Leon I. Goldberg

Direct Renal Vasodilatation Produced by Dopamine in the Dog

The effects on directly measured renal blood flow, mean blood pressure, and calculated renal vascular resistance of intravenous infusions of dopamine, isoproterenol, and norepinephrine were compared. Dopamine, at doses not affecting mean blood pressure, decreased renal vascular resistance and increased renal blood flow. In contrast, isoproterenol decreased both blood pressure and renal vascular resistance but did not consistently increase renal blood flow. Renal artery injection of dopamine produced vasodilatation at doses ranging from 0.75 to 12 μg and biphasic flow responses including transient vasoconstriction at higher doses. It is concluded that the probable basis for the effect of intravenous dopamine infusion on renal blood flow is its direct renal vasodilating action. The direct effect of dopamine on the femoral vascular bed is vasoconstriction. The combination of renal vasodilating, and femoral vasoconstricting, effects is unique and is interpreted as evidence for a renal vasodilating effect of dopamine distinct from the conventional beta-adrenergic mechanism. A possible physiological role for dopamine other than as a precursor to norepinephrine may be related to this property. It is also suggested that the ability of dopamine to alter the distribution of cardiac output in favor of visceral organs may find useful clinical applications.

A Hemodynamic Comparison of Dopamine and Isoproterenol in Patients in Shock

The hemodynamic responses to isoproterenol and dopamine were investigated in 22 patients with the shock syndrome from various etiologies. Dopamine was superior to isoproterenol in seven patients with normal or low peripheral resistance. In this group of patients administration of isoproterenol was associated with unacceptably low blood pressure. Isoproterenol was superior in three patients in whom dopamine did not increase cardiac output. Both amines produced adequate clinical response in four patients, and a combination of isoproterenol and dopamine was necessary for adequate therapy in two patients. Six patients did not respond hemodynamically or clinically to either dopamine or isoproterenol. This investigation has demonstrated that optimal sympathomimetic amine therapy of shock is facilitated by an analysis of hemodynamic status and responses to drug administration.

Comparative systemic and regional hemodynamic effects of dopamine and dobutamine

Dopamine and dobutamine are sympathomimetic amines with divergent peripheral vascular actions. The renal, mesenteric, and femoral vascular and total systemic hemodynamic effects of these amines were compared in pentobarbital-anesthetized dogs. Both agents increased myocardial contractility. Infusion rates of dopamine greater than 5 mug per kilogram per minute increased mean aortic pressure. Dobutamine increased mean aortic pressure. Dobutamine in creased the systolic pressure but did not alter mean aortic pressure. Dobutamine increased cardiac output more than dopamine. Dopamine infusions up to 10 mug per kilogram per minute increased renal and mesenteric blood flow and decreased vascular resistance. Dobutamine had negligible effects on the renal or mesenteric blood flow but produced dose-related increases in femoral blood flow. Dopamine did not significantly alter femoral hemodynamics. These results more clearly define the systemic and regional vascular hemodynamic effects of these agents.

Effects of Maintenance Digoxin Therapy on Systolic Time Intervals and Serum Digoxin Concentrations

Systolic time intervals (STI) and serum digoxin concentrations (SDC) were measured in eight patients with compensated atherosclerotic and/or hypertensive heart disease who received oral digoxin 0.25 mg/day or 0.5 mg/day for alternate two-week periods without a loading dose. Control data were obtained both before and after the four weeks of treatment. After 13 days treatment with digoxin, 0.5 mg/day, there was a significant decrease in total electromechanical systole corrected for heart rate (QS2i), pre-ejection period (PEP), pre-ejection period corrected for heart rate (PEP1) and PEP/left ventricular ejection time (LVET). After the thirteenth dose of 0.25 mg/day there was significant shortening of PEP1 and PEP/LVET. Shortening of QS2i correlated significantly with SDC 24 hours after the thirteenth dose of 0.5 mg. These data suggest that after 13 days of treatment with 0.25 and 0.5 mg/day of digoxin, a positive inotropic effect occurs as reflected by STI shortening. A greater effect was recorded with the 0.5 mg dose.

Attenuation of Postganglionic Sympathetic Nerve Activity by L-Dopa

In anesthetized dogs and cats, intravenous L-dopa reduced the increase in mean blood pressure in response to bilateral carotid occlusion by 77.5% (P<0.01). In the presence of a dopa decarboxylase inhibitor (Ro 4·4602), this effect was absent. Transmission across the superior cervical sympathetic ganglion in the cat was unaltered by the administration of L-dopa. Carotid artery infusion in the dog of 20% of the effective intravenous dose of L-dopa or dopamine failed to inhibit the response to bilateral carotid occlusion. The pressor response to intravenous tyramine in the dog was potentiated (P<0.05) by L-dopa. In the dog, the increase in femoral vascular resistance to lumbar sympathetic nerve stimulation was attenuated (P<0.05) by L-dopa while the response to intra-arterial norepinephrine was unchanged. Thus, inhibition of postganglionic sympathetic nerve activity is a possible mechanism by which L-dopa impaired the carotid sinus reflex.

Effects of Levodopa on Systolic Preejection Period, Blood Pressure, and Heart Rate during Acute and Chronic Treatment of Parkinson's Disease

The effect of levodopa on the externally recorded preejection period (PEP), blood pressure, and heart rate was evaluated in patients with Parkinsons disease during the first 2 weeks of therapy and after 3 months of continuous therapy. During the same time periods, the response of these parameters to graded intravenous doses of dopamine and epinephrine was determined. During the first 2 weeks, levodopa (1.0 and 1.5 g) produced a dose-related shortening of the PEP which was maximal at the time of the 30 or 60-min recordings and remained significant (P < 0.05) for 90 min following the 1.0-g dose and for 120 min after the 1.5-g dose. The drug had no effect on heart rate and reduced arterial blood pressure minimally. Propranolol (10 mg by mouth) prevented the shortening of PEP produced by levodopa. After 3 months of therapy, levodopa (1.5 g) failed to shorten the PEP significantly. However, the effect of dopamine and epinephrine on PEP was not significantly different from that obtained during the first 2 weeks of treatment with levodopa. It is concluded that levodopa exerts a positive inotropic effect which is mediated via beta-adrenergic receptors and that tolerance develops by 3 months of continuous administration. The tolerance does not appear to be caused by impaired responsiveness of the heart since the effect of graded doses of dopamine and epinephrine on the PEP was similar during both acute and chronic administration.

Use of sympathomimetic amines in heart failure

Abstract Sympathomimetic amines that increase cardiac output and decrease total peripheral resistance may be useful in the treatment of certain patients with congestive heart failure. The pharmacologic actions of three such amines, epinephrine, isoproterenol and dopamine, are presented and clinical experience obtained with these amines is reviewed. The myocardial actions of sympathomimetic amines are compared with those produced by digitalis. On the basis of present information, the development of a more ideal sympathomimetic amine for the treatment of congestive heart failure appears to be feasible.

Attenuation of dopamine-induced renal vasodilation in the dog by phenothiazines

Abstract The effects of five substituted phenothiazines and haloperidol on dopamine induced renal vasodilation were investigated in the anesthetized dog. Dose response curves of dopamine and bradykinin were constructed by injecting the vasodilators into the renal artery and without the neuroleptic agents. Chlorpromazine trifluoperazine prochlorperazine and fluphenazine in a dose of 2.5 × 10 -7 moles attenuated the renal vasodilation produced by dopamine without affecting bradykinin. A dose of 5 × 10 -7 moles of thioridazine was required to produce a similar effect. Haloperidol selectively attenuated dopamine vasodilation in a dose of 1.4 × 10 -7 . These experiments support the concept that there is a specific receptor for dopamine in the dog renal vascular bed and suggest that this receptor is similar to the dopamine receptors in the basal ganglia.

Dopamine‐sensitive adenylate cyclase in canine renal artery

To characterize further a putative dopamine receptor in the renal artery, the effects of dopamine on canine renal artery adenylate cyclase activity were studied. Since the femoral artery is thought to be devoid of a similar dopamine receptor, the effects of dopamine on the adenylate cyclase activity of the canine femoral artery were also studied. In tissues from dogs with or without phenoxybenzamine pretreatment, renal artery adenylate cyclase was maximally stimulated by 4 μm dopamine, compared to 20 μm required for the femoral artery enzyme. The concentrations of isoprenaline required to maximally stimulate renal and femoral artery adenylate cyclase were 0·04 and 0·2 μm, respectively. In tissue from the phenoxybenzamine‐pretreated dog, the stimulatory effect of dopamine on the renal artery enzyme was selectively blocked by 0·01 μm haloperidol, but not by 0·2 μm propranolol. In the femoral artery, however, the dopamine stimulation was blocked by both antagonists. Stimulation by isoprenaline of renal and femoral artery adenylate cyclase was blocked by propranolol. These data suggest the concept that dopamine interacts with a specific artery receptor apparently different from α‐ and β‐adrenoceptors.

Cardiovascular effects of levodopa

The patient with Parkinsons disease under treatment with levodopa may be subject to potentially hazardous cardiovascular effects. The most serious side effect of levodopa in patients is ventricular arrhythmia which is unlikely to occur in a subject with normal heart but a risk in patients with myocardial irritability or ischemia. Patients with such a history of ventricular ectopic activity should be treated with caution and monitored electrocardiographically. Levodopa dosage should be increased gradually; if ectopic activity is observed the drug should be discontinued or administered together with an antiarrhythmic agent, the most rational being β‐adrenergic blockers. If these are contraindicated, other antiarrhythmic agents may be successful. Orthostatic hypotension, more common and usually not symptomatic, should be monitored by frequent blood pressure measurements in the standing position, and exercise should be restricted.