shunt occlusion with either saline, nadolol (1 mg/kg), prazosin (0.2 mg/kg), or bilateral stellate transection. As compared with saline treatment, nadolol and stellate transection significantly reduced heart rate (HR), and prazosin significantly reduced mean arterial blood pressure (MAP) (p less than 0.05). However, none of the antiadrenergic interventions significantly reduced the number or frequency of ectopic beats during either the 1a or 1b phases of ischemia. None of the 32 dogs developed ventricular fibrillation (VF) during ischemia, but all dogs fibrillated within 30 s of reperfusion. The size of the ischemic zone ranged from 21 to 38% of the left ventricle, and there were no differences among the four treatment groups. The results suggest that when ischemia is severe, the adrenergic nervous system does not play a significant role in genesis of ischemic-induced ectopy or reperfusion-induced VF.     

Effects of disopyramide on reperfusion arrhythmias in dogs

We tested the effect of disopyramide on reperfusion arrhythmias in mongrel dogs. The control group consisted of 27 dogs. Twenty-nine dogs received two intravenous doses of disopyramide (total: 5.3 mg/kg) before and during the occlusion of the left anterior descending coronary artery. The blood levels of disopyramide averaged 3.95 +/- 0.95 micrograms/ml and 5.9 +/- 1.1 micrograms/ml, 2.5 and 9.5 min after the ligation. The incidence of reperfusion arrhythmias was significantly (p less than 0.05) lower in the treated group (7.5%) than in the control group (33.3%). Disopyramide also lowered the incidence of arrhythmias during the occlusion period (14% vs. 52%, p less than 0.01). Both groups showed a correlation between the incidence of arrhythmias during the occlusion period and on reperfusion.     

Effects of dantrolene sodium on occlusion and reperfusion arrhythmias in the canine heart

The effects of dantrolene sodium on occlusion and reperfusion ventricular arrhythmias (VA) were studied in a canine model. Transient ischemia was induced by a 10 min occlusion period of the left anterior descending coronary artery in 27 control dogs and 32 dogs pretreated with dantrolene sodium (2.5 mg/kg). In the control group, 14 (52%) dogs experienced VA during occlusion. Five of these had ventricular fibrillation, 3 of which were fatal. Eight of 24 control dogs which reached reperfusion experienced ventricular fibrillation during the first 30 sec of reperfusion. Dantrolene sodium did not lower the frequency of VA during occlusion 22/32 (69%). Moreover, the incidence of fatal ventricular fibrillation during occlusion was significantly (p less than 0.025) higher in the drug treated-group (12/32; 37.5%) than in the control group (3/27; 11%). Dantrolene sodium also significantly reduced the time that lasted from the commencement of occlusion to the appearance of ventricular fibrillation (240 +/- 1 sec versus 166 +/- 9 seconds, control and drug group, respectively p less than 0.05) without significantly altering either heart rate or blood pressure (169 +/- 4 b.p.m., and 170 +/- b.p.m.; 101 +/- 10 mmHg and 104 +/- 9 mmHg, before and after dantrolene sodium, respectively). These results indicate that dantrolene sodium might have an arrhythmogenic effect in the ischemic canine heart.     

Pacing-induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase.

1. Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion-induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide. 2. Twenty-two dogs were paced (4 x 5 min periods at 220 beats min(-1)) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg(-1) i.v.), 0.5 h prior to coronary artery occlusion. Sham-operated non-paced dogs with and without aminoguanidine treatment served as controls. 3. Pacing markedly (P<0. 05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia-reperfusion insult 62%) compared to control, sham-operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia-reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min(-1). 4. These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.     

Myocardial salvage by a novel thromboxane A2 synthetase inhibitor in a canine coronary occlusion-reperfusion model

The effects of the new thromboxane A2 (TXA2) synthetase inhibitor sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene)carboxylate (RS-5186), 10 mg/kg i.v., on infarct size, polymorphonuclear leukocytes (PMNs) infiltration, gross myocardial hemorrhage and ventricular arrhythmias were studied using a canine coronary occlusion (2 h)-reperfusion (5 h) model. Infarct size (IS) and risk area (RA) were determined by a dual staining technique. 60 min before coronary occlusion dogs were randomly assigned to either the RS-5186 treated group (n = 11) or the control group (n = 15). RS-5186 reduced infarct size (RS-5186: 26.3 +/- 2.4% of RA (mean +/- SEM) vs control: 50.7 +/- 5.9%, p less than 0.01), and also reduced the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of IS vs control: 22.4 +/- 4.0%, p less than 0.01). The drug also decreased the intensity of PMNs infiltration into the infarcted area (p less than 0.05). However, RS-5186 had no significant influence on the incidence of ventricular arrhythmias. These results suggest that the new thromboxane A2 synthetase inhibitor RS-5186 might be useful in salvaging ischemic myocardium.     

Antiarrhythmic actions of left stellectomy in digitalis-mediated malignant ventricular arrhythmias in the postinfarcted canine heart

Recently, this laboratory has demonstrated an enhanced susceptibility toward the development of ischemia-related lethal ventricular arrhythmias in the presence of therapeutic serum concentrations of digoxin in conscious dogs after myocardial infarction. The present study was performed to assess the effect of the interruption of cardiac sympathetic influences, via subacute left stellate ganglionectomy (LSGX), on digitalis-mediated ischemic ventricular arrhythmias. Commencing 4-5 days after anterior myocardial infarction, 11 dogs with LSGX and 14 sham controls were administered digoxin (0.0125 mg/kg/day i.v.) for 5-7 consecutive days. At baseline testing, programmed ventricular stimulation failed to initiate ventricular tachycardia in any postinfarction dog entered into this evaluation. After treatment, 11/11 digoxin + LSGX (1.33 +/- 0.10 ng/ml serum digoxin) and 14/14 digoxin-treated sham (1.23 +/- 0.14 ng/ml serum digoxin) dogs remained nonresponsive to programmed stimulation testing. The incidence of arrhythmic mortality in response to subsequent ischemia at a site remote from the infarcted anterior region was greater in the digoxin-treated sham group (1.22 +/- 0.21 ng/ml serum digoxin) than in the digoxin + LSGX group (1.33 +/- 0.10 ng/ml serum digoxin); mortality was 6/10 (60%) digoxin sham vs. 1/10 (10%) digoxin + LSGX, p less than 0.005. The underlying anterior myocardial infarct sizes (% of left ventricle: 6.8 +/- 2.3 vs. 6.6 +/- 1.1) did not differ between the digoxin sham and digoxin + LSGX groups. However, the digoxin sham controls developed larger posterolateral myocardial infarctions than did the digoxin + LSGX animals (% of left ventricle: 27.4 +/- 3.0 vs. 16.7 +/- 2.7, p less than 0.05). Norepinephrine concentrations in posterolateral through posteroseptal ventricular sections were not altered by LSGX in a separate group of digoxin-treated postinfarct dogs. The results suggest that left stellate ganglionectomy may reduce the incidence of digitalis-mediated malignant ventricular arrhythmias during ischemia, possibly due to a reduction in the severity of ischemic injury.     

Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg(-1)) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140+/-52 vs 437+/-127% and episodes of ventricular tachycardia 4.0+/-3.2 vs 19.3+/-7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST-segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia-induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.     

可乐定对猫心肌缺血性心律失常的影响

20只猫随机平均分为可乐定用药组及对照组,于左冠状动脉前降枝结扎,造成急性缺血性心律失常模型,预先iv可乐定15μg/kg可明显抑制室性心律失常的发生,减轻心肌超微结构的损伤,并能逆转缺血所致的左室舒张末期压升高,但对左室压力上升速率(LV±dP/dt_(max))无影响。     

Antiarrhythmic effects of flecainide against canine ventricular arrhythmias induced by two-stage coronary ligation and halothane-epinephrine

We studied the electrophysiologic effects of flecainide on noninfarcted and infarcted dog hearts and in dogs anesthetized with halothane and administered intravenous epinephrine. Flecainide demonstrated no effect on atrial conduction times, but significantly (p less than 0.05) increased ventricular conduction times in noninfarcted, infarcted, and halothane-epinephrine-exposed dog hearts. Atrial and ventricular effective refractory periods (ERPs) were significantly (p less than 0.05) increased by flecainide. The increase in ERP was more pronounced in infarcted than in noninfarcted dog hearts. Flecainide significantly (p less than 0.05) decreased the echo zone for two or more repetitive ventricular responses in infarcted dog hearts and eliminated all ventricular arrhythmias observed at 48 h after coronary artery ligation. The dose of epinephrine required to induce ventricular arrhythmias in dogs anesthetized with halothane was significantly increased (p less than 0.05) by flecainide. Acute intravenous administration of flecainide to dogs with infarcted hearts produced sinus arrest, transient third-degree heart block, inability to pace, right bundle branch block, and torsade des pointes. Our results provide evidence that flecainide produces its antiarrhythmic effects by increased ventricular ERP and ventricular conduction time. Caution is advised when administering flecainide to patients with previous history of myocardial infarction.