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The electrophysiologic effects of intravenously administered almokalant, a new class III antiarrhythmic drug, in 7 isoflurane-anesthetized pigs after low and high dose were investigated. Low-dose almokalant included bolus infusion of 0.05 mumol/kg/min for 5 min followed by a continuous infusion of 0.0025 mumol/kg/min for 40 min. Thereafter, a high dose of 0.2 mumol/kg/min for 5 min and 0.01 mumol/kg/min for 40 min was given. PR, QRS, AH, and HV intervals did not change during almokalant administration. The QT interval increased dose dependently from 337 +/- 17 to 442 +/- 20 ms at high dose (p < 0.05). Atrial refractory periods (AERP) were prolonged dose dependently at a 500-ms pacing cycle length from 178 +/- 15 at baseline to 227 +/- 27 and 253 +/- 23 ms during low- and high-dose almokalant infusion, respectively. For pacing cycle lengths of 400 and 300 ms, these values were 180 +/- 11, 207 +/- 25, and 259 +/- 34 and 157 +/- 12, 193 +/- 21, and 234 +/- 28 ms, respectively. At a pacing cycle length of 500 ms, mean ventricular effective refractory period (VERP) was 270 +/- 25 ms as compared with 306 +/- 24 and 337 +/- 17 during low and high dose, respectively. A similar pattern of VERP changes during both low- and high-dose infusion was noted at the shorter pacing cycle lengths, with an increase from 240 +/- 23 to 274 +/- 22 and 279 +/- 24 ms during a 400-ms cycle length and from 210 +/- 17 to 235 +/- 19 and 234 +/- 21 ms during a 300-ms cycle length. The ratio of the VERP and ventricular monophasic action potential duration (VAPD) did not change significantly. The Wenckebach cycle length increased by 36 +/- 36 and 83 +/- 37 ms with low- and high-dose almokalant infusion, respectively. The percent increase of AERP at pacing cycle lengths of 500, 400, and 300 ms during high-dose almokalant was 42, 44, and 49%, respectively; these increases for VERP were 25, 16, and 11%, respectively. In conclusion, prolongation of refractoriness by almokalant was more pronounced at the atrial than the ventricular level. Prolongation of refractoriness was maintained at short pacing cycle lengths especially in the atrium, indicating absence of reverse-use dependence of almokalant in the porcine heart. The marked atrial effects, paralleled by atrioventricular conduction slowing, and the absence of reverse use-dependence all contribute to the feasibility of use of almokalant, in particular in the treatment of supraventricular tachyarrhythmias.

A prototype steerable 8.5 F bipolar catheter fitted with a feedback thermocouple was tested in 7 anaesthetized pigs (30 kg) guided by the electrocardiogram in order to modify the AV nodal and His-Purkinje system conductive properties. Thermal energy was delivered by a pressurized N2O tank (650 psi) via a cardiac cryo unit (Spembly, Hampshire, UK) into the catheter wherein gas expands resulting in a tip temperature as low as -70 +/- 2 degrees C within 10 seconds. Cryoablation under fluoroscopic and electrocardiographic guidance was applied at distinct sites in both ventricles for 60 or 120 seconds. After a follow-up period of 6 weeks, the ablation lesions found were well demarcated with small margins of hypertrophy of myocardial cells. With respect to lesion volume variability (8-207 mm3) and geometry, a relationship between the 0 degree C isothermic period and cryolesion volume was found. Results of an in vitro model corroborated this relationship. Therefore, an isothermic period probably can predict the lesion size and its geometry in terms of lesion depth. This potential therapeutic mode of transcatheter cryoablation deserves further investigation.

In this randomized, blinded study the effect of the angiotensin converting enzyme inhibitor perindopril on electrical stability after myocardial infarction in pigs was compared to placebo. The left anterior descending artery was occluded for 45 min. Perindoprilat (0.06 mg/kg, n = 12) or saline (n = 12) was injected 15 min before reperfusion. Treatment was continued till day 13 with perindopril (12 mg, once daily) or placebo. At day 14 an electrophysiologic study was performed. The release of creatine phosphokinase did not differ significantly. During the subsequent days, seven of 12 placebo-treated pigs died (six within 24 h), whereas two of the 12 perindopril-treated pigs died (one within 24 h; p less than 0.04). Sustained ventricular tachycardia was inducible in one of five placebo-treated pigs versus three of 10 perindopril-treated survivors (NS). Late potentials had developed in one placebo-treated pig but not in pigs that received perindopril. Characteristics of infarct border zone heterogeneity (percentages of a reference electrode in viable myocardium) such as a dispersion of current thresholds (127 +/- 96 vs. 238 +/- 463% in perindopril-treated pigs, NS) and refractoriness (9.8 +/- 8.4 vs. 11.9 +/- 6.0% in perindopril-treated pigs, NS) were comparable. This treatment with perindopril significantly improved survival while electrical stability was comparable between survivors. The latter indicates that a comparable electrical stability 2 weeks after myocardial infarction is obtained in perindopril-treated pigs at a significantly higher survival rate.

In this study the effect of the angiotensin converting enzyme (ACE) inhibitor captopril on beta-receptor responsiveness was investigated in failing rat hearts after experimental myocardial infarction. Infarcted rats were treated for 8 weeks with either captopril added to the drinking water (100 mg/kg/day; n = 5) or drinking water alone (n = 7). Treatment was started 2-3 days before myocardial infarction. A third group of untreated rats without myocardial infarction served as control (n = 6). At the end of the treatment period the hearts were perfused as described by Langendorff, and a cumulative dose-response curve of isoprenaline was obtained in each heart. In comparison with noninfarcted hearts, the response of heart rate and peak pressure rate (dP/dt) to isoprenaline stimulation was significantly depressed in hearts of infarcted rats. Chronic treatment with captopril significantly attenuated the reduced responsiveness to isoprenaline stimulation. This improved responsiveness in captopril-treated rat hearts might be due to prevention of "down-regulation" of myocardial beta-adrenoceptors. Other factors should also be considered, such as prevention of structural alterations in the noninfarcted myocardium, e.g., myocardial hypertrophy and fibrosis. Differences in infarct size did not play an important role, since infarct size was comparable in both groups of infarcted rats. This partial preservation of beta-adrenergic responsiveness was accompanied by a significant reduction in right ventricular weight and lung weight, suggesting that captopril also improved the signs of heart failure. Therefore, the results of this study indicate that early ACE inhibition in myocardial infarction may be useful in preventing deterioration of cardiac function.

The effects of early reperfusion were studied in closed-chest pigs subjected to either 45 min or 3 hr of regional ischemia. Myocardial enzyme release during early reperfusion and electrophysiological stability after two weeks were assessed. Coronary artery occlusion durations of 3 hr and early reperfusion after 45 min were compared. The creatine phosphokinase levels in the coronary effluent were lower after early reperfusion (p less than 0.001). Moreover, in the early reperfusion group, the coronary sinus catecholamine and purine levels rose to higher values than in the 3 hr group. The plasma levels of catecholamines and the plasma renin activity increased rapidly but transiently at reperfusion in the 45 min group. Both the rate-pressure product and the heart rate were elevated at the end of the reperfusion period (p less than 0.001) in the 45 min group. Survival for two weeks was 3 out of 6 animals in the 3 hr group and 5 out of 8 in the 45 min group. In all but one surviving animal, sustained ventricular tachycardias were inducible by programmed stimulation. Abnormally low QRS amplitudes and delayed potentials were found in the signal-averaged electrocardiogram in the early reperfusion group only. In conclusion, early reperfusion causes a reduction of myocardial tissue damage, but simultaneously, neurohumoral parameters showed a greater activation of the sympathetic nervous system and the renin-angiotensin system apparently causing a deleterious increase in oxygen consumption. Therefore, this injurious component of early reperfusion might prevent the potentially beneficial effects of a reduced tissue damage on survival or late arrhythmias.

In the present study, we evaluated the antiarrhythmic interaction (s) of metoprolol and lidocaine in 16 dogs using the ventricular fibrillation threshold (VFT) method. The right ventricle was stimulated with a 100 Hz train of 12.4 ms pulses delivered after every eighth atrial paced beat at a basic cycle length of 300 ms. Lidocaine dosage was 2 mg/kg followed by a 70 micrograms/kg/min infusion and metoprolol dosage was a 75 micrograms/kg bolus. In Group 1, lidocaine was followed by metoprolol; in Group 2, first lidocaine then metoprolol and again lidocaine were given; and in Group 3, dogs received first metoprolol, then lidocaine, and subsequently metoprolol. Drug dose intervals were 45 min. In Group 1, lidocaine elevated the VFT to 149% +/- 20% and metoprolol to 204% +/- 30% of control, (p less than 0.01). In group 2, the VFT remained elevated after the second lidocaine administration (p less than 0.05 vs. Group 1). In Group 3, the VFT was increased by metoprolol to 227% +/- 30% of control (p less than 0.01). Interestingly, defibrillation induced by the combination of metoprolol and lidocaine occurred after 3.2 +/- 0.5 s in four out of 16 animals (p less than 0.05). This "chemical" defibrillation never occurred when only metoprolol or lidocaine alone was administered. Fibrillation was often more organized in the presence of the combination of metoprolol plus lidocaine, which might relate to the observed defibrillation associated with metoprolol plus lidocaine. In conclusion, the combination of metoprolol and lidocaine has no proarrhythmic effects and may enhance the electrical stability of the ventricles as measured by the VFT method.

4-Aminopyridine (1 mg/kg) restored a 35% fall in arterial blood pressure in rabbits evoked by a verapamil infusion (0.5 mg/kg/min) more effectively than calcium-levulate (approx. 13 mg/kg). However, the lethal dose of verapamil for rabbits (mean: 7.1 mg/kg given by intravenous infusion in 14.3 min) was not affected by 4-aminopyridine pretreatment.

The effects of the angiotensin converting enzyme (ACE) inhibitors captopril, enalapril, HOE 498, and its prodrug on reperfusion arrhythmias after 15 min of coronary ligation were investigated in the isolated rat heart. Drug concentrations were equipotent in their effect on angiotensin I pressor response. Furthermore, the effect of indomethacin on ACE inhibition with captopril was studied. Upon reperfusion, ventricular fibrillation occurred in all untreated hearts, in all prodrug HOE 498-treated hearts (15 micrograms/ml), and in 4 of 6 of the enalapril-treated (8 micrograms/ml) hearts. In contrast, in only 2 of 6 (p less than 0.002) of the HOE 498-treated hearts (15 micrograms/ml) and in none (p less than 0.001) of the captopril-treated hearts (80 micrograms/ml) did ventricular fibrillation occur. A massive purine overflow was observed in untreated hearts upon reperfusion. This overflow was significantly reduced by captopril and HOE 498, whereas enalapril and prodrug HOE 498 had no significant effect. Concomitantly, the pressure-rate index was severely impaired after 30 min of reperfusion in the untreated, enalapril, and prodrug HOE 498 groups (33 +/- 9, 52 +/- 11, and 48 +/- 12% of initial values, respectively), but captopril and HOE 498 significantly reduced the impairment of mechanical function (124 +/- 9% and 98 +/- 9%, respectively). In contrast to enalapril and prodrug HOE 498, captopril and HOE 498 markedly reduced noradrenaline overflow during the first minutes of reperfusion. No angiotensin II was detectable in the coronary effluent of untreated hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventricular arrhythmias (VA) are a major cause of sudden death. Life-threatening VA may be present in a variety of both acute and chronic conditions in which cardiac function is compromised: during acute myocardial infarction and subsequent reperfusion; some weeks after acute myocardial infarction, due to residual damage (scar formation with zones of heterogeneity); and as a consequence of congestive heart failure (CHF) resulting from myocardial infarction, dilated cardiomyopathy, hypertension or other causes. Symptomatic suppression of potentially life-threatening VA is unlikely to decrease mortality, since classical antiarrhythmic drugs have failed, so far, to improve life expectancy. Drugs that influence the underlying causes of CHF seem to have a better chance of reducing mortality. There is evidence that ACE inhibitors may exert beneficial effects on arrhythmogenicity by several mechanisms in these situations. Under acute ischaemic conditions both cellular damage and undue increases in circulating catecholamines and angiotensin II may be prevented. This has been demonstrated in various animal models and confirmatory clinical evidence is emerging. Two week after experimental myocardial infarction, the pig heart is less vulnerable to programmed electrical stimulation when ACE inhibitors are administered. Finally, in CHF a variety of proarrhythmic factors, such as left ventricular dysfunction, raised catecholamine levels and, in particular, decreased potassium concentrations, are influenced beneficially by ACE inhibitors.

The purpose of this study was to investigate the protective effects of captopril at three concentrations (1, 10 and 80 micrograms/ml) against reperfusion injury after 15 min of coronary ligation in the isolated perfused rat heart. During ischemia, the apex displacement (AD) and pressure rate index (PI) decreased markedly and only in the presence of 80 micrograms captopril less reduction of the PI was obtained (p less than 0.05). Upon reperfusion, the AD and PI improved significantly in all captopril treated hearts, depending on the concentration used, whereas the untreated hearts showed a further deterioration (p less than 0.05). Ventricular fibrillation upon reperfusion occurred in 6/6 untreated hearts, but only in 4/6 hearts at 1 microgram/ml, in 2/6 hearts at 10 micrograms/ml and 0/6 hearts at 80 micrograms/ml captopril with a significantly shorter duration (p less than 0.05). In control hearts a marked overflow of purines and norepinephrine was found in the coronary effluent upon reperfusion. In contrast, captopril decreased purine overflow, most at 80 micrograms/ml, and norepinephrine levels were undetectable at all concentrations. These results indicate concentration-dependent protective effects of captopril after local ischemia and reperfusion, already present at therapeutic levels. Reduction of cellular injury and suppression of NE release appear to play an important role in the improvement of mechanical function and the reduction of reperfusion arrhythmias.

The effect of captopril (80 micrograms/ml) on coronary flow in the isolated rat heart was compared with the effects of a non-sulfhydryl-converting enzyme inhibitor, ramipril (15 micrograms/ml), and of a sulfhydryl-containing compound with no converting enzyme-inhibiting properties, glutathione (112 micrograms/ml). Drug concentrations were equipotent in their effect on angiotensin I pressor response and equimolar with respect to the sulfhydryl group. Cyclooxygenase products or their stable metabolites (TXB2, 6-keto-PGF1 alpha and PGE2) were measured in the coronary effluent. Furthermore, the effect of mepacrin (1 microM), indomethacin (1 microM), and FPL 55712 (10 microM) on the changes in coronary flow induced by captopril was studied. Both captopril- and glutathione-treated hearts showed a significant increase in coronary flow already after 5 min treatment. After 60 min treatment, coronary flow was further increased to 185 +/- 9% for captopril-treated hearts and to 210 +/- 11% for glutathione-treated hearts when compared to saline treatment. Ramipril treatment resulted in a slower increase in coronary flow, which was significant after 20 min treatment. After 60 min treatment, this increase was 122 +/- 3% when compared to saline-treated hearts. This effect of ramipril was associated with a significant increase in 6-keto-PGF1 alpha overflow when compared to saline-treated hearts. Captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products. The effect of captopril and glutathione on coronary flow appeared to be dose dependent in an equimolar range. Simultaneous mepacrin treatment diminished the effect of captopril on coronary flow; indomethacin had no effect, and FPL 55712 potentiated the effect of captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied a group of 17 dogs 4 to 6 years after infarction produced by 2 hr occlusion of the anterior descending coronary artery followed by reperfusion. Dogs in this "late" infarct group were compared with a group of 24 dogs with "early" healed infarcts (2 to 24 weeks old). With signal-averaging techniques body surface potentials were recorded during sinus rhythm. After thoracotomy epicardial electrograms were recorded from 45 standardized sites within the infarcted region and characteristics of selected electrograms were compared with anatomic features of underlying myocardium. Epicardial recordings from the late infarct group demonstrated earlier local activation (p less than .001) and shorter electrogram duration (p less than .001) when compared with recordings from the early infarct group. There was less temporal dispersion of activation and electrogram duration among the 45 sites in dogs with late infarcts as measured by respective coefficients of variance (p = .007 and less than .001). With programmed stimulation six dogs in the late and eight in the early infarct group exhibited inducible sustained ventricular tachycardia. Mean cycle length of the tachycardia in dogs with late infarcts was significantly shorter (p = .035). Late potentials were notably less prominent in dogs in the late infarct group with ventricular tachycardia than in dogs in the early infarct group. Fewer abnormal electrophysiologic characteristics of late infarcts coincided with relatively less scar in the underlying myocardium. Moreover, the strength of electrophysiologic-anatomic correlations differed in late as opposed to early infarcts. The latter findings suggest long-term evolution of infarct anatomy. We conclude that a substrate for reentrant tachycardia is present in dogs 4 to 6 years after reperfused infarction. Conduction characteristics are less abnormal in these late healed infarcts and are associated with a shorter ventricular tachycardia cycle length and less pronounced late potentials on the body surface.

The effects of captopril and zofenoprilate (the active form of the prodrug zofenopril and also a sulfhydryl-containing angiotension converting-enzyme inhibitor) on coronary flow in the isolated rat heart were compared with the effects of a nonsulfhydryl converting-enzyme inhibitor, ramiprilate (the active form of the prodrug ramipril) and of sulfhydryl-containing compounds with no converting-enzyme inhibiting properties such as glutathione, cysteine, and the (R,S)-isomer of captopril. Drug concentrations of the angiotensin converting-enzyme inhibitors were equipotent in their effect on angiotensin I pressor response. Concentrations of the other compounds were equimolar with respect to the sulfhydryl group. Hearts treated with captopril, its isomer, zofenoprilate, cysteine, and glutathione showed significant increases in coronary flow by 5 min of perfusion. In contrast, ramiprilate treatment resulted in a slower increase in coronary flow that was only significant after 20 min of perfusion. The effect of ramiprilate was associated with a significant increase in 6-keto-prostaglandin (PG) F1 alpha overflow in the coronary effluent compared with that in saline-treated hearts, whereas captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products 6-keto-PGF1 alpha, thromboxane B2, and PGE2. The effects of captopril, zofenoprilate, and glutathione on coronary flow were dose dependent. These results corroborate the view that ramiprilate enhances coronary flow by affecting prostacyclin synthesis, mediated by an increase of endogenous bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)