Propylbutyldopamine. Mechanism of blood pressure lowering in hypertensive patients.

The effects of propylbutyldopamine ( PBDA ), an analog of dopamine lacking significant vasoconstrictor effects, were examined in seven patients with essential hypertension. Cardiovascular hemodynamics, renal plasma flow, urinary sodium excretion, and the renin-angiotensin-aldosterone system were examined during PBDA infusion both before and after administration of low (8 micrograms/kg) and high (40 micrograms/kg) doses of the dopamine receptor antagonist metoclopramide. Infusion of PBDA at a rate of 20 micrograms/kg/min lowered mean arterial pressure from an average control value of 112 +/- 4 to 94 +/- 3 mm Hg during the last 5 minutes of infusion (p less than 0.01), and increased effective renal plasma flow from 330 +/- 22 ml/min to 591 +/- 46 ml/min (p less than 0.01). Changes in heart rate (+ 16% +/- 5% increase from control values of 77 +/- 3 bpm), urinary sodium excretion (+ 13% +/- 5% increase from control value of 121 +/- 11 muEq/min), plasma renin activity (+ 23% +/- 15% increase over control value of 1.3 +/- 0.3 ng angiotensin I/ml/hr), and plasma aldosterone (+ 26% +/- 12% increase over control value of 17 +/- 6 ng/dl) accompanied PBDA infusion. Pretreatment with metoclopramide at a dose of 8 micrograms/kg prior to PBDA infusion partially blunted the blood pressure reduction produced by PBDA alone (-10% +/- 8% vs -20% +/- 4% compared to control values, p less than 0.1) but had no effect on PBDA -induced increases in renal plasma flow (+ 179% +/- 15% vs + 179% +/- 9% compared to control).(ABSTRACT TRUNCATED AT 250 WORDS)

Specialized delivery systems for intravenous nitroglycerin. Are they necessary?

Nitroglycerin is absorbed in vitro into polyvinyl chloride tubing, and it has been recommended that nitroglycerin be administered intravenously through specialized polyethylene infusion sets. To determine if tubing type is essential to achieve physiologic effectiveness, we studied dose responses to intravenous nitroglycerin in 15 patients with heart failure using standard polyvinyl chloride tubing in seven (group 2) and special polyethylene infusion sets in seven (group 1) (one patient was excluded from analysis because of technical difficulties). We monitored heart rate, blood pressure, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output. Cardiac index, systemic and pulmonary vascular resistance, triple index, rate pressure product, stroke volume, stroke volume index, and stroke work index were calculated. Baseline and treatment measurements were obtained from five to 15 minutes after the infusion of 10, 20, 40, and 80 micrograms of nitroglycerin per minute. Over-all, systolic blood pressure decreased (p less than 0.05) about 8 percent and mean blood pressure approximately 12 percent, mean pulmonary artery pressure and mean pulmonary capillary wedge pressure decreased 30 to 40 percent, and the decline in mean right atrial pressure was 35 percent of baseline (all p less than 0.05). Heart rate and cardiac index did not change (p greater than 0.05). Pulmonary vascular resistance decreased slightly (p = 0.07) and systemic vascular resistance significantly (p less than 0.05). When the two groups were compared physiologic changes were virtually identical (p less than 0.05). Two-way analysis of variance for baseline corrected data proved no differences between tubing sets (p less than 0.05), but the infusion concentration rate was highly related to response (p = 0.0001). A significant (p less than 0.05) decrease in mean blood pressure and mean right atrial pressure was noted at lower dose rates (20 micrograms per minute and 40 micrograms per minute, respectively) in group 1. Beneficial hemodynamic effects in heart failure patients can, then, be predicted to occur at 80 micrograms per minute infusion rates; these responses seem independent of the type of infusion tubing system employed. Additionally, when patients given intravenous nitroglycerin for various reasons were followed for 48 hours, the majority receiving infusions via polyvinyl chloride tubing (group 2) did not require dosage adjustments. Also, at lower flow rates, more solution than calculated may be delivered when polyethylene tubing infusion sets are employed with volumetric infusion pumps.

Rapid attenuation of response to nifedipine in primary pulmonary hypertension.

In a 22-year-old woman with primary pulmonary hypertension resistant to all previous attempts to reduce the pulmonary vascular resistance, there was dramatic improvement after the first dose of nifedipine, 20 mg po, which was not sustained with subsequent doses. While there was a persistent reduction in systemic vascular resistance, the initial drug-related reduction in pulmonary vascular resistance was progressively attenuated with the subsequent four doses of nifedipine, 20 mg.

Detection, prediction, and significance of perioperative myocardial infarction following aorta-coronary bypass.

One hundred consecutive patients undergoing aorta-coronary bypass grafting (ACBG) alone, without ventricular venting, were prospectively studied to determine the incidence and consequence of perioperative myocardial infarction (PMI) and the clinical variables that were predictive of PMI. Incidence was determined by serial electrocardiography (ECG) 100 patients; serum CK, GOT, and LDH (100 patients). CK isoenzymes (qualitative 100 patients, quantitated 50 patients); vectorcardiography (VCG) (78 patients); and 99mtechnetium pyrophosphate scintigraphy (TcPyp) (52 patients). The incidence of PMI by ECG was 9%; an additional 8% of cases was diagnosed by enzymes alone. The incidence of diagnostic change by VCG was 19% and by scintigraphy, 25%. Using at least one changed variable of the remaining three as the reference standard, the relative sensitivity and relative specificity of given variables in the diagnosis of PMI were as follows: ECG 67% and 100%, respectively; VCG 85% and 94%; scintigraphy 92% and 97%; and serum enzymes 86% and 96%. By univariate analysis, unstable angina was the only significant predictor of PMI. The operative mortality rate was 2% and the mortality rate at 12 months was 5%. There was a significantly greater mortality rate in patients with PMI diagnosed by ECG (p less than 0.01), in patients with unstable angina pectoris before operation (p less than 0.05), and in women (p less than 0.05).

Effects of dopamine D1 and dopamine D2 receptor agonists on coronary and peripheral hemodynamics.

This study evaluated the coronary dopamine receptors by using the dopamine D1 receptor agonist fenoldopam, dopamine D2 receptor agonist propylbutyldopamine, and their selective antagonists SCH23390 and domperidone. Left circumflex coronary flow (CF), coronary perfusion pressure at constant flow, left ventricular hemodynamics, and total peripheral vascular resistance (TPR) were measured in pentobarbital-anesthetized dogs at constant arterial pressures. At doses of 200, 500 and 5000 nM, both fenoldopam and propylbutyldopamine induced dose-related inotropic effects, as evidenced by maximal dp/dt and cardiac output, an increase in CF, decrease in coronary vascular resistance and a decrease in TPR. Fenoldopam was more potent in its cardiac and coronary effects while propylbutyldopamine was more potent peripherally. On the basis of dosage used, the positive inotropic effects of fenoldopam and propylbutyldopamine were much weaker than dopamine. After beta-receptor blockade, the inotropic and coronary effects of fenoldopam and propylbutyldopamine were extremely attenuated. Domperidone could largely antagonize the propylbutyldopamine-induced inotropic and coronary effects while SCH23390 showed no significant effect. In addition, under our experimental conditions, the fenoldopam- and propylbutyldopamine-induced decreases in TPR were markedly reduced by SCH23390 and domperidone, respectively. The results indicate that the coronary effects of fenoldopam and propylbutyldopamine result not from a primary coronary vasodilating action, but from vasodilation secondary to positive inotropic effects. Both dopamine D1 and dopamine D2 receptors are involved in the peripheral vascular hemodynamics.

Analysis of the effects of dopamine-1 and dopamine-2 receptor agonists on coronary flow.

The coronary flow (CF) at constant perfusion pressure and other hemodynamic variables were measured in anesthetized open-chest dogs. At the same doses of 20, 100, 500 and 2000 nM, the dopamine-1 receptor agonist, fenoldopam, was much more potent than dopamine-2 receptor agonist, N-n-propyl-N-n-butyl dopamine (PBDA), in increasing CF. Under conditions of constant systemic arterial pressure, fenoldopam produced a dose-related increase in maximal +dp/dt (dp/dt) and CF. After adrenergic blockade (combined alpha- and beta-adrenoceptor blockade), however, both cardiac and coronary effects of fenoldopam were greatly attenuated. The coronary effects of both dopamine agonists under uncontrolled arterial pressure were apparently greater than those under constant arterial pressure. Under conditions of uncontrolled arterial pressure and after adrenergic blockade, fenoldopam induced a dose-related decrease in mean arterial pressure (MAP) and corresponding increase in CF. SCH23390 and domperidone markedly inhibited the coronary effects of fenoldopam and PBDA, respectively. Our data suggest that the coronary effects of fenoldopam are predominantly secondary to the fenoldopam-induced decrease in total peripheral resistance (TPR) at small doses and to its positive inotropic action at large doses, while the primary dopaminergic coronary vasodilation plays only a minor role and therefore cannot be of physiological importance in regulating CF.

Hypotensive effects of N,N-din-n-propylodopamine in the anesthetized dog: comparison with sodium nitroprusside.

N,N-Din-n-propyldopamine (DPDA), a dopamine (DA) vascular agonist without beta 1-adrenergic activity, was compared with mitroprusside in pentobarbital-anesthetized dogs. DPDA was infused intravenously at 20, 40, and 80 microgram/kg/min. DPDA caused dose-related reductions in mean arterial pressure when infused at 20 and 40 microgram/kg/min; no further decrease occurred at 80 microgram/kg/min. Sodium nitroprusside, 1-6 microgram/kg/min, approximately equaled the hypotension produced by 40 microgram/kg/min of DPDA. DPDA differed from sodium nitroprusside in causing a more rapid fall in mean arterial pressure and a more rapid recovery upon discontinuation. DPDA had no effect on pulmonary arterial pressure, but sodium nitroprusside reduced it. DPDA reduced heart rate; sodium nitroprusside increased heart rate. Hexamethonium. 10 mg/kg, significantly reduced the hypotension produced by DPDA. The DA antagonist, sulpiride, completely eliminated the reduction in blood pressure caused by DPDA. Neither hexamethonium nor sulpiride affected the hypotension produced by sodium nitroprusside. These studies suggest that DPDA reduces blood pressure in part by inhibiting the sympathetic nervous system and in part by vasodilation secondary to action on DA vascular receptors.

Rapid recurrence of pulmonary hypertension following cessation of nifedipine.

In a young woman with primary pulmonary hypertension, treatment with low-dose nifedipine resulted in resolution of symptoms and of tricuspid regurgitation. On withdrawal of nifedipine, symptomatic pulmonary hypertension recurred within 48 hours and was controlled by reintroduction of low-dose nifedipine.

Chronotropic effects of atropine sulfate and methscopolamine bromide in normal subjects and patients undergoing cardiac catheterization.

The increase in heart rate caused by intravenous injections of atropine sulfate (AS) and methscopolamine bromide (MSB) were compared in 12 healthy volunteers. AS, 200 micrograms, or MSB, 100 micrograms, were injected every 3 min for five doses on successive days. Mean heart rate from the second and fifth injections of MSB was significantly greater than after corresponding injections of atropine. The ratio of equivalent doses of MSB and AS was found to be 1:3. Three subjects with AS and four subjects with MSB exhibited reduced heart rates after the first injection. Excellent correlation of plasma atropine concentrations and heart rate increase were obtained in two volunteers (correlation coefficient, r = 0.84). In the second study, AS, 180 micrograms, and MSB, 60 micrograms, were compared in 20 patients undergoing cardiac catheterization and coronary arteriography. Both drugs produced equivalent increments in heart rate. MSB produced a more predictable dose response than AS. Side effects were similar with both drugs when equivalent doses were used. This study confirms previous investigations that MSB can be titrated by intravenous injections to increase heart rate to desired levels. Absence of central nervous system stimulation by MSB suggests that it may be more appropriate for use in patients with myocardial infarction.

Cocaine depresses the canine myocardium.

The effects of cocaine hydrochloride infusion on left ventricular function in the anesthetized dog were observed under controlled heart rate and blood pressure conditions. In every case an immediate decrease in performance, as evidenced by maximal + rate of change of ventricular pressure (dP/dt), occurred and was a linear function of cumulative dose. Maximal (-) dP/dt also declined, indicating a decreased rate of ventricular relaxation. Right atrial and left ventricular end diastolic pressure increased, with no change in cardiac output or cardiac work, whereas coronary flow decreased slightly. This small decrease in coronary flow was probably related to the decrease in contractile vigor rather than a direct effect of cocaine on vascular tone. Although plasma norepinephrine concentration initially increased, ventricular function did not increase and continued to decline with cumulative cocaine dose. Tissue norepinephrine levels measured in isolated heart-lung preparations were not depleted. These findings indicate a direct toxic action of cocaine on the myocardium, decreasing both contractile performance and relaxation state. Plasma cocaine levels were constant during continuous infusion of the drug, indicating that the progressive toxicity observed did not result from increased circulating cocaine.