Sol I. Rajfer

The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy.

Symptoms of congestive heart failure frequently reflect abnormalities in both systolic and diastolic performance. While much work has been reported regarding the mechanisms by which positive inotropic and vasodilator therapy affect systolic performance, little is known about their effect on diastolic function. In 12 patients with diffuse congestive cardiomyopathy micromanometer left ventricular and aortic pressure measurements were recorded simultaneously with two-dimensionally targeted M mode echocardiograms and thermodilution-determined cardiac output. Each patient received dopamine (2, 4, and 6 micrograms/kg/min), and dobutamine (2, 6, and 10 micrograms/kg/min), and 10 received nitroprusside (0.125 to 2.0 micrograms/kg/min). Baseline hemodynamics were characterized by low cardiac index (2.1 +/- 0.7 liter/min/m2, mean +/- SD), high left ventricular end-diastolic pressure (24 +/- 10 mm Hg), and increased end-diastolic (6.8 +/- 1.0 cm) and end-systolic dimensions (6.0 +/- 1.0 cm). All patients had abnormal left ventricular pressure decay with a prolonged time constant (67 +/- 20 msec) and reduced peak diastolic lengthening rates. Dopamine and dobutamine decreased the time constant of relaxation and increased the peak lengthening rate. Dobutamine also reduced the minimum diastolic pressure from 14 +/- 7 to 10 +/- 9 mm Hg (p less than .01); neither drug reduced end-diastolic pressure. In fact, dopamine elevated end-diastolic pressures in seven patients, despite more rapid pressure decay. Diastolic pressure-dimension relations after dopamine and dobutamine showed a leftward shift with a reduced end-systolic chamber size, but no significant changes in passive chamber stiffness. Nitroprusside decreased left ventricular minimum diastolic pressure by 4 +/- 2 mm Hg and end-diastolic pressure by 7 +/- 4 mm Hg (p less than .01). It did not consistently accelerate left ventricular pressure decay at the doses tested. The decreased end-diastolic pressure with nitroprusside was due to a reduced end-diastolic dimension in five patients. In the other patients, all of whom had elevated right atrial pressures, diastolic pressure-dimension relations showed a parallel downward shift after nitroprusside. Thus, positive inotropic therapy with beta 1-adrenoceptor agonists enhances early diastolic distensibility by accelerating relaxation, augmenting filling, and reducing end-systolic chamber size. Vasodilator therapy is much more effective in lowering diastolic pressures.(ABSTRACT TRUNCATED AT 400 WORDS)

Beneficial Hemodynamic Effects of Oral Levodopa in Heart Failure: Relation to the Generation of Dopamine

Among the positive inotropic drugs available to improve myocardial contractility in congestive heart failure, only digitalis glycosides are suitable for oral administration. In this study, we administered oral levodopa (1.5 to 2.0 g), which is decarboxylated to form dopamine, to 10 patients with severe congestive heart failure. Peak hemodynamic responses occurred one hour after the ingestion of levodopa, with the mean (+/- S.E.M.) cardiac index increasing from 1.8 +/- 0.1 to 2.4 +/- 0.2 liters per minute per square meter of body-surface area (P less than 0.01) and systemic vascular resistance declining from 1905 +/- 112 to 1513 +/- 121 dyn X sec X cm-5 (P less than 0.01). These effects persisted for four to six hours. Left ventricular filling pressure, heart rate, and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose to a peak level of 34 +/- 5 ng per milliliter one hour after drug ingestion and decreased toward base line over the ensuing five hours. A significant correlation was observed between plasma dopamine levels and changes in cardiac index (r = 0.8; P less than 0.02). Five patients enrolled in a trial to evaluate the effectiveness of long-term therapy with levodopa had similar hemodynamic responses to the drug after 6.8 +/- 1.7 months of treatment. Thus, oral administration of levodopa to patients with severe heart failure produced a sustained improvement in cardiac function. The hemodynamic responses observed can be attributed to the activation of beta 1-adrenergic, dopamine, and dopamine receptors by dopamine derived from levodopa.

Comparison of the efficacy and safety of esmolol, a short-acting beta blocker, with placebo in the treatment of supraventricular tachyarrhythmias

The efficacy and safety of esmolol, a short-acting intravenous beta-adrenergic-blocking agent, and placebo were compared in patients with supraventricular tachyarrhythmias (heart rate greater than 120 bpm) in a multicenter, double-blind, partial-crossover study. Seventy-one patients were randomized to receive either esmolol (n = 36) or placebo (n = 35) as initial treatment. Therapeutic failures were crossed over to the other study medication. Therapeutic response was defined as greater than or equal to 20% reduction in heart rate, heart rate less than 100 bpm, or conversion to normal sinus rhythm. The therapeutic response to esmolol during the initial treatment period (72%) was similar to that obtained when esmolol was given as a second agent. The average esmolol dosage producing a therapeutic response was 97.5 micrograms/kg/min. Four patients (6%) converted to normal sinus rhythm during esmolol infusion. In the majority of patients (80%), therapeutic response was lost within 30 minutes following discontinuation of esmolol infusion, a finding indicative of rapid reversal of beta-adrenoceptor blockade. The most prevalent adverse effect during esmolol infusion was hypotension which occurred in eight patients (12%). Hypotension and associated symptoms resolved within 30 minutes after discontinuation of esmolol infusion, which is consistent with the short duration of action of esmolol (elimination half-life of 9.2 minutes).

Effects of long-term therapy with oral ibopamine on resting hemodynamics and exercise capacity in patients with heart failure: relationship to the generation of N-methyldopamine and to plasma norepinephrine levels.

N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA1 receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure. An increase in cardiac index and decline in systemic vascular resistance was observed with each dose, and these hemodynamic effects persisted for 3 to 6 hr. Small transient increments in right atrial and pulmonary capillary wedge pressures occurred 0.5 hr after ingestion of 200 and 300 mg of ibopamine, but these pressures returned to baseline or lower levels within 30 min. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of epinine peaked 0.5 hr after administration of drug and then declined to minimal levels at 3 hr. Ten patients enrolled in a trial to evaluate the efficacy of long-term therapy with ibopamine; after 8 weeks of treatment, the initial hemodynamic responses to the drug were attenuated and no significant improvement in oxygen uptake at peak exercise was observed. A decline in plasma norepinephrine concentrations, which could be attributed to activation of alpha 2-adrenoceptors and/or DA2 receptors on sympathetic nerves, was observed after initial administration of ibopamine and persisted after long-term drug ingestion; no long-term hemodynamic benefit could be ascribed to the reduction in sympathetic activity.

Sustained beneficial hemodynamic responses to large doses of transdermal nitroglycerin in congestive heart failure and comparison with intravenous nitroglycerin

The hemodynamic effects of a new transdermal preparation of nitroglycerin were evaluated in 9 patients with chronic congestive heart failure (CHF). A graded infusion of nitroglycerin was administered initially to establish the dose-response relation for nitroglycerin and estimate the dose of topical nitroglycerin to be applied. Significant hemodynamic improvement was observed 0.5 to 1.0 hour after the cutaneous application of the nitroglycerin-impregnated polymer. The peak effect occurred at 6 hours, with the left ventricular filling pressure decreasing from 24 +/- 2 to 18 +/- 1 mm Hg (mean +/- standard error of the mean) (p less than 0.01) and the cardiac index increasing from 2.0 +/- 0.2 to 2.6 +/- 0.2 liters/min/m2 (p less than 0.01). The systemic vascular resistance decreased from 1,860 +/- 198 to 1,531 +/- 162 dynes s cm-5 (p less than 0.01). Heart rate and mean arterial pressure were unchanged. Significant hemodynamic benefit was observed for 24 hours, and no rebound deterioration occurred upon withdrawal of the drug. The average dose of transdermal nitroglycerin applied was 51 +/- 6 cm2 (1.7 +/- 0.2 mg/kg; 6 of the 9 patients received 64 cm2). Thus, topical application of a new nitroglycerin-impregnated polymer induces an improvement in cardiac performance that is sustained for 24 hours in patients with chronic CHF. However, substantial doses of the drug may be required to produce a satisfactory hemodynamic response in most patients with CHF.

Sustained hemodynamic improvement during long-term therapy with levodopa in heart failure: Role of plasma catecholamines

Long-term therapy with oral sympathomimetic amines in patients with heart failure has been limited by the eventual development of diminished pharmacologic efficacy. However, a previous investigation in five subjects with heart failure suggested that long-term ingestion of levodopa, which is decarboxylated endogenously to dopamine, produces a sustained improvement in cardiac function. In the present study, levodopa was administered orally (1.5 to 2.0 g) to 14 patients with heart failure while hemodynamic responses and plasma catecholamines were monitored. Initially, an increase in cardiac index and stroke volume index was accompanied by a decline in systemic vascular resistance, mean pulmonary capillary wedge pressure and mean right atrial pressure. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of dopamine rose substantially after drug ingestion and correlated significantly with changes in cardiac index (r = 0.73, p less than 0.05). After 12 weeks of treatment with levodopa, the changes in cardiac index, stroke volume index, systemic vascular resistance and plasma dopamine levels persisted (n = 12 patients). Moreover, a significant decrease occurred in the heart rate at rest. Although there was an initial tendency for plasma norepinephrine concentrations to increase, a return to control levels was documented after long-term treatment. Thus, tolerance to the hemodynamic actions of levodopa did not develop during long-term administration of the drug. The hemodynamic responses observed can be ascribed to the activation of beta 1-adrenoceptors and dopamine1 receptors by dopamine generated from levodopa. The dopamine2 activity of dopamine does not appear to be responsible for the improvement in cardiac performance produced by levodopa.

Role of the beta2 adrenoceptor in mediating positive inotropic activity in the failing heart and its relation to the hemodynamic actions of dopexamine hydrochloride

In patients with severe congestive heart failure, it has been suggested that since myocardial beta 1 adrenoceptors are selectively down-regulated, activation of beta 2 receptors may be a preferable approach to augmenting contractility. Accordingly, dopexamine hydrochloride (1, 2 and 4 micrograms/kg/min) and dopamine (2 and 4 micrograms/kg/min) were administered to 8 patients with dilated cardiomyopathy. Left ventricular (LV) dimensions, thicknesses and pressures were obtained using simultaneous high-fidelity pressure measurements and echocardiographic recordings. LV contractility was assessed using the load-independent relation between LV end-systolic wall stress and rate-corrected velocity of fiber shortening. Cardiac index increased in a dose-related manner with both drugs, and was accompanied by a decline in systemic vascular resistance, a measure of peripheral arteriolar tone. LV end-diastolic pressure was unaltered except for a decrease from 29 +/- 6 to 19 +/- 5 mm Hg (p less than 0.017) at the highest dose of dopexamine hydrochloride. Heart rate was unchanged during the infusion of dopamine but increased significantly with dopexamine hydrochloride. LV end-systolic wall stress, a measure of LV internal load, decreased with both drugs. With dopamine, a dose-dependent positive inotropic effect was observed. Dopexamine hydrochloride, at the 4 micrograms/kg/min infusion dose, exerted a mild positive inotropic effect comparable to that noted with dopamine at 2 micrograms/kg/min. Thus, dopamine and dopexamine hydrochloride improved overall LV performance. With dopamine, a substantial positive inotropic effect occurred in association with a reduction in LV afterload. The increased cardiac index observed with dopexamine hydrochloride was due primarily to peripheral vasodilatation and a positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dopamine on left ventricular afterload and contractile state in heart failure: Relation to the activation of beta1-adrenoceptors and dopamine receptors☆

Although long-term therapy with oral beta-adrenoceptor agonists in patients with heart failure is generally associated with the development of diminished pharmacologic efficacy, the ingestion of levodopa, which is decarboxylated endogenously to dopamine, is associated with a sustained improvement in cardiac function. The beneficial hemodynamic actions of dopamine in patients with heart failure have been attributed to a positive inotropic effect that is mediated through activation of beta 1-adrenoceptors. However, a reduction in left ventricular afterload resulting from the activation of dopamine receptors may also lead to an improvement in the performance of the failing heart. To ascertain the relative importance of the positive inotropic and afterload-reducing effects of dopamine in patients with heart failure, dopamine (2, 4, 6 micrograms/kg per min), dobutamine (2, 6, 10 micrograms/kg per min) and nitroprusside (0.125 to 2.0 micrograms/kg per min) were administered to 13 patients with dilated cardiomyopathy while monitoring left ventricular wall thickness and dimensions by echocardiography and left ventricular and aortic pressures with a micromanometer-tipped catheter. Altering left ventricular afterload, quantified as end-systolic circumferential wall stress, with nitroprusside allowed generation of the left ventricular end-systolic circumferential wall stress-velocity of fiber shortening relation that represented the baseline contractile state of the myocardium. Left ventricular velocity of fiber shortening was elevated during the administration of dobutamine and dopamine when compared with measurements obtained with nitroprusside at the same left ventricular end-systolic circumferential wall stress. Furthermore, left ventricular end-systolic wall stress decreased with dopamine but not with dobutamine. Thus, the beta 1-adrenoceptor activity of dopamine and dobutamine augmented the contractile state of the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of adrenoceptors and dopamine receptors in modulating left ventricular diastolic function.

Although both dopamine and dobutamine are potent positive inotropic agents, multiple studies indicate that dopamine may produce a rise in left ventricular (LV) filling pressure, while dobutamine often has the opposite effect. To ascertain the pharmacological and hemodynamic mechanisms responsible for the elevation in LV filling pressure observed with dopamine, we administered incremental infusions (2, 4, and 6 micrograms/kg/min) of dopamine to 18 open-chest, anesthetized dogs in the presence and absence of rauwolscine (selective alpha 2-adrenoceptor antagonist) (n = 7), terazosin (selective alpha 1-antagonist) (n = 6), and domperidone (selective dopamine2 antagonist) (n = 5), while measuring pressures in the LV and left atrium and changes in dimension in the LV short-axis (with ultrasonic piezo crystals). Dobutamine (2, 4, and 6 micrograms/kg/min) was infused in five additional dogs before and after administration of rauwolscine. The time constant of isovolumic pressure decay, peak lengthening rate (mm/sec), LV end-diastolic pressure, and diastolic pressure-dimension relation were computed. A significant elevation in LV end-diastolic pressure and a parallel increase in LV end-diastolic chamber size was observed with dopamine, while a decline in LV end-diastolic pressure occurred with dobutamine. Yet both dopamine and dobutamine caused a dose-related acceleration of pressure decay and augmentation of peak lengthening rate. Furthermore, heart rate declined during the administration of dopamine but rose with dobutamine. In the presence of either rauwolscine or terazosin, dopamine infusion resulted in a positive chronotropic effect and dose-dependent reductions in LV end-diastolic pressure and end-diastolic chamber dimension; arterial pressure fell only after terazosin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathomimetic amines: Potential clinical applications in ischemic heart disease

Sympathomimetic amines are useful in the treatment of patients with ischemic heart disease complicated by heart failure and shock. These agents influence the cardiovascular system by action on alpha-adrenergic, beta-adrenergic, and dopamine receptors. Recent evidence has demonstrated the existence of subtypes of the classic adrenergic and dopamine receptors that mediate distinct physiologic effects. The relative actions of sympathomimetic amines on these receptors differ substantially, resulting in considerable variation in their cardiac and peripheral vascular effects. Two classes of sympathomimetic amines are being intensively investigated at present: (1) compounds acting predominantly on beta 1-adrenergic receptors (i.e., they increase cardiac contractile force with little or no peripheral vascular effects) and (2) compounds acting on both beta 1-adrenergic and dopamine receptors. Orally active compounds of these two classes have been synthesized recently and are now under study for the treatment of patients with heart failure. Results of preliminary studies with such components are briefly reviewed.