Dose-ranging study of NG-nitro-L-arginine pharmacokinetics in rats after bolus intravenous administration.

1. NG-nitro-L-arginine (10, 30 and 100 mg/kg) was administered intravenously to the male Wistar rat. Plasma was collected over 48, 72 and 120 h and was analysed for the drug by hplc. Pharmacokinetic parameters were calculated using a non-compartmental method. 2. Drug concentration-time profiles of individual rats after all doses studied exhibited secondary peaks, while geometric mean concentration-time curves showed plateaus. 3. NG-nitro-L-arginine plasma concentrations divided by dose almost coincided. Pharmacokinetic parameters were not dose-dependent in the range of 10-30 mg/kg, but changed after 100 mg/kg of NG-nitro-L-arginine indicating some decline from linearity. 4. NG-nitro-L-arginine is a low-extracted drug in rat as the total clearance was low (0.05-0.07 l/h/kg). Half-life and mean residence time were found to be long (17-30 and 23-40 h, respectively). Despite its low lipophilicity, NG-nitro-L-arginine exhibited large steady-state and terminal volumes of distribution (1.4-2.2 l/kg and 1.4-2.4 l/kg, respectively). Together with the double peak phenomenon, these results may be explained by assuming NG-nitro-L-arginine is involved in a recirculation process in the body.

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)

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.

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.

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.

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.

Ventricular arrhythmias after reperfusion: is there a correlation with infarct size?

The aim of this investigation was to examine whether any correlation exists between enzymatically estimated infarct size and arrhythmias arising in response to coronary reperfusion. Four hour occlusion of the left anterior coronary artery followed by reperfusion was carried out in conscious dogs. Serum creatine phosphokinase (CPK) analysis and planimetric determination of infarct size were performed. The Holter monitoring technique was used to analyze the arrhythmias. A good correlation was observed between the number of premature ventricular complexes (PVC) occurring during 4-h coronary artery occlusion and peak serum CPK values (CPKmax; r = 0.74). While PVC in the early 2-h reperfusion phase and on days 1 and 2 of the late reperfusion phase did not show a correlation with CPKmax nor with occlusion arrhythmias, arrhythmic activity on day 3 of the late reperfusion phase correlated well with CPKmax (r = 0.71) and occlusion arrhythmias (r = 0.75). Whereas it cannot be ruled out that arrhythmias on days 1 and 2 are related to coronary reperfusion as well as to the established infarction, we speculated that arrhythmias on day 3 are delayed arrhythmias in response to the occlusion procedure and not a consequence of reperfusion. Providing that arrhythmias occurring in the early reperfusion phase are almost exclusively induced by the arrhythmogenic phenomenon of reperfusion, we conclude that in contrast to occlusion arrhythmias, reperfusion arrhythmias are not markers of infarct size. Thus, a higher number of arrhythmias after reperfusion is not necessarily associated with a larger infarct size.

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.

[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.

Programmed electrical stimulation in conscious dogs: electropharmacologic testing of amrinone.

In order to assess possible proarrhythmic properties of amrinone, serial programmed electrical stimulation was performed via several previously implanted electrodes in 12 conscious dogs during the late reperfusion phase following experimental myocardial infarction. In 6 dogs, programmed electrical stimulation was carried out before and following the administration of amrinone (Wincoram) at cumulative doses of 0.3, 1 and 3 mg/kg, i.v., while the rest served as control group and received matching volumes of saline. Amrinone decreased atrioventricular refractoriness but did not alter ventricular refractory periods in both normal and infarct zones. Amrinone (3 mg/kg) substantially enhanced intraventricular conduction. Induction of ventricular arrhythmias was attempted only at base line and following 3 mg/kg of amrinone. Inducibility was unaltered by amrinone. However, in two experiments we observed more severe forms of arrhythmia to be inducible following drug administration. The number of extrastimuli necessary for the induction of arrhythmias was decreased in two cases during treatment. In the control group, neither the nature of induced arrhythmias nor the number of extrastimuli was changed. We conclude that, in our model, amrinone exerts a moderate proarrhythmic effect when assessed by programmed electrical stimulation. This arrhythmogenic property may be due to an enhancement of intraventricular conduction.

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.

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.

Efficacy of nitroglycerin in stress-induced regional myocardial dysfunction is dependent on the chosen model: investigations in anesthetized and conscious dogs.

The antianginal efficacy of nitroglycerin (1 microgram/kg per min) was investigated in two different experimental models, one using chloralose-anesthetized open-chest dogs, the other using conscious, chronically instrumented dogs. Heart rate, arterial pressure, left ventricular dp/dtmax, and left ventricular end-diastolic pressure were registered. Left ventricular regional contractile function in the area supplied by the left circumflex coronary artery (LCX) and the left anterior descending artery (LAD) were assessed using sonomicrometry. In both models, the coronary flow reserve was limited by a hydraulic occluder around the LCX. Cardiac stimulation was achieved by a bolus injection of isoproterenol (ISO 0.5 microgram/kg) in the anesthetized animals and by graded treadmill exercise in the conscious animals. In both cases, transient contractile dysfunction occurred in the area supplied by the stenosed vessel. This contractile dysfunction was completely abolished by nitroglycerin in the conscious animals, while nitroglycerin failed to show any antianginal effect in the anesthetized dogs. Although hemodynamic differences in open and closed chest should be considered, remarkable differences in mechanisms of blood-pressure regulation according to the mode of stimulation were observed: in contrast to the situation during treadmill exercise, the ISO-induced decrease in arterial blood pressure does not correspond to the clinical picture of an anginal attack. These results show that it is most important to mimic the complex pathophysiological reactions of angina pectoris in man as closely as possible in the experimental model.

Holter monitoring in conscious dogs. Assessment of arrhythmias occurring during ischemia and in the early reperfusion phase.

Myocardial ischemic episodes of 5 min, 15 min, and 4 hr duration, with interposed reperfusion periods, were induced in the same conscious, chronically instrumented dogs. A drop in systolic blood pressure and an increase in heart rate and in the arrhythmic ratio (AR% = number of ectopic beats x 100/total number of beats, as assessed by Holter monitoring) was registered in response to the induction of myocardial ischemia. Reperfusion-induced salvage after coronary occlusion of 5 and 15 min duration was documented by an immediate return of systolic blood pressure, heart rate, and AR to the preocclusion control level. However, after coronary occlusion lasting for 4 hr, reperfusion induced a further drop in blood pressure and an increase in heart rate and in AR. We conclude that in conscious dogs, reperfusion-induced arrhythmias do not occur after short-lasting myocardial ischemic episodes. Reperfusion after long-lasting ischemia induces marked ventricular ectopic activity, yielding an arrhythmic ratio of more than 80%. Although these reperfusion-induced arrhythmias impair the hemodynamic state, they are well tolerated in the conscious dog and can be assessed by the Holter monitoring technique. This new experimental approach promises to be of clinical relevance for investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Holter monitoring in conscious dogs. Assessment of arrhythmias occurring in the late reperfusion phase after coronary occlusion.

Arrhythmias occurring in the late reperfusion phase, i.e., up to 3 days after episodes of 5 min, 15 min, and 4 hr of coronary occlusion (CAO), were investigated in six conscious, chronically instrumented dogs using the Holter monitoring technique. The arrhythmic ratio (AR% = number of premature ventricular complexes x 100/total number of beats) of a 24-hr preocclusion control record was 0.004% and did not differ from the values assessed for day 1 (0.004%) and 2 (0.001%) of the late reperfusion phase after 5 min CAO. After 15 min, CAO increased, but insignificantly elevated AR values were registered on days 1 (2.5%), 2 (0.26%), and 3 (0.1%) of the late reperfusion phase. On day 1 of the late reperfusion phase after 4 hr CAO, the AR increased markedly to 75%. On day 2 of this phase, the AR was lower (20%) but still significantly elevated. On day 3, the AR was 3.5%, a value still markedly, although not significantly, above the preocclusion control level. We conclude that in conscious dogs, arrhythmias in the late reperfusion phase do not occur after 5 min CAO. However, after 15 min CAO and, especially, after 4 hr CAO, an increase in arrhythmic activity occurs in the late reperfusion phase and gradually declines towards the preocclusion control level over a period of 3 days. Thus, it could be demonstrated that the long-term assessment of reperfusion arrhythmias by ECG monitoring using the Holter technique is feasible in conscious dogs. This method represents a promising approach to clinically relevant experimental investigations on the therapeutic efficacy of a new antiarrhythmic drugs.

Effects of niguldipine, a new dihydropyridine calcium antagonist, on regional blood flow, cardiac performance and myocardial metabolism in anaesthetized open-chest dogs.

The haemodynamic and metabolic effects of niguldipine (0.01, 0.025 and 0.5 mumol/kg i.v.), a novel dihydropyridine calcium antagonist, were evaluated in 18 anaesthetized open-chest dogs. The following parameters were continuously measured: heart rate, arterial and pulmonary arterial blood pressure, left and right atrial pressure, left ventricular dp/dtmax, cardiac output, regional blood flow in the circumflex branch of the left coronary artery, and in 1 renal and 1 femoral artery. At predetermined intervals, contents of O2, CO2, H+ ions, glucose, lactate and free fatty acids were determined in blood drawn from the left atrium and a regional cardiac vein. Niguldipine induced a dose-dependent decrease in both systolic and diastolic arterial blood pressure, which led to an increase in heart rate and cardiac output. Mean left atrial pressure was markedly reduced by all doses. Coronary blood flow increased dose-dependently and persistently. Perfusion in the renal and femoral vascular beds also increased, but only transiently and to a lesser extent. Calculation of vascular conductances revealed a preferred vasodilating drug effect on the coronary vascular bed. Right atrial and systolic and diastolic pulmonary artery pressures were not noteworthy altered. Balances of metabolic substrates, O2, CO2 and H+ ions did not indicate any major drug effect of niguldipine on myocardial metabolism.

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.

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.

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)

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.