Increased tissue factor and thrombomodulin expression and histopathological changes in placentas of pregnancies with preeclampsia.

INTRODUCTION: Preeclampsia has a global frequency of 2-8% and a frequency of 10% in developing countries. In Colombia, preeclampsia causes 42% of maternal mortality. Alterations in placental homeostasis have been proposed to be involved in its pathophysiology. The aim of this study was to compare mRNA and protein levels of tissue factor (F3) and thrombomodulin (THBD) and the histopathological findings of placentas. MATERIALS AND METHODS: We studied 16 placentas from patients with preeclampsia and 19 term placentas with uncomplicated pregnancy. An expert pathologist, who was masked to the group assignment, conducted an evaluation to determine specific histological changes. Assessments of mRNA and protein levels of F3 and THBD were performed using real-time PCR and ELISA, respectively. RESULTS: Cases and controls differed in the frequency of decidual arteriopathy (p = 0.027), acute infarction (p = 0.001) and hyperplasia of the syncytiotrophoblast (p = 0.0017). Cases had increased levels of F3 mRNA (p = 0.0124) and protein (p <  0.0001) and THBD mRNA (p <  0.0001) and protein (p <  0.0001). CONCLUSION: In placenta of patients with preeclampsia, we detected abnormal expression of F3 and THBD with increased protein and mRNA levels. The role of these molecules in the pathogenesis of this disease and in alterations of hemostatic and histopathological aspects of placentas need further studying.

Expression of cystathionine beta-synthase and histopathological observations in placentas of patients with Down syndrome.

UNLABELLED: Down syndrome is the most frequent aneuploidy in live births, with an overall frequency of 1/600-700 births. The overexpression of cystathionine ß-synthase is thought to participate in the presentation of some phenotypes observed in Down syndrome. OBJECTIVE: The aim of this study was to compare the expression levels of cystathionine ß-synthase and histopathological observations from placentas of infants with Down syndrome and healthy newborns. MATERIALS AND METHODS: Six placentas of fetuses/infants with Down syndrome and sixteen placentas of healthy fetuses were studied. Cystathionine ß-synthase mRNA and protein expression were performed by real-time PCR and immunohistochemistry, respectively. RESULTS: We observed an increase in cystathionine ß-synthase mRNA expression (p = 0.0465) and protein levels (p = 0.009) in placentas of fetus/infants with Down syndrome compared with controls. Significantly more circinate edges (p = 0.0007) and trophoblast inclusions (p = 0.0037) were observed in the group with Down syndrome compared with control group. CONCLUSION: The results demonstrate overexpression of cystathionine ß-synthase mRNA and protein in placentas of fetuses/infants with trisomy 21. Further histological abnormalities were found in placentas of patients with Down syndrome, suggesting an alteration in the development of placenta.

Comparative effect of PGE2 and PGI2 on renal function.

Rapid degradation of prostacyclin (PGI2) inherent to its molecular structure has long been a major limitation in assessing the natriuretic effect of this prostaglandin. The recent availability of the stable PGI2 analogue iloprost now allows for a comparative study with prostaglandin E2 (PGE2). In the present study conducted in six anesthetized dogs, the intrarenal effects of two consecutive doses (1 and 4 ng x kg(-1) x min(-1)) of PGE2 on renal blood flow, glomerular filtration rate, and urinary sodium excretion were compared with the effects of two identical doses of iloprost. The selected doses of PGE2 were those producing a maximal natriuretic and vasodilator response without affecting mean arterial pressure. A washout period was allowed between administration of PGE2 and iloprost. PGE2 infusion significantly increased fractional sodium excretion from 0.69+/-0.1 to 2.79+/-1.1% and 4.27+/-1.2%% (P<.05), respectively. These changes in fractional sodium excretion induced by PGE2 were associated with significant increases in renal blood flow from 151.1+/-62 to 185+/-64.3 and 185.6+/-64.3 mL/min (P<.05), respectively; however, no significant alterations were seen in glomerular filtration rate, from 29.5+/-9.4 to 35.2+/-12.2 and 32.7+/-7.8 mL/min (NS), and mean arterial pressure, from 117.6+/-26 to 113.9+/-24.1 and 112.3+/-24.1 mm Hg (NS) during control and PGE2 infusion. At identical doses, sequential infusion of PGI2 had no effect on renal blood floww and glomerular filtration rate, producing natriuresis only at the highest dose, a fractional sodium excretion from 0.69+/-0.1 to 0.8+/-0.28 mm Hg (NS) and 1.05+/-0.34% (P<.05), respectively. In conclusion, the present study confirms that PGE2 exerts a natriuretic effect during increases in renal blood flow. In contrast, PGI2 had no hemodynamic effect, and the natriuresis was markedly blunted.

Sympathoexcitatory effect of hypothalamic/hypophysary inhibitory factor in rats.

We recorded changes in arterial blood pressure, heart rate, and renal sympathetic nerve activity in response to intracerebroventricular injection of bovine hypothalamic/hypophysary inhibitory factor and ouabain in conscious Wistar rats. Ouabain at 0.3 to 0.6 microgram caused dose-related increases in blood pressure, heart rate, and nerve activity (peak increases: 19 +/- 2 mm Hg, 42 +/- 4 beats per minute, and 48 +/- 4%, respectively; P < .05 versus basal). These responses were all blocked by central antibody Fab fragments, which bind ouabain and related steroids with high affinity. The inhibitory factor significantly increased blood pressure but decreased heart rate and nerve activity. Dose-dependent increases in blood pressure as well as heart rate and nerve activity were observed when the inhibitory factor was injected after intravenous injection of the vasopressin antagonist D-(CH2)5Tyr-(Me)AVP. Central Fab fragments, however, did not affect these responses. Both ouabain and the inhibitory factor inhibited Na+,K+-ATPase activity in vitro. Fab fragments blocked this inhibition by ouabain but not by the inhibitory factor. These data indicate that the ouabainlike sympathoexcitatory effect of this factor is masked probably by a potent central effect on vasopressin release. In contrast to rat brain "ouabain," this factor does not exhibit a high affinity for the Fab fragments, supporting the previous finding that this compound is structurally a nonouabain Na+,K+-ATPase inhibitor.

Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension?

To evaluate the relative contributions of past or present GH hypersecretion and of hypertension to the cardiac abnormalities present in acromegaly, we have studied the serum GH and insulin-like growth factor I concentrations, systolic and diastolic blood pressures, and morphological and functional cardiac indexes as measured by echocardiography-Doppler, in 39 patients with active or cured acromegaly, 16 hypertensive controls, and 17 normotensive controls. Hypertension was present in 42.8% of patients with active acromegaly and in 28.0% of patients in which acromegaly was cured. Hypertension was independently related to an increase in indexes of cardiac morphology (left ventricular mass, left ventricular posterior wall thickness, interventricular septum thickness, relative wall thickness with respect to the diastolic diameter of the left ventricle, and left atrial end-systolic diameter), systolic function (stroke volume, fractional shortening, and end-systolic stress), and diastolic function (isovolumic relaxation time and maximal late diastolic flow velocity) and to a reduction in the early to late maximal diastolic flow velocity ratio. Acromegaly was related to an increase in left ventricular mass, stroke volume, cardiac output, and isovolumic relaxation time, which were independent from the presence of hypertension. End-systolic stress was reduced by acromegaly. In the five patients in which active acromegaly was successfully treated, left ventricular mass and left ventricular posterior wall thickness were reduced 1 yr later. In conclusion, the asymptomatic morphological and functional cardiac abnormalities present in acromegalic patients are independently related to acromegaly and hypertension, pointing to the existence to a specific acromegalic myocardiopathy that might be aggravated by the coexistence of hypertension.

High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus.

The current recommendation for strict metabolic control of type 1 diabetes mellitus requires the administration of supraphysiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis, as occurs in insulin-resistant states. At present, the prevalence of hyperandrogenic disorders in women with type 1 diabetes mellitus is unknown. Eighty-five women with type 1 diabetes mellitus were evaluated for symptoms and signs of hyperandrogenism. In 68 of the patients, several serum androgen and hormone concentrations were measured. The polycystic ovary syndrome (PCOS) was defined by the presence of menstrual dysfunction, together with clinical and/or biochemical evidence of hyperandrogenism, and exclusion of other etiologies. Eighteen healthy women, menstruating regularly, served as controls for the androgenic profiles. Thirty-three patients (38.8%) presented hyperandrogenic disorders (16 had PCOS, and 17 had hirsutism without menstrual dysfunction). Type 1 diabetic patients with PCOS presented increased serum total and free testosterone concentrations, and serum androstenedione levels, but had normal serum sex hormone-binding globulin and dehydroepiandrosterone-sulfate levels. Hirsute type 1 diabetic women without menstrual dysfunction presented normal serum androgen levels. There were no significant differences between hyperandrogenic and nonhyperandrogenic type 1 diabetes mellitus women in clinical variables such as the duration of diabetes, age at diagnosis of diabetes, conventional or intensive insulin therapy, mean daily insulin dosage, or metabolic control. In conclusion, women with type 1 diabetes mellitus have a high prevalence of hyperandrogenic disorders, including PCOS and hirsutism.

Effect of furosemide on renal function in the stenotic and contralateral kidneys of patients with renovascular hypertension.

In a group of six patients diagnosed as having unilateral renovascular hypertension due to fibromuscular dysplasia, inulin glomerular filtration rate, (GFR) and PAH renal plasma flow, (RPF) clearances, urine flow (V), urine sodium (UVNa), potassium (UVK), urinary excretion of prostaglandin E2 (UVPGE2), thromboxane B2 (UVTxB2), and 6-keto prostaglandin F1 alpha (UVPGF1 alpha) were measured in each kidney before and after the i.v. administration of furosemide (20 mg). The basal values of GFR, RPF, UVNa, UVPGE2, UVTxB2, and UV6-keto-PGF1 alpha were lower (p less than 0.01) in the stenotic kidney. Furosemide increased RPF 11% and 50%, GFR 25% and 62%, and V 142% and 280% in the contralateral and stenotic kidney respectively. The increase of UVNa was similar in the two kidneys. In the stenotic kidney, both UVPGE2 and UV6-keto-PGF1 alpha increased significantly (p less than 0.01) with furosemide while UVTxB2 remained unchanged. Furosemide did not alter the rate of excretion of the three prostaglandins measured in the contralateral kidney. We conclude that furosemide significantly improves renal circulatory and excretory function of the stenotic kidney. Since prostaglandin excretions also increased, the vasodilatation in the stenotic kidney may be prostaglandin mediated.

Renal effects of amino acid infusions in patients with panhypopituitarism.

Strong evidence indicates that a high protein diet accelerates end-stage renal disease by increasing glomerular capillary pressure subsequent to renal vasodilatation. The mechanisms underlying this vasodilatation remain undefined, but they have been suspected to be mediated by a pituitary factor. To test this possibility, we measured changes in renal plasma flow and glomerular filtration rate induced by an intravenous infusion of a solution of amino acids in two patients with panhypopituitarism. These patients exhibited changes in renal hemodynamics comparable to those recorded in nine healthy volunteers. The results do not support involvement of the pituitary gland in the acute renal response to amino acids.

Effects of long-term treatment with indomethacin on renal function.

The prolonged effects (42 days) of indomethacin treatment on the renin-angiotensin-aldosterone axis, renal hemodynamics, and renal excretory function in humans were studied. Indomethacin produced a 41% sustained depression in the 24-hour excretion of prostaglandin E2 and a mild (7%) decrease in inulin clearance but did not affect the clearance of p-aminohippurate, the 24-hour excretion of sodium and potassium, or the basal values of plasma aldosterone; however, it decreased the basal values of renin and prevented the stimulated (3 hours of walking) responses of plasma renin activity and plasma aldosterone. Indomethacin also produced a decrease in both the diuretic and saluretic response to furosemide and in the renal ability to concentrate urine. The indomethacin-induced hyporeninism and hypoaldosteronism were more pronounced when the subjects were receiving a sodium-restricted diet. This finding indicates that prolonged administration of anti-inflammatory drugs induces chronic hyporeninism and hypoaldosteronism. Prolonged treatment with indomethacin also produced some of the symptoms of a syndrome of hypoprostaglandinism, such as decreased plasma renin activity, plasma aldosterone, and urinary prostaglandin E2 in association with increases in plasma potassium levels and diastolic pressure.

Insulin resistance in patients with a recent diagnosis of coronary artery disease.

OBJECTIVE: To elucidate whether insulin resistance is present in coronary artery disease (CAD) at diagnosis and to study its relationship with other known cardiovascular risk factors. METHODS: We evaluated the incidence of insulin resistance in 40 newly diagnosed CAD patients. Fifteen healthy subjects were used as a control group. The patients and controls had no previous history of metabolic disorders, and were not being administered any medication that might have affected their insulin sensitivity. Immediately after diagnosis of CAD, a standard 75 g oral glucose-tolerance test (OGTT) and an insulin suppression test (IST) were performed on separate days. The IST consisted of a constant infusion of glucose, insulin and somatostatin for 150 min; insulin resistance was estimated by determining the steady-state plasma glucose (SSPG) concentrations during the last 60 min of the test. The insulin sensitivity index (ISI) was calculated by the formula ISI = (glucose infusion rate/SSPG]x10(3). RESULTS: Insulin resistance, defined by an ISI below the normal range derived from the control group, was present in 82.5% of the CAD patients. As a group, the patients with CAD displayed lower ISI (means +/- SD:29.23 +/- 11.23 versus 50.33 +/- 9.37 dl/kg per min, P < 0.001) than did controls. Serum triglycerides and uric acid were higher and high-density lipoprotein cholesterol levels were lower in patients than they were in controls. No differences were observed in fasting plasma insulin, glucose, total and low-density lipoprotein cholesterol concentration. An abnormal OGTT result was observed in 27 patients. The ISI was low in 88.8% of the patients with an abnormal OGTT result and in 69% of the 13 patients with a normal OGTT result. CONCLUSIONS: Insulin resistance and even impaired glucose tolerance are common findings in CAD at diagnosis. The changes in the lipid profile and in uric acid levels paralleled the changes in insulin sensitivity. These results suggest that insulin resistance might play a role in the development of coronary atherosclerosis and that its early diagnosis might be important in the prophylaxis of CAD.

Diagnosis of insulin resistance.

Soon after the discovery of insulin, the importance of insulin sensitivity assessment was recognised. Recently, the role of insulin resistance in cardiovascular morbidity and mortality has been widely accepted and many methods for in vivo assessment of insulin resistance have been developed. They may be classified as 'closed-loop' techniques (in which insulin and glucose concentrations are allowed to interact freely), 'open-loop' techniques (in which insulin and/or glucose levels are fixed) and 'model methods' (which use a mathematical model to analyse the interactions between insulin secretion patterns and glucose disposal). Although there is no ideal method available to date, open-loop techniques avoid many of the difficulties involved in the interpretation of closed-loop or model methods, and are preferred by most investigators. The glucose clamp technique is recognised as the 'gold standard' for assessment of insulin sensitivity; however, the insulin suppression test is adequate in most circumstances and is much simpler to perform.

Course of metabolic syndrome following the biliopancreatic diversion of Larrad.

BACKGROUND: The authors assessed the effect of Larrad's biliopancreatic diversion (BPD) on the main components of the metabolic syndrome. PATIENTS AND METHODS: Plasma concentrations of glucose, insulin, total cholesterol (TC), HDL and LDL cholesterol, triglycerides, LDL/HDL and TC/HDL ratios, and blood pressure and body weight were retrospectively evaluated in 40 patients 3-6, 12, 24 and 60 months after undergoing BPD for morbid obesity with metabolic syndrome. RESULTS: 3-6 months after BPD, glycemia and insulinemia had normalized in 97.5% of the patients and remained stable over the following 5 years. Over this period of 3-6 months to 5 years following BPD, total and LDL cholesterol levels fell by 45.2% and 53.1%, respectively. From 12 months onwards, triglyceride levels decreased appreciably, dropping by 57.4% at 5 years. HDL cholesterol concentrations failed to vary significantly or increased to normal levels in patients showing low initial values. At 5 years, high blood pressure had resolved in 75% of patients and the amount of excess weight lost was 65.5% (+/-14.6). No patient required reversal of the BPD due to severe gastrointestinal or metabolic complications. CONCLUSIONS: Technically adapted to the patient's weight, the Larrad BPD effectively stabilizes the main components of the metabolic syndrome. The BPD has low morbidity rate and should be considered a therapeutic option for patients who do not respond to medical treatment.

Effects of hyperinsulinemia on the regulation of regional blood flow and blood pressure in anesthetized dogs: hemodynamic role of nitric oxide.

The purpose of this study was to investigate whether acute hyperinsulinemia induces selective hemodynamic effects in the mesenteric, renal, and iliac vascular beds, and to determine whether nitric oxide (NO) plays a role in the regulation of blood flow and mean arterial pressure (MAP) during acute hyperinsulinism. In eight anesthetized dogs (Group A), the response to a hyperinsulinemic test was determined before and after NO inhibition, with L-nitro-arginine methyl esther (L-NAME), during the last 45 min of the experiment. In seven dogs (Group B), NO inhibition was induced before and maintained throughout hyperinsulinemia. In Group A, the hyperinsulinemic test did not alter MAP, but induced a significant reduction in both renal and mesenteric blood flow without a significant change in iliac blood flow. In contrast, the administration of L-NAME in Group B was followed by a significant decrease in mesenteric, renal, and iliac blood flow, but mean arterial pressure remained unchanged. In this group, hyperinsulinemia instituted after the blockade of NO was followed by a significant elevation in blood pressure levels, concomitant with reductions in blood flow to the three vascular beds. In summary, acute hyperinsulinemia induced a redistribution of blood supply, which preserves skeletal muscle irrigation while reducing blood flow to the kidney. Nitric oxide participates in this redistribution because L-NAME infusion abolishes the compensatory influence on skeletal muscle blood flow.

Effects of cicaprost and fosinopril on the progression of rat diabetic nephropathy.

We have studied the effects of chronic therapy with cicaprost (a PGI2 analog), fosinopril (a converting enzyme inhibitor), and the combination of both drugs on the progression of experimental diabetic nephropathy. Uninephrectomized streptozotocin-induced diabetic rats were maintained for 8 months with plasma glucose between 13.7 and 22.0 mmol/L to hasten renal damage. Systemic and renal parameters were measured periodically, and at sacrifice structural and morphometrical renal studies were performed to evaluate diabetic injury. Control rats exhibited characteristic features of this model, such as high blood pressure and plasma creatinine and urinary albumin excretion, together with prominent alterations in the kidney (renal and glomerular hypertrophies, mesangial matrix expansion, and tubular alterations). The three therapies attenuated equivalently the progression of diabetic renal injury, as estimated by lower urinary albumin excretion, renal and glomerular hypertrophies, and a better renal architectural preservation. No synergistic action was appreciated with the combined therapy. However, renal preservation achieved with cicaprost was not linked to reductions in systemic blood pressure, whereas in the groups treated with fosinopril the hypotensive effect of this drug could have contributed to the positive outcome of the therapy. Therefore, nephroprotection exerted by this PGI2 analog in this model seems more related to the derangement of renal local mechanisms than to systemic blood pressure control. Finally, the possibility that an impaired prostacyclin synthesis or bioavailability is involved in the pathogenesis of the diabetic nephropathy in this model underlies our results.

Effects of L-arginine infusion on renal hemodynamics and sodium excretion during hypo-, normo-, and hyperinsulinemia, as studied in dogs.

The response of renal hemodynamics and sodium excretion (NaU) to an infusion of L-arginine, in the presence (experiment I) or absence (experiment II) of endogenous insulin secretion and during a sustained hyperinsulinemic euglycemic state (experiment III), was studied in 10 age-matched beagle dogs. The experiments were preceded by a standard oral glucose tolerance test (OGTT), performed 1 week before experiment I. One week resting periods were allowed between experiments I, II, and III. No differences in renal hemodynamics and NaU were observed between basal (experiment I) and insulin secretion suppressed states (experiment II). L-Arginine infusion increased renal plasma flow (RPF), glomerular filtration rate (GFR), and NaU to a similar extent in both experiments. The hyperinsulinemic-euglycemic state (experiment III) induced a decrease in renal hemodynamics and NaU. In this situation, the infusion of L-arginine increased NaU, but was unable to increase RPF and GFR. Our data suggest that a sustained hyperinsulinemic state can interact with the physiological vasoactive mechanisms involved in the regulation of renal vasculature. These results may be pertinent to human disease, especially in pathological conditions in which insulin resistance is present.

Effects of chronic combined treatment with captopril and pravastatin on the progression of insulin resistance and cardiovascular alterations in an experimental model of obesity in dogs.

Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. However, the progression of these alterations in relation to weight gain has not been investigated in detail. Therefore, we studied the evolution of insulin resistance and associated risk factors in a model of experimental obesity in dogs. We also studied whether chronic exposure to these pathogenic factors could induce cardiac and vascular alterations. Twenty male age- and body weight-matched beagle dogs were divided into four groups (n = 5), according to diet and pharmacologic therapy received, and followed for 2 years. Control animals were maintained with a regular diet, while the 15 remaining animals were fed a high-fat diet. The Obese group of dogs received no therapy, whereas the Capto group received 25 mg/12 h captopril, and the Prava+Capto was treated with 10 mg/24 h pravastatin plus the same dose of captopril throughout the study. Periodical determinations of clinical and biochemical parameters were made, and the degree of insulin resistance was also estimated. After the 2-year follow-up, the dogs were killed and vascular thickening in the aorta and the coronary arteries was evaluated. In addition, cardiac hypertrophy was estimated by heart weight and free-wall left ventricular width. Chronic pravastatin plus captopril treatment, together with decreasing weight gain rate, ameliorated the progression of insulin resistance and associated risk factors (hyperinsulinemia, hypercholesterolemia) related to this severe model. In addition, this combined therapy showed cardioprotective action, as cardiac and vascular hypertrophy observed in the Obese group was prevented. These positive results seems to emerge from the synergistic effects of both drugs, as captopril as monotherapy induced only a slight benefit on these parameters.

Effects of UP269-6, a new angiotensin II receptor antagonist, and captopril on the progression of rat diabetic nephropathy.

To estimate the effects of UP269-6, a nonpeptide angiotensin II receptor antagonist, and captopril, a converting enzyme inhibitor, on the progression of nephropathy, 77 uninephrectomized diabetic rats were maintained for 8 months with plasma glucose levels from 300 to 500 mg/dL. Systemic and renal parameters were periodically measured, and, at the time of death, a histological evaluation of renal damage was performed. Control rats (no additional treatment but insulin) showed increased blood pressure and urinary albumin levels, together with prominent alterations in the kidney (renal and glomerular hypertrophies, tubular atrophy, and 19% of sclerotic glomeruli). Captopril (50 mg/kg/day) and UP269-6 (10 mg/kg/day) reduced blood pressure and albumin excretion levels, and improved histological renal preservation (lower renal and glomerular hypertrophies, tubular atrophy, and percentage of sclerotic glomeruli: 5% and 7%, respectively). Finally, a low dose of UP269-6 (1 mg/kg/day), which induced an intermediate level of blood pressure between control and the other treated groups, produced an equivalent degree of nephroprotection. Our data demonstrate the efficacy of this new angiotensin II receptor antagonist on the progression of diabetic renal damage. These results also reinforce the role attributed to angiotensin II in the development of renal derangement in this model, as UP269-6 is devoid of agonistic effect on the kinin system.

Effects of hyperinsulinemia on vascular blood flows in experimental obesity.

Human obesity, which is very common in Polycystic Ovaries Syndrome and in "X Syndrome", constitutes an insulin-resistance state in which multiple clinical, biochemical and hemodynamic alterations coexist. Insulin resistance in the obese has been recently associated with an endothelial dysfunction. To investigate the possibility that clinical and metabolic derangements related to insulin resistance could induce changes in vascular blood flows, we have studied the levels of mesenteric (MBF), renal (RBF) and femoral (FBF) blood flows in Beagle dogs kept for 2 years on a normal (control group) or high fat diet (obese group). This experimental model exhibits many of the abnormalities with the human syndrome. In addition, we have tested the effects of chronic treatment with captopril (capto group) in monotherapy or in association with pravastatin (prava+capto group) on the hemodynamic changes associated with this diet. After the two year follow-up, Transonic flow probes were placed around the three arteries to measure basal blood flows and their response to a hyperinsulinemic-normoglycemic test in anesthetized animals. During this test the degree of insulin sensitivity was estimated. In association with higher body weight, blood pressure, insulin resistance, and fasting levels of insulin and total cholesterol, the obese group exhibited decreased basal levels of FBF and a greater femoral vasoconstriction during hyperinsulinism (P < 0.05 vs control). Combined therapy with captopril and pravastatin ameliorated the reduction in basal FBF and hyperinsulinism-induced vasoconstriction (P < 0.05), in addition to the beneficial effects on insulin sensitivity, and clinical and metabolic parameters. Synergistic beneficial effects of both drugs on lipid and carbohydrate profiles may account for this positive outcome, by attenuating the atherogenic process associated with this model.

Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist?

To study ovarian and adrenal steroid profiles of women with idiopathic hirsutism, we compared sex steroid and basal and corticotropin (ACTH)-stimulated adrenal steroid levels before and after ovarian suppression induced by a long-acting gonadotropin-releasing hormone agonist analog (GnRH-a) in 24 hirsute women without hyperandrogenemia. Twelve healthy women served as controls for basal and ACTH-stimulated adrenal steroid levels. Serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estradiol (E2), basal and ACTH-stimulated 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), delta 4-androstenedione (delta 4-A), 11-deoxycortisol (S) and cortisol (F), and basal and luteinizing hormone-releasing hormone (LHRH)-stimulated gonadotropin levels were measured before and 21 days after 3.75 mg intramuscular triptorelin in hirsute women. Basal T levels and basal and ACTH-stimulated delta 4-A, DHEA, and DHEAS levels were not different in hirsute women with respect to controls. Basal and ACTH-stimulated 17OHP was elevated, and decreased to normal after ovarian suppression with triptorelin. Although basal and ACTH-stimulated delta 4-A levels were normal, the delta delta 4-A/delta F and delta delta 4-A/delta 17OHP ratios were elevated and remained elevated after ovarian suppression, suggesting enhanced adrenal delta 4-17,20-lyase activity. T, F, S, and DHEAS levels were not affected by ovarian suppression. Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids. We conclude that idiopathic hirsute women with normoandrogenemia show an increase in ovarian secretion of 17OHP and a minimally increased adrenal delta 4-17, 20-lyase activity, suggesting that mild forms of ovarian and adrenal functional hyperandrogenism may be present in these patients with otherwise unexplained hirsutism.

Aging abolishes the renal response to L-arginine infusion in essential hypertension.

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.