Arj Girbes

Renal and Endocrine Effects of Fenoldopam and Metoclopramide in Normal Man

The effects of fenoldopam (FD), a selective dopamine-1 (DA1) agonist in doses from 0.05 to 0.50 micrograms/kg/min and of the aselective dopamine antagonist metoclopramide (MCP) on blood pressure (BP), sodium excretion and renal hemodynamics were investigated in 10 healthy volunteers. During FD infusion the diastolic BP fell 9 mm Hg with a rise in heart rate. During combined infusion of FD and MCP no changes in BP occurred. Effective renal plasma flow rose for all doses of FD with a maximal increase of 36% and was not influenced by MCP infusion. Glomerular filtration rate remained unchanged. FD induced an increase in sodium and calcium excretion compared to placebo study, which was abolished by MCP. A marked rise of plasma renin activity during FD infusion was noted, blunted by MCP. MCP induced a marked increase of aldosterone, sustained, but blunted, during subsequent FD infusion, suggesting a DA1-mediated influence on aldosterone secretion. During infusion of FD alone, an increased urinary dopamine excretion was observed. We conclude that FD induces: (1) systemic and renal vasodilation and (2) natriuresis by direct stimulation of DA1 receptors in the proximal tubule, which is (partially) counteracted by a rise of plasma renin activity and subsequently of aldosterone.

Use of dopamine in the ICU - Hope, hype, belief and facts

Dopamine is frequently administered in the ICU to critically-ill patients. The widespread use of dopamine does not only involve states of distributive and cardiogenic (imminent) shock, but also prophylaxis for deterioration and/or improvement of kidney- and bowel perfusion. Although many studies have shown an increase of renal- and (in some studies) improvement of splanchnic circulation, well controlled studies have failed to demonstrate a better outcome with respect to renal function and/or survival of prophylactic dopamine administration. Furthermore, evidence exists that norepinephrine is more efficacious in fluid resuscitated septic shock patients to restore blood pressure than dopamine, without jeopardizing the renal function. It is concluded that the widespread use of dopamine in the ICU should be reassessed.

NEUROHUMORAL AND HEMODYNAMIC-EFFECTS OF IBOPAMINE IN A RAT MODEL OF CHRONIC MYOCARDIAL-INFARCTION AND HEART-FAILURE

SummaryThere is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control treatment (50%) or ibopamine (50%) for 3 weeks. At the end of the study, plasma and tissue neurohumoral parameters, as well as hemodynamics, were determined. In infarcted rats, the elevated plasma norepinephrine (PNE) levels were reduced by ibopamine (251±19 vs. 138±32 pg/ml; p<0.05). Other plasma neurohormones measured (epinephrine, renin, aldosterone, and angiotensin converting enzyme [ACE]) were not significantly increased in rats with myocardial infarction and were not affected by ibopamine. Cardiac (tissue) ACE was increased in infarcted rats (12.1±1.9 U/l/min) and was significantly lowered by ibopamine (9.6±1.0 U/l/min; p<0.05); renal ACE was unaffected. Blood pressure and heart rate were similar in the two groups and were not influenced by ibopamine treatment. In conclusion, in chronic myocardial infarction and CHF in rats, ibopamine reduces the elevated levels of PNE and cardiac ACE. Further research will be needed to determine whether this effect may lead to a favorable influence on disease progression in CHF.

EFFECTS OF IBOPAMINE ON EXERCISE-INDUCED INCREASE IN NOREPINEPHRINE IN NORMAL MEN

Summary: The effects of 100 mg ibopamine, an orally active aselective dopamine (DA) agonist, on plasma catecholamines was evaluated in 8 healthy men during sympathetic stimulation by graded exercise in a single-blind, placebo-controlled cross-over study. The exercise consisted of progressive cycling activity ≤90% of the previously determined VO2max. Graded exercise resulted in an increase in systolic and mean blood pressure (SBP, MBP), heart rate, norepinephrine (NE) and epinephrine level, with a decrease in diastolic BP (DBP). The increase in NE was significantly blunted by ibopamine as compared with placebo. No differences for BP, heart rate (HR), or epinephrine between placebo- and ibopamine study day were noted. In previous studies, ibopamine decreased resting plasma NE in patients with congestive heart failure (CHF), whereas plasma NE was not altered by ibopamine in healthy volunteers. This different outcome in both categories might therefore be explained by the absence of substantial sympathetic stimulation in normal humans at rest. Because it is reasonable to assume that the effect of ibopamine on systemic and local hemodynamics is negligible as compared with the effect of exercise in the healthy volunteers, the plasma decrease caused by ibopamine is probably related to stimulation of DA2-receptors. In conclusion, ibopamine blunts the increase of plasma NE during graded exercise in healthy men.

RENAL AND SYSTEMIC HEMODYNAMIC-EFFECTS OF IBOPAMINE IN PATIENTS WITH MILD-TO-MODERATE CONGESTIVE-HEART-FAILURE

Summary To study the hemodynamic and renal effects of the orally (p. o.) active dopamine (DA) agonist ibopamine, we examined 10 patients with mild to moderate congestive heart failure (CHF). who were stable while treated with digoxin and diuretics. All patients were in New York Heart Association (NYHA) functional class II-III; their mean age was 63 years (range 51–79 years), and mean left ventricular ejection fraction (LVEF) was 28% (range 18–360%). The protocol consisted of a control study-day with measurements of renal characteristics including glomerular filtration rate (GFR). effective renal plasma How (ERPF), and filtration fraction (FF). One-week later, systemic and renal hemodynamics were measured simultaneously before and after patients received one 100-mg tablet of ibopamine. Ibopamine caused a slight but significant increase in both FRPF (from 288 ± 32 ml/min/1.73 m2 at baseline to 316 ± 32 ml/min/1.73 m2 after ibopamine) and GFR (from 77 ± 8 to 85 ± 8 ml/min/1.73 m2; both p < 0.05); FF was not affected (mean value 0.26 ± 0.02). Sodium excretion was not influenced by ibopamine. but diuresis increased significantly. Cardiac output (CO) increased significantly (from 4.0 ± 0.4 L/min at baseline to a maximum of 5.0 L/min after ibopamine, p < 0.05). mainly due to decreased systemic vascular resistance (SVR). Heart rate (HR) and blood pressure (BP) were unchanged throughout the studies. The percentage of contribution of CO to renal blood flow (RBF) was not significantly affected by ibopamine. In conclusion, ibopamine causes a slight but significant increase in both ERPF and GFR and a significant increase in diuresis, but no increase in sodium excretion in patients with mild to moderate CHF. In addition, the drug increases CO and decreases SVR to a similar extent. Therefore, the renal effects of ibopamine with equal pre- and postglomerular vasodilation, appear to be primarily due to its systemic hemodynamic effects.

Effects of spirapril and captopril on regional blood flow in chronic congestive heart failure : a comparison between a short- and a long-acting angiotensin-converting enzyme inhibitor

Spirapril is a new angiotensin-converting enzyme (ACE) inhibitor with a long duration of action. To determine whether duration of inhibition of serum ACE activity may affect regional blood flow (RBF), we compared spirapril with captopril, an ACE inhibitor with a short duration of action. Both the short- and long-term effects were studied in patients with mild to moderate congestive heart failure (CHF). Calf, renal, and hepatic BF measurements were performed in the morning before intake of the study medication; 24 h after the previous dose of spirapril (n = 9 patients) and 12 h after the previous dose of captopril (n = 9 patients). Serum ACE activity after 1, 6, and 12 weeks was significantly reduced in patients receiving spirapril, but not in those receiving captopril. The decrease in mean arterial pressure (MAP) was more pronounced in the spirapril group. Calf BF showed a slight but not significant increase in both spirapril- and captopril-treated patients. Effective renal BF increased significantly only in patients treated with spirapril. Although filtration fraction (FF) tended to decrease in the spirapril group, the decrease was significant only in the captopril group. No changes were observed in hepatic BF. Cerebral BF (CBF) measurements were performed after intake of the first dose of study medication and after 12 weeks, immediately after drug intake. Significant reduction in MAP in the two treatment groups both after the first dose and after 12 weeks did not affect CBF. Despite a significantly prolonged decrease in MAP and serum ACE activity in spirapril-treated patients, no marked differences in RBF were noted between the two ACE inhibitors.