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Background The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. Methods We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). Results The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. Conclusions Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

A defect in the endothelium-dependent vasorelaxation could contribute to the development of arterial hypertension through the facilitation of renal vasoconstriction and sodium retention. In this study, we tested the hypothesis that aging impairs kidney function in essential hypertension through a derangement of nitric oxide-dependent renal mechanisms. To this end, we compared the renal response to an intravenous infusion of the precursor of nitric oxide synthesis, L-arginine, in young and aged essential hypertensives. In young hypertensives, L-arginine induced a significant increase in renal plasma flow, glomerular filtration rate, natriuresis and kaliuresis, without changes in filtration fraction. These effects were not observed in aged hypertensives. Neither PRA nor PA were affected by L-arginine infusion in any group. These results indicate that aging produces a derangement of endothelial function in essential hypertension.

A group of eight normotensive female volunteers with regular menstrual cycles were studied during two menstrual cycles: a control cycle and one in which they received lisuride, a D1-D2 dopamine agonist (0.025 mg/8 hr). The following tests were performed in both halves of both cycles: 1) the response of prolactin (PRL) to thyrotropin-releasing hormone (TRH) administration; 2) the response of plasma renin activity (PRA) and plasma aldosterone (PA) to furosemide for 2 hours in the upright posture; and 3) the response of PRL, PRA, PA, plasma potassium (K), and cortisol (F) to metoclopramide administration. An increased response of PRL to TRH and PA to furosemide in the upright position and to metoclopramide were found in the luteal phase of the control study (p less than 0.05). After lisuride administration, in the interphase, differences in the responses of PRL to TRH and PA to furosemide in the upright position disappeared, whereas that of PA to metoclopramide increased further. We conclude that the increase of aldosterone normally observed during the luteal phase of the menstrual cycle is at least partly conditioned by diminished dopaminergic tone and that the response of aldosterone secretion to furosemide-induced sodium depletion and its response to metoclopramide stimulation may be modulated by two different types of dopamine receptors.

The participation of renal prostaglandins in the nephrotic syndrome has been investigated by the measurement of the urinary excretion of prostaglandin E2 (PGE2), renal function and the renin-angiotensin-aldosterone system before, during and after the administration of indomethacin in a group of patients diagnosed as having chronic idiopathic glomerulonephritis with and without nephrotic syndrome. Our results indicate increased renal production of PGE2 in nephrotic patients. This contributes to the maintenance of renal function, probably by counteracting an activated renin-angiotensin system and could be accompanied by a simultaneous and deleterious enhancement of the degree of proteinuria. Nevertheless, the participation of angiotensin II in this last even cannot be excluded.

The hypothesis that pregnancy induced hypertension (PIH) is associated with abnormal physiological control of plasma renin activity (PRA) was tested by studying the effects of graded infusion of angiotensin II (ANG II) on PRA, plasma aldosterone (PA), and blood pressure in normal pregnancy, PIH, non-pregnant women in luteal and follicular phase of the menstrual cycle, and males. PIH occurring in the second trimester was associated with elevated PRA, PA and blood pressure compared with all other groups, and reduced urinary thromboxane excretion compared with normal pregnancy. Exogenous ANG II infusion failed to suppress existing PRA in patients with PIH, in contrast to all other groups, but increased PA in all groups. It is concluded that PIH occurring in the second trimester is associated with elevated PRA, PA and blood pressure. The inability of circulating ANG II to reduce PRA in PIH may constitute a major alteration underlying the pathophysiology of PIH.

To evaluate the renal effects of nisoldipine (N), a dihydropyridine derivative, we have evaluated the variations of blood pressure (BP), heart rate, glomerular filtration rate (GFR), renal plasma flow (RPF), 24-h natriuresis, and renal capacity to excrete an i.v. sodium load (2,000 ml isotonic saline in 4-h) in response to a 4-day course of therapy with placebo (P) and N in six normotensive volunteers and six mild-to-moderate essential hypertensive patients. Both volunteers and patients were studied on two constant diets (20 and 150 mEq of sodium daily). No parameters changed after P. On the contrary, N induced a significant fall of BP (p less than 0.01) in the group of patients but not in volunteers. In both groups RPF and GFR increased significantly (p less than 0.05-0.01) while on a low sodium intake but remained constant when sodium intake was high. In the two groups studied, nisoldipine exhibited natriuretic properties manifested by an increase in the 24-h output of sodium as well as by an increased renal capacity to excrete the i.v. sodium load. These natriuretic properties were present in both situations of sodium load and could be facilitated by the change in renal hemodynamics observed when the intake of sodium was low.