Rafael García-Robles

Blood Pressure Control and Physician Management of Hypertension in Hospital Hypertension Units in Spain

Goal blood pressure (BP) was defined by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) and the World Health Organization–International Society of Hypertension (WHO/ISH) as <140 mm Hg systolic and <90 mm Hg diastolic for the general and <130 mm Hg systolic and <85 mm Hg diastolic for special high-risk populations. However, there are few reports that address BP control among special subgroups of hypertensives by reference to targeted BP. We therefore conducted a study to evaluate BP control of 4049 hypertensives in 47 hospital-based hypertension units in Spain. Overall, 42% of patients achieved goal BP (<140 mm Hg systolic and <90 mm Hg diastolic). Only 13% of diabetic patients and 17% of those with renal disease achieved the BP goal (<130 mm Hg systolic and <85 mm Hg diastolic), and only 10% and 12%, respectively, achieved the even more rigorous goal (<130 mm Hg systolic and <80 mm Hg diastolic). Likewise, only 18% of patients in JNC-VI risk group C and 17% of WHO/ISH high-risk patients attained a goal BP <130 mm Hg systolic and <85 mm Hg diastolic. BP control (<125 mm Hg systolic and <75 mm Hg diastolic) was extremely low (2%) in patients with proteinuria >1 g/d. Poorer BP control was observed among patients at high risk, with diabetes, renal disease, or obesity, than in lower-risk groups. BP control was lower for systolic than for diastolic BP. In >50% of uncontrolled patients, no measures were taken by doctors to optimize pharmacologic treatment, and approximately one-third of patients were still using drug monotherapy. Control of BP, particularly of systolic BP, is still far from optimal in hospital-based hypertension units. Patients at high risk, with diabetes or proteinuria, warrant focused attention. Moreover, a more aggressive behavior of doctors treating uncontrolled hypertension is needed.

Circulating leptin concentrations in women with hirsutism.

OBJECTIVE To evaluate serum leptin concentrations in hirsute women. DESIGN Controlled clinical study. SETTING Tertiary institutional hospital. PATIENT(S) Thirty-three hirsute women and 11 healthy female controls. INTERVENTION(S) Serum samples were obtained at baseline and on day 1 (gonadal stimulation) and day 21 (gonadal suppression) after the IM injection of a single 3.75-mg dose of triptorelin. MAIN OUTCOME MEASURE(S) Leptin, T, sex hormone-binding globulin (SHBG), insulin, and glucose levels and free androgen index. RESULT(S) Leptin levels were increased in hirsute women in comparison with control subjects at baseline and on day 1. Leptin levels increased on day 1 compared with baseline and then decreased to baseline by day 21. Leptin levels correlated with body mass index (r = 0.76), SHBG levels (r = -0.52), free androgen index (r = 0.38), insulin levels (r = 0.46), and the glucose/insulin ratio (r = -0.38). When the effect of obesity on these results was removed by analysis of covariance and partial correlation analysis, leptin levels remained elevated only on day 1 and the only correlations that remained significant were those of leptin with insulin (r = 0.24) and the glucose/insulin ratio (r = -0.24). CONCLUSION(S) The increased leptin levels found in hirsute women are related mainly to obesity and also to insulin resistance. Leptin levels increased during gonadal stimulation and returned to baseline during gonadal suppression, suggesting that leptin also is influenced by the gonadal axis.

Hypertensive Renal Damage in Metabolic Syndrome Is Associated with Glucose Metabolism Disturbances

Recent evidence highlights the relationship between metabolic syndrome (MS) and increased risk of cardiovascular (CV) diseases. Mild renal function abnormalities are associated with an enhanced CV risk, considered to be due to the presence of associated risk factors. Hence, MS and renal abnormalities could be linked and contribute to augment CV risk. For estimating the prevalence of diminished creatinine clearance (CC; <60 ml/min per 1.73 m(2)) in hypertensive patients with or without MS and for investigating the factors accompanying this abnormality, 1625 hypertensive patients, aged 18 yr or older, were included. The presence of MS was defined according to the Adult Treatment Panel III criteria. The overall prevalence of MS was 49.4% (n = 802). No significant difference was found for CC between those with and without MS, albeit the presence of MS was accompanied by greater urinary albumin excretion (P = 0.01). The prevalence of a diminished CC was also similar in the two groups. MS-positive patients presented a progressive decay in CC when classified as normoglycemic (n = 319), impaired fasting glucose (n = 237), and diabetic patients (n = 246; 85.9 +/- 30.2, 81.8 +/- 26.8, and 75.2 +/- 25.7 ml/min per 1.73 m(2), respectively; P = 0.0007 linearity test) and the opposite for microalbuminuria (29.5 +/- 45.5, 45.0 +/- 96.6, and 74.1 +/- 146.3 mg/24 h, respectively; P = 0.001 linearity test). In multiple regression analysis, factors related to the finding of a diminished CC in MS and non-MS patients were similar. Hypertensive patients at a relatively young age present with an elevated prevalence of minor abnormalities of renal function that is mostly related to the presence of metabolic alteration of glucose together with age and BP.

Lack of an ovarian function influence on the increased adrenal androgen secretion present in women with functional ovarian hyperandrogenism

OBJECTIVE To evaluate whether ovarian function might have an influence on the adrenal hyperandrogenism present in patients with functional ovarian hyperandrogenism. DESIGN Controlled clinical study. SETTING Tertiary institutional hospital. PATIENT(S) Twenty-nine hirsute women with functional ovarian hyperandrogenism and 12 normal controls. INTERVENTION(S) The ACTH and GnRH tests were performed before and during triptorelin-induced ovarian suppression in patients. The normal women served as controls for the ACTH test. MAIN OUTCOME MEASURE(S) Basal and ACTH-stimulated steroid values. RESULT(S) All patients presented elevated T and free androgen index, which normalized after triptorelin. Patients with functional ovarian hyperandrogenism and adrenal hyperandrogenism, defined by elevated basal DHEAS (n = 10), presented enhanced delta 4-17, 20-lyase activity, which persisted during ovarian suppression. delta 4-17,20-lyase activity was normal in the functional ovarian hyperandrogenism patients without adrenal hyperandrogenism (n = 19). No correlation was observed between the any of the indexes of the adrenal enzymatic activities evaluated and plasma E2 or T. CONCLUSION(S) Increased adrenal delta 4-17,20-lyase activity is present in functional ovarian hyperandrogenism women with adrenal hyperandrogenism. No influence of the excess ovarian androgens or estrogens was found on any of the adrenal enzymatic pathways explored.

Ovarian suppression with triptorelin and adrenal stimulation with adrenocorticotropin in functional hyperadrogenism : role of adrenal and ovarian cytochrome P450C17α

OBJECTIVES To validate combined ovarian suppression with triptorelin and adrenal stimulation with ACTH in the diagnosis of female hyperandrogenism and to provide new insights into the adrenal-ovarian relationship present in this disorder. DESIGN Comparison of sexual steroids and basal and ACTH-stimulated steroid levels before and after ovarian suppression induced by triptorelin. SETTING Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain. PARTICIPANTS Thirty-nine nonselected women with hyperandrogenism. MAIN OUTCOME MEASURES Serum levels of T, 17-hydroxyprogesterone (17-OHP), 17-hydroxy-pregnenolone, DHEA and DHEAS, androstenedione (delta 4-A), 11-deoxycortisol, and cortisol. RESULTS Elevated T independent of ovarian suppression pointed to an adrenal disorder in six patients (one with an androgen-producing adenoma, two with late-onset 21-hydroxylase deficiency, three with functional adrenal hyperandrogenism). Nineteen patients had functional ovarian hyperandrogenism as elevated T normalized after ovarian suppression and were subdivided into ovDHEAS+ (n = 7) and ovDHEAS = (n = 12) subgroups depending on the presence of DHEAS hypersecretion. Finally, 14 patients had idiopathic hirsutism according to normal T before and after ovarian suppression. Comparisons of initial hormonal values between groups and with reference values obtained from normal women (n = 11) disclosed in functional adrenal hyperandrogenism an elevation of T and basal and stimulated DHEAS, delta 4-A, and 17-OHP with respect to normal women. These abnormalities were also present in ovDHEAS+ except for basal delta 4-A, which was normal, whereas only T and stimulated 17-OHP were elevated in ovDHEAS =. In the idiopathic group all steroids were normal with the exception of a mild elevation in stimulated DHEAS. CONCLUSIONS These results show a continuum of abnormalities in hyperandrogenic women, suggesting an enhanced cytochrome P450c17 alpha activity in the adrenal and the ovary as the shared mechanism between functional adrenal hyperandrogenism and functional ovarian hyperandrogenism.

How far should blood pressure be reduced in diabetic hypertensive patients

EPIDEMIOLOGY OF DIABETES: Diabetes mellitus and arterial hypertension are closely related diseases that strongly predispose an individual to atherosclerotic cardiovascular disease and to renal failure. High blood pressure is twice as frequent in diabetics compared with the general population, and often precedes and contributes to the development of diabetic nephropathy. The prevalence of coexisting arterial hypertension and non-insulin-dependent diabetes mellitus (NIDDM) is increasing as populations age, giving an increased prevalence of both diseases. TREATMENT OF HYPERTENSIVE DIABETIC PATIENTS: The goal of treating arterial hypertension in diabetic patients is to prevent death and disability associated with high blood pressure. In addition, other reversible risk factors for cardiovascular disease, seen so frequently in hypertensive diabetics, also need to be addressed. The optimal goal of blood pressure control in diabetics has not been established, but there are indications that it should be lower than the 130/85 mmHg systolic/diastolic pressure recommended by current guidelines. In the presence of multiple associated risk factors, most guidelines suggest a threshold for intervention of > or = 140/90 mmHg. In particular, in hypertensive diabetic patients intervention must be early and aggressive.

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.

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.

Hyperuricemia, low urine urate excretion and target organ damage in arterial hypertension

Background: Hyperuricemia can be the consequence of an increased urate production, a decreased renal excretion, or both. An increased prevalence of hyperuricemia has been described in essential hypertensive patients partly due to a decreased renal urinary urate excretion (UUE). Hyperuricemia has been shown to be associated with an increased risk of cardiovascular disease in hypertensive patients in some but not in all epidemiological studies in which this relationship has been investigated. Objective: To assess the influence of low UUE in the association between serum urate, renal function and hypertension severity. Patients and Methods: This cross‐sectional study was carried out in a sample of 677 male hypertensive patients, aged 35–60 years, with essential arterial hypertension consecutively attended in a hospital hypertension unit. The presence of hypertension‐related organ damage at diagnosis was classified according to classical WHO criteria as grade 1, 2 or 3. Urate underexcretion was defined as 24‐h urinary urate below the product serum urate × 100. Results: Mean serum urate levels were 6.4 ± 1.6 mg/dl in the total sample. Hyperuricemia (serum urate >7 mg/dl) was present in 28.5% of patients and only 17.0% had underexcretory hyperuricemia. This subgroup of patients exhibited the higher rate of hypertension‐related target organ damage (TOD). A multivariate analysis, showed that underexcretory hyperuricemia but not hyperuricemia remained an independent predictor of TOD (odds ratio 2.5. 95% CI 1.6–3.89). Serum urate correlated positively with serum creatinine in hyperuricemic patients (r = 0.50, p < 0.001), but not in patients with underexcretory hyperuricemia (r = 0.21, p = 0.18). Conclusions: Underexcretory hyper‐uricemia is strongly related to hypertensive organ damage and this relationship does not seem to be mediated by a decreased renal function. This aspect could underline the predictive value of hyperuricemia independently of serum creatinine. UUE could improve the clinical predictive value of hyperuricemia as a cardiovascular risk factor.

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.