Cardiac electrophysiologic effects of orally administered DPI 201-106 in conscious canines: effects of pharmacologic autonomic blockade or cardiac transplantation

This study assessed the cardiac electrophysiologic effects of DPI 201-106 (DPI), a novel orally absorbable positive inotropic agent, the administration of which has been associated with electrocardiographic (ECG) QT and T-wave changes. In the intact conscious dog, oral administration of both 8 and 16 mg/kg DPI produced marked sinus cycle length prolongation (8 mg/kg, + 11%; 16 mg/kg, + 9%) within 60 min of DPI administration (p less than 0.05 vs. baseline). DPI also tended to prolong right atrial refractory periods, and increase sinus node recovery time. In addition, DPI exhibited a negative dromotropic effect on the atrioventricular (AV) node, prolonging both AV node effective and functional refractory periods and tending to increase the minimum atrial paced cycle length at which AV conduction of 1:1 was maintained. DPI also significantly increased right ventricular effective refractory period (ERP) at both doses studied and increased ventricular functional refractory period (FRP) at the 16-mg/kg dose. Finally, although DPI administration was associated with QT interval prolongation, this effect was slight when corrected for sinus cycle length (SCL) (QTc, +3%). When administered concomitantly with propranolol and atropine or after surgical cardiac denervation, DPI-induced electrophysiologic changes were largely attenuated or abolished. Thus, findings in this study indicate that the apparent cardiac electrophysiologic effects of DPI are predominantly of neurally mediated origin in this animal model.     

Clinical and hemodynamic effects of dobutamine in acute myocardial infarction with left heart failure

We studied the clinical and hemodynamic effects of dobutamine infused for 24 hr into 10 patients with acute myocardial infarction (less than 4 days) complicated by left heart failure (pulmonary wedge pressure greater than 15 mm Hg, cardiac index less than 3.0 liters/min/m2). We measured pulmonary arterial pressures, pulmonary wedge pressure, right atrial pressure, and intravascular systemic blood pressures. The thermodilution method was used for determinations of cardiac output, and the electrocardiogram was followed with a computerized arrhythmia monitoring system. After 1 and 3 hr of infusion with the optimal dose (averaging 8 micron/kg/min), there was a very significant increase of cardiac index (29%) and a decrease of pulmonary wedge pressure (37%) with a moderate increase of heart rate (20%) an without significant changes in blood pressure. After 24 hr of dobutamine infusion, much of the improvement in left ventricular function was lost. This may be attributed either to a decrease of drug action or to an unfavorable evolution of the clinical status. We conclude that infusion of dobutamine is an effective, potent, and well-tolerated short-term procedure in the management of left heart failure during the acute stage of myocardial infarction.     

Acute hemodynamic effects of intravenous amiodarone in patients with coronary artery disease

The acute hemodynamic effects of intravenous amiodarone (Cordarone injectable; Labaz) were studied during cardiac catheterization in 16 male patients with coronary artery disease (age range, 38-64 years; mean, 53 years). Amiodarone was administered as a bolus at a dosage of 5 mg/kg bodyweight over a 1-min period. Measurements were made 5, 10, and 15 min thereafter. The drug had little effect on heart rate, aortic pressure, cardiac index, and vascular resistances. There were small and nonsignificant increases in left ventricular end-diastolic pressure and end-diastolic volume. The ejection fraction decreased slightly and not significantly. In addition to some increases in pulmonary wedge, pulmonary artery, and right atrial pressures, the significant findings were a 15% decrease in maximal dP/dt and a 12% decrease in left ventricular work. These changes point to a slight negative inotropic effect of amiodarone.     

Comparative haemodynamic effects of lidocaine, mexiletine, and disopyramide

The effect of intravenous boluses of lidocaine (5 mg/kg), mexiletine (3.5 mg/kg), and disopyramide (5 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance, left ventricular end-diastolic pressure, and peak rate of change of left ventricular pressure (peak LV dP/dt) were assessed in the conscious rabbit. Plasma levels for the three drugs corresponded to the human therapeutic range 3 min after administration. All three drugs had negative inotropic effects and reduced HR. Lidocaine reduced peak LV dP/dt by 26%, mexiletine by 41%, and disopyramide by 53%. The three drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: disopyramide caused a 21% fall in CO, associated with a significant vasoconstriction; mexiletine did not lower CO, as it caused a substantial vasodilation; and lidocaine did not produce any substantial change in either CO or vascular resistance. Cardiac autonomic blockade did not alter these changes. These results confirm that disopyramide has a marked cardiodepressant effect, and demonstrate that, although lidocaine depresses myocardial contractility in the conscious rabbit, it has little effect on other haemodynamic parameters. The experiments also show that mexiletine is a more profound negative inotrope than lidocaine, but that, as it produces a significant fall in MAP and thus a reduction in afterload, the CO is maintained.     

Effects of N-acetylprocainamide and recainam in the pharmacologic conversion and suppression of experimental canine atrial flutter: significance of changes in refractoriness and conduction

The electrophysiologic determinants of the pharmacologic conversion and the prevention of atrial flutter are poorly defined. This study investigated the effects of pharmacologically induced changes in atrial conduction velocity and refractoriness, in the conversion and suppression of atrial flutter induced in the open-chest anesthetized dog by intercaval crush and rapid atrial pacing. The effects of an intravenous infusion of the new class III antiarrhythmic drug N-acetylprocainamide (30 mg/kg over 15 min) and the class Ic antiarrhythmic drug recainam (10 mg/kg over 20 min followed by 10 mg/kg/h) were evaluated. N-acetylprocainamide restored sinus rhythm in 10 of 15 (66%) dogs, while recainam converted only 2 of 10 (20%). N-acetylprocainamide prevented reinduction in 3 (20%), while recainam was effective in none. In the atria, N-acetylprocainamide induced significant increases in effective refractory period (+27%, p less than 0.01), functional refractory period (+22%, p less than 0.01), and in atrial flutter cycle length (+13%, p less than 0.01). Recainam increased effective refractory period (+28%, p less than 0.01), functional refractory period (+20%, p less than 0.01), conduction time at atrial paced cycle length of 150 msec (+70%, p less than 0.01) and atrial flutter cycle length (+56%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lidocaine on myocardial function and on isoprenaline-induced circulatory changes in man.

14 non-cardiac patients aged 42 to 71 years (mean 49 years) were studied. Part I 1 mg/kg or 2 mg/kg of lidocaine were administered i.v. on two consecutive days and systolic time intervals (STI) were obtained at one minute intervals for 30 minutes. No change in STI was observed after lidocaine injection. In Part II, a bolus of 5 mug of isoprenaline was given i.v. before and after an injection of 2 mg/kg of lidocaine. Isoprenaline caused a highly significant increase in the heart rate, shortening of the total electromechanical systole, pre-ejection period, electromechanical delay, isovolumic contraction time as well as PEP/LVET and ICT/QS1, indices (in all cases p less than 0.001). 2 mg/kg lidocaine had no blocking or potentiating action on the catecholamine-induced circulatory changes. In Part III, after the isoprenaline challenge, a dose of 2 mg/kg of lidocaine was administered and the bolus injection was followed by an infusion of 30 mug/kg/min. Lidocaine per se caused no change in STI in the course of the infusion over 90 minutes, and there was no difference between isoprenaline-induced changes in STI before and during lidocaine infusion. These results suggest that lidocaine has no negative inotropic effect in the therapeutic dose range in man. Lidocaine caused no change in the systolic time intervals, it had no blocking or potentiating action on the isoprenaline-induced circulatory changes, and it had no negative inotropic effect in therapeutic doses in man.     

Electrophysiological effects of propafenone in untreated and propafenone-pretreated guinea-pig atrial and ventricular muscle fibres

The electrophysiological effects of propafenone (10(-7) to 10(-4) M) were studied on guinea-pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 10 mg kg-1, for 28 days. In untreated atria propafenone produced a dose-dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline. In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD. Propafenone depressed the amplitude and Vmax and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K-depolarized papillary muscles. Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria. In ventricular muscle fibres pretreated with 3 mg kg-1, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg-1 exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg-1; further addition of propafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments. It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.     

Systemic and regional hemodynamic effects of perindopril in congestive heart failure.

The acute systemic and regional hemodynamic responses to a single oral dose (4 mg) of the angiotensin converting enzyme inhibitor perindopril were investigated in 10 patients with severe congestive heart failure. Perindopril produced significant and long-lasting decreases in systemic vascular resistance (-18%), right atrial pressure (-60%), and mean pulmonary capillary wedge pressure (-28%), whereas it significantly increased cardiac index (+ 12%). Brachial (+ 130%, pulsed Doppler technique) and renal (+ 34%) blood flows were also significantly increased whereas hepatic blood flow remained unchanged. Brachial flow/cardiac output and renal flow/cardiac output ratios increased significantly from 0.8 to 1.6 and from 13.2 to 16.5, respectively. The maximal decreases in forearm and renal (but not in systemic) vascular resistances were correlated with the basal plasma norepinephrine concentrations but not plasma epinephrine concentrations or plasma renin activity. We conclude that in severe heart failure (a) perindopril considerably improves systemic hemodynamics and exerts an inhomogeneous vasodilating effect, resulting in a redistribution of flows toward the forearm and renal territories, (b) norepinephrine is a major determinant of the arteriolar tone in these two vascular beds, and (c) the pulsed Doppler is a particularly suitable method to non-invasively detect and assess hemodynamic improvements in heart failure patients.     

Electrophysiologic actions of lidocaine in a canine model of chronic myocardial ischemic damage--arrhythmogenic actions of lidocaine

Lidocaine facilitated the induction of ventricular arrhythmias by programmed electrical stimulation in 16 dogs, 5 to 14 days after a temporary (90-min) occlusion of the left anterior descending coronary artery. In these 16 animals, programmed stimulation failed to produce ventricular tachyarrhythmias in any animal before lidocaine administration (3 mg/kg), while after lidocaine administration, programmed stimulation produced nonsustained ventricular tachycardia in four animals (25%), sustained ventricular tachycardia in nine animals (56%), and ventricular fibrillation in one animal (6%). Delayed electrical activity in ischemically injured ventricular myocardium produced by premature ventricular stimuli (mean +/- SD = 179 +/- 34 ms) was delayed further by the administration of lidocaine (237 +/- 42 ms, p less than 0.01), resulting in continuous local electrical activity between the final premature ventricular stimulus and the initial beat of the resultant ventricular tachycardia. Lidocaine administration did not alter myocardial refractoriness in normal ventricular tissue, but it prolonged refractoriness in ischemically injured ventricular myocardium. These results show that lidocaine can have arrhythmogenic actions when administered in the presence of existing ischemic injury, possibly the result of increased delay in activation of ischemically injured ventricular myocardium with localized reentry of myocardial electrical activity.     

The dopamine congener, ibopamine, in congestive heart failure

The hemodynamic effects of the dopamine congener, ibopamine, were investigated in nine patients with chronic congestive heart failure. A placebo-controlled design was utilized. Placebo and ibopamine in doses of 100, 200, and 300 mg were given orally as a single dose to each patient on 4 successive days. Dopamine at 1, 2, 4, and 6 micrograms/kg/min intravenously, was used as an internal standard. Ibopamine did not significantly change heart rate, systemic and pulmonary arterial pressures, pulmonary capillary wedge pressure, or mean right atrial pressure. Significant decreases of systemic arterial resistance (19%) and total pulmonary arterial resistance (21%), and significant increases of cardiac index (20%) and stroke volume index (16%) were elicited by ibopamine at doses of 200 and 300 mg. Peak effects occurred at 1 to 2 h with a duration of action of less than 4 h. The 2 changes were comparable with those obtained by dopamine 2-4 micrograms/kg/min. Except for mild changes at 30 min postdosing, the inotropic indices of the systolic time intervals were not altered significantly by ibopamine. Ibopamine elicits significant hemodynamic effects in patients with chronic congestive heart failure; in large part, these effects appear to be mediated through vasodilatory properties rather than direct positive inotropy.     

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, in anesthetized dogs

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, were studied and compared with those of pentazocine and butorphanol in anesthetized dogs. Eptazocine (1 mg/kg, i.v.) increased the heart rate (HR), left ventricular dP/dt (LVdP/dt) and cardiac output (CO), and scarcely affected the blood pressure (BP), left ventricular end-diastolic pressure (LVEDP), right atrial pressure, pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure. On the other hand, eptazocine (3 mg/kg, i.v.) decreased BP, LVdP/dt, CO and LVEDP and did not influence the pulmonary circulation. Pentazocine (1 mg/kg and 3 mg/kg, i.v.) increased BP, LVdP/dt and CO, while HR was not altered. Pentazocine also increased PAP. Butorphanol (0.1 mg/kg and 0.3 mg/kg, i.v.) decreased BP, HR and LVdP/dt, while other hemodynamic parameters were not changed. In spontaneously breathing anesthetized dogs, eptazocine (1 mg/kg and 3 mg/kg, i.v.) caused a decrease of respiratory minute volume. The fall in PO2 and pH, and a rise in PCO2 were simultaneously observed in blood gas analysis. These respiratory depressant effects of eptazocine were short-lasting, and they were less potent than those of pentazocine. Butorphanol scarcely affected the respiration. These results suggest that eptazocine has different cardiohemodynamic effects than other analgesics and produces mild respiratory depression.     

Hemodynamic action of verapamil in dogs with controlled aortic pressure--influence of sympathetic activation

Verapamil was given to 18 anesthetized dogs (alpha-chloralose 100 mg/kg) as a bolus injection (200 micrograms/kg) followed by constant rate infusion (10 micrograms/kg per min). Hemodynamic parameters were evaluated before and during verapamil administration. After a suitable period of time for complete reversal of hemodynamic effects, verapamil administration as well as hemodynamic measurements were repeated during graded aortic occlusion. This technique stabilized central aortic pressure so that the level of reflex baroreceptor stimulation could be kept constant. Atrio-ventricular conduction disturbances observed in 5 dogs during balloon occlusion are attributed to lack of sympathetic stimulation. Without balloon occlusion, verapamil produced significant decreases in peripheral systemic vascular resistance and pressure and marked increases in cardiac output. Heart rate, pulmonary arterial and pulmonary wedge pressures did not change significantly. During graded aortic occlusion, systemic resistance and cardiac output were less markedly affected but there was an increase in both pulmonary arterial and wedge pressures.     

Cardiac electrophysiology of the antiarrhythmic agent recainam (Wy-42,362) in anesthetized dogs: relation to plasma and myocardial concentrations

The present study was undertaken to characterize the cardiac electrophysiologic effects of the investigational class I antiarrhythmic agent recainam (Wy-42,362) on the canine heart in situ, and to determine the possible relationship between these effects and the concentration of drug in plasma and myocardium. Cardiac conduction times and refractory periods were measured at a paced cycle length of 300 ms in open-chest anesthetized dogs by recording atrial, ventricular, and His bundle electrograms. Recainam was infused intravenously (as a loading + maintenance dose) at either (a) 7.5 mg/kg/20 min + 5 mg/kg/60 min (low-dose group) or (b) 15 mg/kg/20 min + 10 mg/kg/60 min (high-dose group). Samples of plasma and ventricular myocardium were removed at selected times for subsequent analysis. At the end of the maintenance infusion, low-dose recainam produced a plasma concentration of 4.1 +/- 0.5 micrograms/ml and significantly increased atrial conduction time only. Plasma levels with high-dose recainam reached 9.4 +/- 3.5 micrograms/ml at end infusion, and produced significant increases in all measured electrophysiologic parameters except ventricular refractory period. Myocardial levels of recainam were undetectable in the low-dose group, but increased linearly with plasma concentration in the high-dose group with a myocardium/plasma ratio of nearly 1:1. Changes in ventricular conduction time, H-V interval, atrial and ventricular refractory periods, and Wenckebach cycle length correlated significantly with recainam concentration in plasma. In addition, drug levels in the ventricle correlated with the observed changes in both ventricular conduction time and ventricular refractory period. The data suggest that recainam plasma levels may serve as a useful guide in monitoring electrophysiologic response to this agent.     

Defibrillation energy requirements during moricizine and moricizine-lidocaine therapy.

Defibrillation energy requirements may be altered by antiarrhythmic agents. We investigated the effects of moricizine on the defibrillation threshold (DFT) in 18 pentobarbital-anesthetized pigs. The animals were randomized, in a blinded fashion, to moricizine or control (0.9% saline) treatment groups. Each group underwent three treatment phases: baseline, drug infusion (moricizine or saline), and drug infusion combined with lidocaine. Moricizine (2 mg/kg loading dose, 1.5 mg/kg/h infusion) and lidocaine (5 mg/kg loading dose, 4 mg/kg/h infusion) were dosed to achieve therapeutic concentrations. After 5 s of induced ventricular fibrillation, defibrillation was performed using a cardiac defibrillator interfaced with two epicardial electrode patches. DFTs were determined at baseline, during the drug phase, and during the combination of lidocaine with moricizine or saline. DFT values in the animals randomized to the control group were 15.2 +/- 4.2, 14.0 +/- 3.3, and 17.8 +/- 8.7 J at baseline, saline infusion, and saline combined with lidocaine, respectively. No significant differences were observed among the treatment phases. DFT values in the animals randomized to moricizine group were 12.1 +/- 2.8, 13.8 +/- 5.2, and 22.9 +/- 7.1 J at baseline, moricizine infusion, and moricizine combined with lidocaine, respectively. The DFT values during the lidocaine-moricizine combination treatment phase were significantly greater than baseline and moricizine alone (p < 0.002). The mean change in the DFT from baseline to moricizine (14% increase) was significantly different than the mean change in the DFT from baseline to saline (8% decrease) (p = 0.03). Lidocaine added to moricizine increased the DFT by 84%, which was significantly different from the 27% increase in the DFT when lidocaine was added to saline (p = 0.02). We conclude that moricizine minimally increases the DFT, but the combination of moricizine with lidocaine results in a synergistic rise in the DFT that may have detrimental clinical implications.     

Interaction of metoprolol and lidocaine on the ventricular fibrillation threshold in the anesthetized dog

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.     

Positive inotropic and hemodynamic properties of flosequinan, a new vasodilator, and a sulfone metabolite

Flosequinan, a new orally active vasodilator, and its sulfone metabolite were evaluated for inotropic activity in isolated ferret papillary muscles and pentobarbital anesthetized open-chest dogs. In vitro, flosequinan and its sulfone derivative increased tension development in a concentration-dependent manner (1-50 microM) in electrically stimulated papillary muscles pretreated with the beta-adrenergic blocking agent atenolol (2 microM). Peak increases in tension of 75 +/- 17%, and 111 +/- 46% with potencies (EC50) of 15 and 10 microM were observed for flosequinan and its metabolite, respectively. In vivo, flosequinan increased left ventricular dP/dtmax (74 +/- 12%) and right ventricular contractile force (CF) (104 +/- 10%) after administration of 1.875 mg/kg, i.v. Inotropic activity was dose-dependent and remained elevated for at least 60 min postinfusion. Flosequinan also increased heart rate (HR) (14 +/- 2%) and reduced mean arterial pressure (-9 +/- 3%). The i.v. potency of flosequinan (ED50 = 0.45 mg/kg) and its metabolite (ED50 = 0.38 mg/kg) were similar to that of the inotropic vasodilator amrinone (ED50 = 0.38 mg/kg). Inotropic activity was not significantly altered by pretreatment with propranolol (0.5 mg/kg) and atropine (1.0 mg/kg), further supporting the in vitro data indicating that flosequinan can directly stimulate myocardial contractility independent of beta-adrenergic receptor activation. Additional hemodynamic studies were conducted in an acute heart failure model produced by an overdose of propranolol. Flosequinan (2 mg/kg, i.v.) increased cardiac output (CO) (50 +/- 9%) and stroke volume (SV) (29 +/- 8%) while reducing total peripheral vascular resistance (TPR) (-36 +/- 4%), right atrial pressure (-62 +/- 5%), and left ventricular end-diastolic pressure (LVEDP) (-41 +/- 2%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic assessment of milrinone therapy in severe heart failure patients.

To assess the inotropic, vasodilator, and after-load-reducing effects of intravenous milrinone in patients with severe congestive heart failure, a simple noninvasive echocardiographic study coupled with a right catheterization was performed in 12 patients. Milrinone was administered intravenously as a 50 micrograms.kg-1 bolus followed by a 24-h milrinone infusion at a rate of 0.5 mg.kg-1.min-1 [corrected]. Echocardiographic left ventricular end-diastolic diameter (Ded), end-systolic diameter (Des), and wall thickness were measured at baseline and at 24 h of milrinone infusion, before and after a sublingual nitrate administration (0.8 mg of nitroglycerin) that induced load variations. Hemodynamic measurements were performed simultaneously. Left ventricular end-systolic meridional wall stress (Ses) was then calculated. The slopes of percent fractional shortening (percent FS)/Ses and Ses/Des, obtained during sublingual nitrate administration, were traced. Both end-systolic relations are an index of the contractile state. Milrinone therapy improved hemodynamics in all patients, resulting in stabilized hemodynamic conditions between 12 and 24 h of continuous milrinone infusion. At these times, the cardiac index increased to 30% while the capillary pulmonary wedge pressure and systemic vascular resistance decreased to 26 and 24%, respectively (all p less than 0.01). The average slope of Ses/Des shifted upward from 47.5 +/- 30 to 69.25 +/- 34 (p less than 0.05) and the average slope of (percent FS)/Ses shifted from -0.032 +/- 0.025 to -0.082 +/- 0.061 (p less than 0.01), both variations attesting the inotropic effect of milrinone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effective plasma concentrations of sulmazol (AR-L 115 BS) on haemodynamics in chronic heart failure.

Sulmazol (AR-L 115 BS) is a new inotropic drug which has arterial and venous vasodilating properties. We used it in seven patients with severe refractory heart failure to determine the effective plasma concentration levels and the most effective bolus dose on haemodynamics. The haemodynamic monitoring included a Swan-Ganz catheter in the pulmonary artery and a radial catheter. Haemodynamic measurements and plasma concentration determinations were performed before sulmazol injection and at 5, 10 and 30 min after a bolus 0.25, 0.50, 0.75 mg/kg. We observed a gradual increase in cardiac index and decrease in pulmonary wedge pressure when plasma concentration levels rose but the beneficial effects were mainly observed for sulmazol plasma concentrations above 1 microgram/ml. A bolus injection of 0.75 mg/kg was effective in all cases: a significant increase of cardiac index (1.9 to 2.5 1 min-1 m-2; P less than 0.001) and a significant decrease in pulmonary wedge pressure (30 to 25 mm Hg; P less than 0.005) and right atrial pressure (13 to 10 mm Hg, P less than 0.01) were observed. In these patients sulmazol improved the severely deteriorated left ventricular function without affecting heart rate and blood pressure.     

Hemodynamic effects of a new calcium antagonist, bepridil, in patients with coronary artery disease

Hemodynamic Effects of the New Calcium Antagonist Bepridil in Patients with Coronary Artery Disease. For the evaluation of the hemodynamic effects of the new calcium antagonist bepridil 11 patients with coronary artery disease were studied. The following parameters were measured before, immediately after and 20 min after injection of 3 mg/kg bepridil i.v.: pulmonary capillary wedge pressure, pulmonary artery pressure, cardiac output, mean aortic pressure, peripheral vascular resistance, prolongation of the QT-interval in the ECG. Bepridil led acutely to a slight deterioration of the left ventricular function with a significant increase of the preload, but this negative effect was neutralized by the concomitant decrease of the afterload. These results indicate a favorable hemodynamic profile of this new agent.