Hyperinsulinemia as a determinant of microalbuminuria in essential hypertension.

OBJECTIVE: To analyze the relationship between insulinemia and urinary albumin excretion in a group of nonobese, young adult hypertensive patients, who had never been treated with antihypertensive drugs. PATIENTS AND METHODS: Forty-nine patients who fulfilled the inclusion criteria were included. Twenty-four-hour ambulatory blood pressure monitorings, urinary albumin excretion (UAE) measurements, and an oral glucose-tolerance test measuring glucose and insulin, were performed, and left ventricular mass was measured by echocardiography. Hypertensive patients were classified as normoalbuminuric when their UAE was < 30 mg/24 h (40 patients; mean UAE 13.4 +/- 7.0 mg/24 h), and as microalbuminuric when their UAE was 30-300 mg/24 h (nine patients; mean UAE 90.5 +/- 86.6 mg/24 h). RESULTS: In comparison with that of the normoalbuminuric group, the fasting plasma glucose concentration for the microalbuminuric group was only slightly higher (100 +/- 9 versus 95 +/- 8 mg/dl, NS). In contrast, the fasting insulin concentration in the microalbuminuric group was significantly higher than that observed in the normoalbuminuric group (25.2 +/- 6.7 versus 16.6 +/- 5.2 microU/ml, P<0.0001). During the oral glucose-tolerance test, the area under the curve (AUC) for glucose (317 +/- 41 versus 253 +/- 53 mg/dl x 2/h, P<0.001) and the AUC for insulin (253 +/- 171 versus 124 +/- 43 microU/ml x 2/h, P<0.001) were significantly higher in the microalbuminuric group than were those AUC observed in the normoalbuminuric group. After adjustments for age, sex, body mass index and average 24 h ambulatory mean blood pressure were made, the fasting insulin level was associated independently with an increase in UAE in a multiple regression model with base 10 logarithm of the UAE as the dependent variable. Variations in fasting insulin level alone accounted for 33% of the UAE variance. In contrast, the 24 h ambulatory mean blood pressure, rather than the insulin level, was the strongest predictor of the left ventricular mass index. CONCLUSIONS: Mild hypertensive patients with microalbuminuria were hyperinsulinemic in the absence of obesity, and their insulin level was the main determinant of microalbuminuria in these patients. Microalbuminuria in essential hypertension seems to identify patients with a cluster of cardiovascular risk factors and a bad risk profile. Thus, assessment of microalbuminuria may be useful in the stratification of risk in essential hypertension.

Effects of captopril on sympathetic activity, lipid and carbohydrate metabolism in a model of obesity-induced hypertension in dogs.

Ten age-matched beagle dogs were kept on a high-fat diet and followed for 12 weeks. During this period the animals were divided into two groups (n = 5), either with or without oral captopril treatment. Dogs were tested periodically for biochemical and clinical parameters, and at the end of the study animals were killed and thoracic aorta samples were obtained for histologic evaluation. From the third week, the captopril group presented significantly lower values of mean arterial pressure, plasma norepinephrine, and fasting glucose and cholesterol levels than those attained in the nontreated group. Furthermore, aorta samples from untreated animals showed profuse staining for fat content at the intima and adventitia layers, while this reaction was restricted to the outer layer in treated dogs. These data suggest that the beneficial effects of captopril therapy in this obesity-induced hypertension model could be based on blood pressure control, together with reduction of serum glucose, cholesterol, and sympathetic activity levels. In addition, captopril treatment could play a role in the retardation of the early stages of vascular atherogenetic lesion.

Cicaprost, a prostacyclin analog, protects renal function in uninephrectomized dogs in the absence of changes in blood pressure.

Ten dogs presenting mild chronic renal failure and hypertension after 27 months of uninephrectomy, during which they received a high sodium and high protein diet, were divided in two groups (n = 5) and followed for 15 months. The same diet was maintained and one of the groups received cicaprost treatment. The animals were periodically tested for biochemical and clinical parameters, and at months 0, 3, 6, and 15, glomerular filtration rate and renal plasma flow (RPF) were measured. Renal biopsies were made after 6 months of follow-up. Control group showed a higher thickening of pre- and intraglomerular portions of arteriolar vessels and an enhancement of mesangial matrix when compared with the treated group. Cicaprost also induced a significant elevation in RPF and a significant decrease in filtration fraction. All these findings suggest that cicaprost, an oral stable prostaglandin I2 analog, could have a protective renal effect in this experimental model.

Natriuretic effects of dopamine agonist drugs in models of reduced renal mass.

In addition to recognized neurotransmitter properties in the central nervous system, dopamine (DA) plays a role in the physiological activity of the kidney through its hemodynamic and natriuretic effects. On the basis of these data, some pharmacological interventions have focused their attention on the use of DA-related drugs to improve renal sodium handling. We summarize the data obtained from two studies using two DA agonist drugs, lisuride (LIS) and fenoldopam (FEN), in two situations of reduced renal mass. During an intravenous sodium load performed on 10 uninephrectomized dogs, LIS induced a significant blockade of the concomitant pressor response, estimated by lower blood pressure and norepinephrine levels. Under these same conditions, FEN significantly decreased blood pressure and elevated the natriuretic response. In a second study, when FEN was administered at nonhypotensive doses to chronic renal failure patients, it evoked an enhancement of diuresis, natriuresis, and creatinine clearance. These data seem to confirm the involvement of DA in the regulation of cardiovascular homeostasis and its role in renal sodium handling. Furthermore, these beneficial effects support the use of DA-related drugs in the field of hypertension.

Renal effects of fenoldopam in refractory hypertension.

Fenoldopam, a dopamine-1 (D1) agonist, was administered by a 6-h intravenous infusion to patients with refractory hypertension [diastolic blood pressure (DBP) greater than 115 mmHg while on triple therapy] in order to achieve a fall in DBP of 30 mmHg. The evolution of blood pressure, heart rate, glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, renal excretion of sodium, potassium, chloride, calcium, uric acid, phosphate, plasma renin activity (PRA), aldosterone and prolactin were evaluated. A significant fall in blood pressure (P less than 0.01) accompanied by an increase in heart rate (P less than 0.01) was attained after 30 min. GFR and RPF increased significantly (P less than 0.01) but the filtration fraction fell. Urine volume and urinary output of sodium, potassium, chloride, calcium, uric acid and phosphate increased markedly (P less than 0.01). Meanwhile, plasma potassium fell (P less than 0.01) and the hormonal parameters showed no significant change. We concluded that in refractory hypertension fenoldopam has potent renal and systemic vasodilatory properties through which blood pressure falls. The hypotensive effect of fenoldopam is also facilitated by its marked diuretic and natriuretic properties. The absence of variations of plasma prolactin confirm the D1 selectivity of fenoldopam and the lack of increase in PRA indicates that fenoldopam blocks the renin-angiotensin-aldosterone system.

Partial purification of a sodium pump inhibitor from bovine adenohypophysis. Its comparison with the natriuretic factor isolated from hypothalamus.

Adenohypophysis and hypothalamic bovine tissues were homogenized, lipid extracted, salt removed and loaded onto 2 successive mu Bondapak HPLC columns, semipreparative and analytic, respectively. In vitro sodium-pump inhibitory activity, recovered from each tissue, showed similar chromatographic patterns, but hypothalamus seems to contain a major hydrophobic material which appears at the end of the run, when acetonitrile gradient raised 40% approximately. Digitalis-like activity disappears along the purification procedure, and this fact suggests a clear dissociation between (Na/K)ATPase inhibition and digoxin-like activity, measured as crossing with digoxin antibodies.

Effect of converting enzyme inhibitors in hypertensive patients with non-insulin-dependent diabetes mellitus.

The aim of this study was to evaluate the effect of captopril on carbohydrate metabolism in diabetic patients with essential arterial hypertension. Sixteen patients with non-insulin-dependent diabetes mellitus and hypertension were studied. Captopril was employed in different doses, and where patients receiving 100 mg/day remained hypertensive, hydrochlorothiazide 50 mg/day was added. Treatment was maintained for 90 days in 14 patients, 2 being excluded because of side effects. Basal blood pressure was normalized in 8 patients (57%) with captopril alone, and in 6 patients (43%) following the addition of hydrochlorothiazide. Basal glucose levels were not altered. Oral glucose tolerance tests performed during captopril treatment showed a lower glucose response, without changes in the insulin response. There was significant weight loss during the study. We conclude that captopril appears to be a safe treatment in essential hypertension associated with non-insulin-dependent diabetes mellitus, producing no deleterious effects on metabolic control.

Effect of exogenous angiotensin II infusion after one year of captopril therapy in essential hypertension.

The effect of exogenous angiotensin II on plasma renin activity (PRA), plasma renin concentration (PRC) and plasma aldosterone (PA) was investigated in a group of 8 patients with essential hypertension after one year of captopril therapy. The results were compared with those obtained in a group of 18 normotensive volunteers not on captopril. Angiotensin II was infused at increasing doses until a pressor response (increase of diastolic blood pressure by 20 mm Hg) was evoked. The normotensive volunteers exhibited the expected decline of PRA during angiotensin II infusion. However, no significant change was observed in PRA nor in PRC levels in the group of hypertensive patients. The PA values increased significantly both in volunteers and patients (P less than 0.02). The dose of angiotensin II necessary to evoke a pressor response was higher in the hypertensive patients than in the normotensive volunteers (6.0 +/- 2.6 s.d. ng/kg/min vs 2.5 +/- 0.9; P less than 0.01). We conclude that patients with essential hypertension, after chronic treatment with captopril, show no inhibition of renin secretion in contrast with the controls. They also require more angiotensin II to evoke a pressor response during infusion of this peptide.