Comparison of the haemodynamic effects of the selective bradycardic agent UL-FS 49, with those of propranolol during treadmill exercise in dogs.

1. To clarify whether the bradycardic agent UL-FS 49 exhibits a positive inotropic effect even in the absence of improvement in regional myocardial function of an underperfused myocardial area, this study was undertaken in dogs with unimpaired coronary flow. 2. We also investigated the haemodynamic and functional effects of the negative chronotropic and inotropic beta-adrenoceptor blocker propranolol. 3. UL-FS 49 did not depress total or regional myocardial performance. Moreover, an increase in positive left ventricular dp/dt max at rest suggests a positive inotropic effect of UL-FS 49. 4. Propranolol, in contrast to UL-FS 49, led to a marked reduction in positive dp/dt max, stroke volume and systolic wall thickening at rest and during exercise. Additionally, propranolol decreased the exercise values of cardiac output, left ventricular work and left ventricular power to a far greater extent than UL-FS 49. 5. In contrast to propranolol, the selective bradycardic agent UL-FS 49 did not decrease total or regional ventricular performance and caused less reduction in cardiodynamic parameters during exercise. 6. These results suggest that patients with moderate coronary insufficiency or patients with coronary vessel disease and mild left ventricular failure may attain a higher exercise limit under selective bradycardia with UL-FS 49 in comparison to that possible with a beta-adrenoceptor antagonist, such as propranolol.

The effects of nitroglycerin on exercise-induced regional myocardial contractile dysfunction are not diminished by pretreatment with dihydroergotamine.

1 Because controversy exists regarding the effects of dihydroergotamine (DHE) on the performance of underperfused myocardium, the effects of DHE were investigated in a model of exercise-induced regional myocardial dysfunction in conscious dogs. 2 We also investigated a possible functional antagonism between DHE and nitroglycerin that might reduce the latter drug's antianginal efficacy. 3 Investigations were carried out in conscious dogs. After stenosis of the circumflex branch of the left coronary artery that minimally affected resting myocardial function, treadmill exercise induced transient regional contractile dysfunction. Heart rate, arterial blood pressure, left ventricular dp/dtmax and left ventricular end-diastolic pressure were registered. Regional contractile performance was assessed by ultrasonic distance measurement in the underperfused and in a normally perfused area. 4 DHE (5 micrograms kg-1, i.v.) induced a decrease in left ventricular dp/dtmax at rest and during exercise. DHE did not cause a deterioration in contractile function in the ischaemic myocardium, but led to a slight although not significant improvement in regional myocardial function. 5 After pretreatment with DHE, infusion of nitroglycerin (15 micrograms kg-1, i.v.) induced an improvement in the underperfused myocardial area during treadmill exercise, accompanied by a decrease in diastolic arterial pressure and left ventricular end-diastolic pressure and an increase in left ventricular dp/dtmax. 6 These results suggest that DHE will not worsen exercise-induced angina pectoris, and that the antianginal efficacy of nitroglycerin will not be neutralized by pretreatment with DHE.

Antiarrhythmic efficacy of labetalol as assessed by programmed electrical stimulation.

1. The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs. 2. Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg-1 90 min-1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3 mg kg-1 and up to 30 min after 3 mg kg-1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg-1 but was not significantly altered after 1 mg kg-1 labetalol. 3. Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV-conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD-area. With the exception of the alterations in the PQ interval and 2:1 AV-conduction point the effects described above were dose-dependent. 4. Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg-1). 5. The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.

The effects of nitroglycerin on regional myocardial contractile dysfunction produced by treadmill exercise or isoprenaline stimulation in dogs.

1. To compare different methods of cardiac stress testing that are clinically applied in the management of coronary heart disease, 2 groups of dogs each were chronically instrumented and subjected to treadmill exercise or isoprenaline infusion in the presence of coronary stenosis. 2. It was of interest to determine differences in haemodynamic and regional myocardial contractile parameters, the response to antianginal therapy (nitroglycerin 15 micrograms kg-1 15 min-1, i.v.), and, in particular, whether this response differed according to the mode of cardiac stimulation, i.e. treadmill exercise or isoprenaline infusion. 3. After stenosis of the circumflex branch of the left coronary artery which affected resting myocardial function only minimally, treadmill exercise or isoprenaline infusion induced transient regional contractile dysfunction. Heart rate, arterial blood pressure, left ventricular end-diastolic pressure and left ventricular dp/dtmax were registered and myocardial oxygen demand was calculated. Regional contractile performance was assessed by ultrasonic distance measurement in the underperfused and in a normally perfused area. 4. Treadmill exercise led to an increase in systolic arterial and left ventricular end-diastolic pressure. In contrast, isoprenaline-induced stimulation led to a decrease in diastolic arterial and left ventricular end-diastolic pressure. Regional contractile function in the critically underperfused area showed a deterioration during both modes of stress. Nitroglycerin completely abolished stress-induced contractile dysfunction only in the group where treadmill exercise was employed for stimulation. 5. The inability of nitroglycerin to prevent myocardial dysfunction in the isoprenaline group may be due to exhaustion of the arterial and/or venous vasodilator potency of nitroglycerin in the presence of adrenoceptor vasodilatation induced by isoprenaline. 6. These findings indicate that clinical antianginal drug testing and the evaluation of the course of disease in patients with coronary heart disease may be highly dependent on the test method chosen.

Effects of alinidine on exercise-induced regional contractile dysfunction in dogs.

The effects of the bradycardiac agent alinidine on hemodynamic parameters and regional contractile function were investigated in 6 chronically instrumented dogs trained to submit to 5 consecutive treadmill exercise runs. The experiments were performed during stenosis of the circumflex branch of the left coronary artery (LCX). After 2 control runs which had induced regional contractile dysfunction of comparable intensity, alinidine was infused intravenously at a dosage of 1 mg/kg per 5 min. The drug significantly reduced the resting function of both the LCX area (-16%) and the area perfused by the unstenosed anterior descending branch of the left coronary artery (LAD, -3%). However, the exercise-induced dysfunction of the LCX area was markedly improved in the 1st post-drug run and completely abolished during the 2nd and 3rd post-drug runs. As indicated by the reduction of heart rate (-18%) and positive dp/dtmax (-24%) during peak exercise, this improvement may be attributed to a bradycardiac and a negative inotropic effect of this drug. Further benefit may be ascribed to a decreased in arterial blood pressure after alinidine.

Effects of beta-adrenoceptor antagonism upon delayed reperfusion arrhythmias in conscious dogs.

Whereas isolated heart preparations or anesthetized animals have been used to assess the actions of beta-adrenoceptor antagonists upon reperfusion-induced arrhythmias, this study evaluated the possible antiarrhythmic effects of beta-adrenoceptor antagonism in conscious animals. Conscious, chronically instrumented dogs were subjected to a temporary occlusion of the left anterior descending coronary artery for 4 h. After the first hour of reperfusion, flestolol (N-(1,1-dimethyl-2- ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy)-propylamine sulfate), an ultra short-acting beta-adrenoceptor antagonist, was administered i.v. at infusion rates of 1 and 2.6 micrograms/kg per min. A control group received the equivalent volume of saline during this period. Delayed reperfusion-induced arrhythmias were evaluated by using a computerized analysis system. Treatment with flestolol did not affect the total number of beats, the number of normal and ectopic beats, and the arrhythmic ratio, i.e. the ratio of ectopic beats to the total number of beats. Hence, beta-adrenoceptor antagonism does not appear to suppress delayed ectopic activity during coronary reperfusion in conscious dogs.

Can exercise-induced regional contractile dysfunction be prevented by selective bradycardic agents?

Propranolol (0.5 mg X kg-1 X 5 min-1), alinidine (1 mg X kg-1 X 5 min-1) and the benzazepinon UL-FS 49 (0.5 mg X kg-1 X 5 min-1) were investigated in a canine model of exercise-induced transient myocardial dysfunction, mimicking exercise-induced functional impairment during angina pectoris in man. Each drug was infused intravenously, after two control treadmill exercise runs had shown comparable, ultrasonically assessed regional contractile dysfunction in an area supplied by a partly stenosed branch of the left coronary artery. All three drugs abolished exercise-induced regional contractile dysfunction. Propranolol and alinidine comparably decreased heart rate and positive dp/dtmax during exercise. UL-FS 49 showed a marked negative chronotropic effect without affecting positive dp/dtmax. Thus, prevention of exercise-induced regional contractile dysfunction has been shown for the first time using a selective bradycardic agent.

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs.

The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 micrograms/kg/min (i.v.). During 80 micrograms/kg/min lidocaine (mean plasma level 3.5 micrograms/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 micrograms/kg/min and 4 of 8 to 120 micrograms/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p less than 0.05), 67.7 ms (p less than 0.05), 70.0 ms (p less than 0.01) respectively. In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting.

Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction.

As yet the antiarrhythmic efficacy of ajmaline with regard to suppressing the induction of sustained ventricular tachycardia after myocardial infarction has not been determined. Therefore, programmed electrical stimulation was performed in 8 conscious, chronically instrumented mongrel dogs 8-20 days after a 4-hour occlusion of the left anterior descending coronary artery. At baseline all animals responded with sustained ventricular tachycardia. Thereafter, ajmaline was administered at two consecutive i.v. doses: a bolus of 0.7 mg kg-1 followed by infusion of 2 mg kg-1 h-1 and infusion of 4 mg kg-1 h-1. The induction of sustained ventricular tachycardia was prevented in 2/8 animals by 2 mg kg-1 h-1 ajmaline and in 1/8 animals by 4 mg kg-1 h-1 ajmaline. During sinus rhythm only 4 mg kg-1 h-1 ajmaline significantly increased QRS-duration and intraventricular activation times, but during rapid right ventricular pacing (cycle length = 330 ms) both doses of ajmaline increased QRS duration and intraventricular conduction times. 4 mg kg-1 h-1 ajmaline also increased the cycle length of induced sustained ventricular tachycardia. In 3 animals induction of sustained ventricular tachycardia during infusion of 4 mg kg-1 h-1 ajmaline was achieved by introduction of less extrastimuli than at baseline. Furthermore the coupling intervals of extrastimuli that induced sustained ventricular tachycardia were substantially prolonged by this dose. Inhomogeneity of conduction between left ventricular normal zone and left ventricular infarct zone was significantly increased by 4 mg kg-1 h-1 ajmaline during rapid right ventricular pacing, but not during sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the bradycardic agent UL-FS 49 on exercise-induced regional contractile dysfunction in dogs.

The effects of the bradycardic agent UL-FS 49 on hemodynamic and segmental parameters were studied in a canine model of exercise-induced myocardial dysfunction which mimics exercise-induced angina pectoris. Ten dogs, trained to subunit to five treadmill exercise cycles consisting of 4 min of running and 11 min of recovery, were chronically instrumented with a microtip manometer in the left ventricle, two pairs of crystals for sonomicrometry, a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Control experiments with coronary stenosis clarified the reproducibility of exercise-induced regional contractile dysfunction and recovery of function in the intervening resting periods. In each individual dog, a similar degree of stenosis was used in the subsequent experiments with UL-FS 49. After two control runs, which exhibited regional contractile dysfunction of comparable magnitude, UL-FS 49 was administered intravenously at a dosage of 0.5 mg/kg/5 min (6 dogs) or 0.25 mg/kg/5 min (4 dogs). Both doses of UL-FS 49 markedly reduced heart rate without alteration of left ventricular positive dp/dtmax at rest and during exercise. A marked improvement of regional function in the area perfused by the stenosed coronary artery was also observed during exercise. This beneficial effect of selective bradycardia, here observed with UL-FS 49, remains to be confirmed in clinical trials.

Bepridil abolishes exercise-induced regional contractile dysfunction in dogs.

The effects of bepridil, a calcium antagonist, on hemodynamic parameters and regional contractile function were investigated in six dogs trained to submit to five treadmill exercise cycles consisting of 4 min of running and 11 min of recovery. The animals were chronically instrumented with a microtip manometer in the left ventricle, two pairs of piezoelectric crystals for sonomicrometry and a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Experiments were started 1 week after surgery. After a warming-up exercise the vessel was partly stenosed by external filling of the hydraulic occluder. Stenosis was considered adequate and maintained when hemodynamic and functional parameters were virtually unchanged at rest, but episodes of comparable regional contractile dysfunction of the area perfused by the stenosed artery occurred in response to exercise in five subsequent runs; the same degree of stenosis was used for the experiments with bepridil. After two runs with comparable regional contractile dysfunction bepridil was infused intravenously at a dosage of 2 mg/kg per 5 min. The exercise-induced dysfunction was minimally improved in the 1st post-drug run but completely abolished during the 2nd and 3rd post-drug runs. This marked improvement may be partly attributable to the hemodynamic effects of this drug, namely a diminished increase in heart rate and left ventricular end-diastolic pressure and even a reduction in end-diastolic segment length during exercise. These results support the findings of initial clinical trials and suggest a beneficial effect of bepridil in the treatment of exercise-induced angina pectoris in man.

Efficacy of verapamil against ventricular arrhythmias induced by programmed electrical stimulation in the late myocardial infarction phase in dogs.

The aim of the present study was to investigate the antiarrhythmic potential of verapamil in the late myocardial infarction period in conscious dogs. Verapamil was administered in cumulative doses (0.3 + 0.3 mg kg-1). The drug significantly lowered systolic and diastolic blood pressure after both doses. ECG signals showed short-lasting significant decrease in RR and QT intervals together with an increase in QTc interval. The parameters of the atrioventricular conduction system (PQ interval, 2:1 AV-conduction point) were significantly prolonged over the entire observation period. Ventricular effective refractory periods remained unaltered. In contrast to results obtained during acute ischaemia and in the first week thereafter, the present study demonstrates that verapamil moderately increases intraventricular conduction time 14 days after acute myocardial infarction. Verapamil prevented the induction of arrhythmias by programmed electrical stimulation (PES) in only 11% of all induction attempts. The lack of lengthening of refractory periods in the presence of a prolongation of intraventricular conduction time may be responsible for the poor antiarrhythmic efficacy. We conclude that verapamil is only of negligible value for the management of PES-induced ventricular arrhythmias in the late myocardial infarction period.

Verapamil abolishes exercise-induced regional contractile dysfunction in dogs.

The effects of the Ca++-antagonist verapamil on hemodynamic and regional myocardial functional parameters were studied in a canine model of exercise-induced myocardial dysfunction which mimics exercise-induced angina pectoris. Six dogs, trained to submit to five treadmill exercise cycles, each consisting of 4 min of running and 11 min of recovery, were chronically instrumented with a microtip manometer in the left ventricle, two pairs of crystals for sonomicrometry, a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Control experiments with coronary stenosis clarified the reproducibility of exercise-induced regional contractile dysfunction and recovery of function in the intervening resting periods. In each individual dog, the same degree of stenosis was used in the subsequent experiments with verapamil. After two control runs which exhibited regional contractile dysfunction of comparable magnitude, verapamil was administered intravenously at a dosage of 0.3 mg/kg over a period of 5 min. Verapamil induced an increase in heart rate at rest due to sympathetic counterregulation secondary to a reduction of systolic and diastolic blood pressure. The exercise-induced increases in heart rate and rate-pressure product were reduced after verapamil, but the exercise-induced increase in left ventricular dp/dtmax was not significantly diminished. The hemodynamic changes led to a marked improvement of regional function during exercise in the area perfused by the stenosed coronary artery. In a study using identical experimental conditions, the Ca++-antagonist bepridil at a dosage of 2 mg/kg/5 min abolished the exercise-induced regional contractile dysfunction to a similar extent as verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiovascular pharmacology. An example of the need of clinically relevant pharmacological research]. / Herz- und Kreislaufpharmakologie. Ein Beispiel der Notwendigkeit kliniknaher pharmakologischer Forschung.

Like all other scientific disciplines, preclinical pharmacological research is subject to permanent changes. New measuring devices and the possibility of continuous on line data acquisition have markedly influenced basic research in this field. Another aim of modern cardiovascular pharmacology is the testing of promising drugs in clinically relevant animal models of disease, particularly under conditions, referring to the everyday situation in patients, e.g. physical activity. Investigations carried out in this way allow an exact assessment of the clinical efficacy of new drugs, and are, thus, clearly indispensable, also from the ethical point of view, before primary evaluation of the drug in man.

A model of transient myocardial dysfunction in conscious dogs. Regional shortening in the presence of impaired coronary flow reserve and treadmill exercise.

An experimental model of treadmill exercise-induced regional myocardial dysfunction was developed in conscious dogs to mimic exertional angina pectoris in man. Twenty mongrel dogs, trained to run on a treadmill, were chronically instrumented with a miniature pressure transducer in the left ventricle and a hydraulic occluder placed around the circumflex branch of the left coronary artery. Two pairs of piezoelectric crystals for sonomicrometry were implanted subendocardially to measure regional myocardial function. Experiments were started 1 week after surgery. In the first group of ten dogs exercise with constant work load of 10 km/hr and 10% elevation during partial left coronary artery stenosis, induced by external filling of the occluder, produced comparable episodes of regional dysfunction in the left coronary artery area during five subsequent treadmill runs and recovery of function after each run. The second group of ten dogs, exercised with left coronary artery stenosis and increasing working load, exhibited minimal regional dysfunction in the left coronary artery area while running at 6 km/hr and 6% elevation, but maximal regional dysfunction during peak exercise (10 km/hr and 10% elevation). This load dependency and recovery of function after the runs was demonstrated during five identical consecutive exercise cycles. This model, in contrast to those using ameroid constrictors, enables various drugs to be tested in a single instrumented dog over a period of several weeks.

Propranolol ameliorates exercise-induced regional myocardial dysfunction in dogs.

The effects of propranolol (0.5 mg/kg) on exercise-induced regional myocardial dysfunction were investigated in an animal model with limited coronary reserve. Limited coronary reserve was accomplished in conscious, chronically instrumented dogs by external filling of a hydraulic cuff occluder placed on a coronary vessel which did not impair resting myocardial function but induced severe dysfunction during treadmill exercise. Propranolol led to a distinct reduction of heart rate, myocardial contractility and systolic blood pressure, thereby ameliorating exercise-induced regional myocardial dysfunction.

Mode of QT correction for heart rate: implications for the detection of inhomogeneous repolarization after myocardial infarction.

In 22 conscious, chronically instrumented dogs, the relationship between R-R interval and QT interval was better explained by linear regression than by nonlinear regression according to Bazett's formula. The correction formula QTL = QT-0.1*(RR-1000), which is based on the assumption of a linear relationship between QT and R-R interval, was then compared with Bazett's formula regarding its capability to detect inhomogeneous repolarization 5 to 7 days after temporary occlusion of the left anterior descending coronary artery. This comparison was performed only in those dogs exhibiting changes in QRS duration of less than 5 msec in response to myocardial infarction (n = 12). In these animals, myocardial infarction resulted in a significant dispersion of repolarization between the left ventricular normal zone and the infarct zone and a shift to the right of strength-interval curves of the infarct zone with respect to the normal zone, indicating local dispersion of refractoriness. As opposed to QTc (Bazett's formula), QTL was significantly (p = 0.04) prolonged after occlusion. Hence the adequacy of QT correction contributes significantly to the detection of inhomogeneous ventricular recovery after acute myocardial infarction.

Mechanism of antiarrhythmic efficacy of propafenone as assessed by programmed electrical stimulation in conscious dogs.

Programmed electrical stimulation (PES) was performed in 18 conscious, chronically instrumented mongrel dogs 6-21 days after a 4-h occlusion of the left anterior descending coronary artery (LAD). At baseline, 8 of 10 animals responded with sustained ventricular tachycardia (SVT) and 2 of 10 responded with ventricular fibrillation (VF). Cumulative administration of 2 and 4 mg/kg propafenone intravenously (i.v.) prevented induction of the baseline arrhythmia in 7 of 10 (p less than 0.05) and 5 of 10 (p = 0.1) animals, respectively. Cumulative administration of two doses of saline to 8 control animals with SVT inducible at baseline did not affect subsequent inducibility. QRS duration was only slightly prolonged after 2 mg/kg propafenone (+3.5 +/- 1.1 ms, p less than 0.05). Administration of 4 mg/kg was associated with a further increase in QRS duration (+8.0 +/- 2.3 ms, p less than 0.01) and a decrease in sinus cycle length (-60.0 +/- 17.2 ms, p less than 0.05). Propafenone consistently and significantly prolonged ventricular refractoriness only in responders. Furthermore, at both dosages, there was a negative correlation between drug-induced increases in ventricular refractoriness and baseline refractoriness (r = -0.72, p = 0.02; r = -0.81, p = 0.005 with 2 mg/kg and 4 mg/kg propafenone, respectively). Thus, the lesser antiarrhythmic efficacy of 4 mg/kg as compared with 2 mg/kg may result from excessive increases in intraventricular conduction time and/or unfavorable hemodynamic effects of this dose. Furthermore, our study confirms an association of the antiarrhythmic efficacy of propafenone with increases in ventricular refractoriness. In addition, the present investigation demonstrated that such increases in refractoriness are most likely to occur at short baseline values.

Effects of specific bradycardic agents on exercise-induced regional myocardial dysfunction in dogs.

Alinidine and ULFS 49, two specific bradycardic agents were comparatively investigated with propranolol in a model of exercise-induced regional myocardial contractile dysfunction in dogs. Standardized treadmill exercise resulted in a marked decrease in regional function in the myocardium supplied by the critically stenosed circumflex branch of the left coronary artery. All three drugs prevented exercise-induced myocardial dysfunction. The effect on the exercise-induced increase in heart rate and left ventricular dp/dt, however, suggests different modes of action. Propranolol prevents dysfunction by a marked negative inotropy and negative chronotropy, alinidine by a marked negative chronotropy and moderate negative inotropy, but ULFS 49 prevents dysfunction solely by a marked negative chronotropic effect.

Programmed electrical stimulation after myocardial infarction and reperfusion in conscious dogs.

The hemodynamic and electrophysiologic variables and the inducibility of arrhythmias were studied before coronary artery occlusion (CAO, 4h) and on days 4, 14, and 28 of the late reperfusion phase in conscious, chronically instrumented dogs. Despite a lack of significant changes in the hemodynamic and the electrophysiologic variables, the response to programmed electrical stimulation (PES) before and after CAO with subsequent reperfusion varied substantially. Before intervention arrhythmias such as sustained ventricular tachycardia (SVT) or ventricular fibrillation (VFib) could not be induced by PES via ultrasonic crystals located subendocardially (LAD and LCX region) or via common stimulation electrodes (right ventricle) in any of six instrumented animals. All six animals were inducible after CAO and reperfusion. Five animals showed SVT and one animal showed VFib in response to stimulation on days 4 and 14 of the late reperfusion phase after CAO. On day 28 four animals showed SVT, and two showed VFib. Antiarrhythmic drug testing carried out in the late reperfusion phase with lidocaine (1 mg/kg bolus followed by continuous infusion) revealed 50% efficacy at a dosage of 40 micrograms/kg/min, 100% at 80 micrograms/kg/min, and 67% at 120 mu/kg/min. The persistent inducibility of arrhythmias for the entire experimental period of 24 days may be attributable to the following features of our model: 1. Electrical stimulation carried out from three different locations. 2. The use of up to three extrastimuli in the PES studies. 3. The use of conscious dogs during CAO, reperfusion, and PES. This novel experimental approach thus promises to be of clinical relevance for the investigation of new antiarrhythmic drugs.