Increased central body fat deposition precedes a significant rise in resting blood pressure in male offspring of essential hypertensive parents: a 5 year follow-up study.

OBJECTIVES: As long as offspring of essential hypertensive parents (OHyp) are lean, their blood pressure usually remains within normal limits. The mechanism(s) transforming this 'genetically dysregulated normotension' into hypertension are unclear. We hypothesized that OHyp are not only genetically prone to develop hypertension, but may also have a particular propensity to accumulate central body fat. DESIGN: A 5-year follow-up cohort study. SETTING: University Hospital in Switzerland. PARTICIPANTS: Seventeen young (25 +/- 1 years, mean +/- SD), lean healthy normotensive male OHyp and 17 age- and sex-matched offspring of normotensive parents (ONorm) paired for baseline blood pressure with the OHyp. MAIN OUTCOME MEASURES: Resting and exercise blood pressure, body weight, body mass index (BMI) and waist-to-hip ratio were assessed at baseline and after 5 years. RESULTS: At baseline, body weight, BMI, waist-to-hip ratio and blood pressure did not differ significantly between OHyp and ONorm. At follow-up, body weight was increased in both groups (from 73.9 +/- 6.0 to 77.7 +/- 8.1 kg in OHyp, P = 0.008, and from 71.5 +/- 6.9 to 73.5 +/- 6.6 kg in ONorm, P = 0.03). BMI followed a similar pattern. In contrast, waist-to-hip ratio increased in OHyp (from 0.84 +/- 0.03 to 0.87 +/- 0.03, P = 0.012), but not in ONorm (from 0.84 +/- 0.03 to 0.84 +/- 0.04, P = 0.79) and was therefore higher in OHyp at follow-up (P = 0.011, OHyp versus ONorm). Peak systolic blood pressure during dynamic exercise also rose at 5 years in the OHyp (from 182 +/- 10 to 214 +/- 17 mmHg, P = 0.0001) while resting systolic blood pressure only tended to do so (from 121 +/- 7 to 128 +/- 12 mmHg, P = 0.07). In ONorm, resting and peak dynamic exercise systolic blood pressure remained unchanged (119 +/- 11 versus 121 +/- 9 mmHg, baseline versus follow-up, P = 0.40, and 186 +/- 12 versus 196 +/- 22 mmHg, P = 0.10, respectively). Thus, systolic peak exercise blood pressure was significantly (P = 0.014) elevated at follow-up in OHyp compared to ONorm, while resting systolic blood pressure only tended (P = 0.06) to do so. CONCLUSIONS: Initially lean normotensive OHyp have a disparate long-term course of central body fat as compared to ONorm. Thus, OHyp are not only genetically prone to develop hypertension, but they also have a particular propensity to accumulate central body fat, even before a distinct rise in resting blood pressure occurs. The exaggerated blood pressure response to exercise observed at follow-up in the OHyp represents another marker that confers them a greater risk of developing future hypertension.

Diastolic dysfunction precedes myocardial hypertrophy in the development of hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy and impaired diastolic function may occur early in systemic hypertension, but longitudinal studies are missing. METHODS: We performed an echocardiographic follow-up study in young initially normotensive male offspring of hypertensive (OHyp) (n = 25) and normotensive (ONorm) (n = 17) parents. Blood pressure (BP), LV mass, and mitral inflow were determined at baseline and after 5 years. Pulmonary vein flow pattern assessment and septal myocardial Doppler imaging were additionally performed at follow-up. RESULTS: At follow-up, BP was not significantly different between the two groups (128 +/- 11/84 +/- 10 v 123 +/- 11/81 +/- 5 mm Hg, OHyp v ONorm) but five OHyp had developed mild hypertension. LV mass index remained unchanged and was not different between the two groups at follow-up (92 +/- 17 v 92 +/- 14 g/m2). Diastolic echocardiographic properties were similar at baseline, but, at follow-up, the following differences were found: mitral E deceleration time (209 +/- 32 v 185 +/- 36 msec, P < .05) and pulmonary vein reverse A wave duration (121 +/- 15 v 107 +/- 12 msec, P < .05) were prolonged in the OHyp as compared to the ONorm. Compared to the normotensive subjects, the five OHyp who developed hypertension had more pronounced alterations of LV diastolic function, that is, significantly higher mitral A (54 +/- 7 v 44 +/- 9 cm/sec, hypertensives v normotensives, P < .05), lower E/A ratio (1.31 +/- 0.14 v 1.82 +/- 0.48, P < .05), increased systolic-to-diastolic pulmonary vein flow ratio (1.11 +/- 0.3 v 0.81 +/- 0.16, P < .005), longer myocardial isovolumic relaxation time (57 +/- 7 v 46 +/- 12 msec, P < .05) as well as smaller myocardial E (10 +/- 1 v 13 +/- 2 cm/sec, P < .05) and E/A ratio (1.29 +/- 0.25 v 1.78 +/- 0.43, P < .05), despite similar LV mass (91 +/- 16 v 93 +/- 18 g/m2). CONCLUSIONS: Over a 5-year follow-up, initially lean, normotensive, young men with a moderate genetic risk for hypertension, developed Doppler echocardiographic alterations of LV diastolic function compared to matched offspring of normotensive parents. These alterations were more pronounced in the OHyp who developed mild hypertension and occurred without a distinct rise in LV mass.

Metabolic profile of indapamide sustained-release in patients with hypertension: data from three randomised double-blind studies.

OBJECTIVE: To evaluate the influence of indapamide sustained-release (SR) 1.5 mg/day, a thiazide-related sulfonamide diuretic, on serum levels of lipids (total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and triglycerides), glucose and uric acid, and renal function (serum urea and creatinine levels). METHODS: Pooled data from three randomised, double-blind, controlled studies are analysed. Two of these studies were of short duration (2 and 3 months), one of which included a 9-month nonblind extension phase, and the third was a 12-month prospective study. Short- and long-term metabolic effects of the treatment could thus be analysed. All studies were conducted in patients with mild-to-moderate hypertension; the total population randomised in these studies comprised 1195 patients, of whom 505 had left ventricular hypertrophy (LVH). RESULTS: After 2 to 3 months' treatment with indapamide SR 1.5 mg/day, there was no significant change from baseline in serum lipid levels and glucose levels. This neutral effect was maintained after 9 and 12 months of treatment. Renal function was not affected by short- or long-term indapamide SR 1.5 mg/day therapy. Serum uric acid level was slightly increased after short-term therapy, but was restored to baseline values during long-term therapy with indapamide SR 1.5 mg/day. CONCLUSIONS: Indapamide SR 1.5 mg/day has no deleterious effect on glucose metabolism, serum levels of lipids and uric acid, or renal function. This antihypertensive agent can be considered to be an attractive therapeutic choice for all patients with mild-to-moderate hypertension, including the elderly and patients with increased cardiovascular risks, i.e. those with LVH.

Nephropathy subsequent to hyperlipidemia.

The relationship between lipid abnormalities and the pathogenesis of renal disease is still unclear. Although most patients with primary hyperlipidemia do not develop renal function impairment, experimental and clinical data indicate a possible damaging effect of a disturbed lipid metabolism on the kidney. We report the case history of a patient with hyperlipidemia and mild nephropathy in which an accidentally removed kidney showed intrarenal arteriosclerosis which occured before the development of other cardiovascular risk factors, indicating that primary dyslipidemia induced nephroangiosclerosis.

Hypovolemia contributes to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus.

PURPOSE: To investigate whether body sodium content and blood volume contribute to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. SUBJECTS AND METHODS: Exchangeable sodium, plasma and blood volumes, and catecholamine, renin, and aldosterone levels were assessed in 10 patients with Type II diabetes mellitus who had orthostatic hypotension and control groups of 40 diabetic patients without orthostatic hypotension and 40 normal subjects of similar age and sex. In subgroups, clinical tests of autonomic function and cardiovascular reactivity to norepinephrine and angiotensin II infusions were performed. RESULTS: In diabetic patients with orthostatic hypotension, mean (+/- SD) supine blood pressure was 165/98 +/- 27/12 mm Hg (P <0.05 compared with other groups) and mean upright blood pressure was 90/60 +/- 38/18 mm Hg. Compared with controls, diabetic patients with orthostatic hypotension had a 10% lower blood volume. They also had less exchangeable sodium than patients with diabetes who did not have orthostatic hypotension (P <0.01). Compared with both groups of controls, diabetic patients with orthostatic hypotension had decreased 24-hour urinary norepinephrine excretion and a reduced diastolic blood pressure response to handgrip (P <0.05). Moreover, they displayed reduced products of exchangeable sodium or blood volume and sympathetic function indexes. Cardiovascular pressor reactivity to norepinephrine was enhanced (P <0.01) and beat-to-beat variation decreased (P <0.01) in both groups of diabetic patients. Microvascular complications were more prevalent in the diabetic patients with orthostatic hypotension (90% vs 35%). CONCLUSIONS: Patients who have Type II diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension.

Metabolic effects of temocapril in hypertensive patients with diabetes mellitus type 2.

Compared with other angiotensin-converting enzyme (ACE) inhibitors, the elimination of temocapril is less dependent on renal function. To investigate the metabolic and antihypertensive effects of temocapril in diabetic hypertensives, 30 patients with diabetes mellitus type 2 and mild to moderate hypertension [diastolic blood pressure (BP) 90-115 mm Hg] and without azotemia (plasma creatinine < 180 microM) were evaluated in a prospective randomized double-blind placebo-controlled study. After a 4-week placebo run-in, they received temocapril, 20 mg daily (n = 19), or placebo (n = 11) for 6 weeks. Insulin sensitivity index (SI), determined by the Minimal Model method of Bergman, serum lipoproteins, plasma renin activity, fibrinogen, and microalbuminuria were assessed at the end of the placebo run-in phase and the double-blind treatment phases. Temocapril but not placebo administration produced a significant decrease in supine BP (152/92+/-5/3 vs. 162/98+/-5/2 mm Hg; p < 0.01) and increase in plasma renin (p < 0.05). Variation of SI during temocapril treatment did not reach statistical significance (0.95+/-0.2 before vs. 1.44+/-0.4 x 10(-4)/min/mU/L after treatment). During administration of temocapril or placebo, no significant changes in fasting plasma glucose, insulin, and serum levels of total triglycerides, cholesterol, lipoprotein cholesterol fractions, or fibrinogen were observed. Microalbuminuria decreased significantly on temocapril treatment (49+/-10 vs. 79+/-17 mg/24 h; p < 0.01) but not on placebo. These findings demonstrate that in hypertensive patients with diabetes mellitus type 2, short-term treatment with temocapril is neutral to insulin sensitivity, lipoprotein metabolism, and fibrinogen, and significantly reduces microalbuminuria.

Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men.

OBJECTIVES: Elevated plasma endothelin (ET)-1 levels have been described in insulin-resistant states such as syndrome X, obesity, non-insulin-dependent diabetes mellitus, and in some studies in essential hypertension. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/or insulin sensitivity in humans, we assessed these variables during low, non-pressor-dose ET-1 compared with placebo infusion. DESIGN: In a randomized, single blind, crossover design, 10 lean normotensive male subjects received either an intravenous infusion of subpressor doses of ET-1 dissolved in polygeline or a control infusion of polygeline only (placebo). Using dynamic assessment by the minimal model approach with the modified frequent sampling intravenous glucose tolerance test (FSIGT) the following and other parameters were measured: insulin sensitivity; acute insulin response to glucose (AIR(G)) calculated as the average of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were subtracted; the initial area under the curve (AUC(1-19)) from insulin values between time 0 and 19 min and the first-phase insulin secretion (phi1) from insulin kinetics parameters. RESULTS: ET-1 infusion reduced AIR(G) (to 34.85 +/- 4.27 compared with 49.3 +/- 6.9 microU/ml during placebo, P=0.017) and the acute C-peptide response to glucose (to 2.33 +/- 0.41 compared with 3.1 +/- 0.44 ng/ml, P=0.018), decreased plasma insulin levels during the FSIGT compared with placebo (analysis of variance P<0.0001) and decreased the AUC(1-19) (to 2.1 +/- 0.2 compared with 2.9 +/- 0.3 U/l per 20 min, P<0.01) while phi1 tended to be lower. S1 measured during ET-1 infusion was unaltered (11.11 +/- 1.91 x 10(-4) versus 10.88 +/- 2.11 10(-4)/min per mU per l, NS). CONCLUSIONS: These findings demonstrate that an increase in circulating ET-1 to levels observed in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity.

[New principle in therapy of erectile dysfunction: sildenafil]. / Neues Prinzip zur Therapie der erektilen Dysfunktion: Sildenafil.

Erectile dysfunction may have psychological as well as a variety of organic causes. This necessitates in each case a careful medical evaluation. Various commonly used drugs, as well as alcohol and narcotics, may interfere with erection and should, whenever possible, be discontinued before starting treatment. Organic diseases should be identified and, if feasible, specially treated. In the remaining majority of afflicted men, psychological treatment and partner counseling may produce an improvement, but ultimately what is necessary remains an effective and safe medication. The drug, Sildenafil, introduces a new therapeutic principle. During sexual nerve stimulation, nitric oxide (NO) is released from nerves into the cells of the penile erectile bodies. NO activates in turn its "second messenger", the substance cyclic GMP, and the latter induces the vasorelaxation and blood filling of the erectile bodies. Orally administered Sildenafil competitively inhibits phosphodiesterase type 5, which physiologically inactivates cyclic GMP in the erectile bodies. Thus, Sildenafil increases in men with erectile dysfunction the NO-stimulated cyclic GMP concentration and, thereby, improves erection. This new therapy is attractive because 1. Sildenafil is the first pill (for oral use) with established efficacy that benefits most men with insufficient erection; 2. compared with previous therapeutic approaches (such as drug injections in the penis, instillations into the urinary duct, vacuum pumps or even prostheses), Sildenafil is at least as effective, is easy to take and appears well tolerated with no risk of a prolonged erection; 3. remarkably, this medication stimulates erection only during sexual arousal and, thus, has a rather "natural" effect, and 4. side effects (including headache, facial flushing and dyspepsia or epigastric discomfort) were mostly of mild degree and transient, so that only 4% of men interrupted treatment for this reason. Sildenafil does not need to be taken daily, but may be taken, when needed, 1 hour before a planned sexual activity. The new pill has the potential to enliven the boys "wunder horn" with fresh sound.

Normotensive offspring of hypertensive parents: no evidence of left ventricular diastolic dysfunction in a cross-sectional study.

Left ventricular filling alterations occur early in the development of systemic hypertension. We tested the hypothesis that alteration of diastolic filling might be present in a normotensive population with increased genetic risk for hypertension in the absence of increased left ventricular mass. In a blinded study we compared 31 lean, normotensive offspring of hypertensive parents having normal left ventricular mass (risk group) with 30 matched individuals without family history of hypertension (control group). Left ventricular diastolic function was assessed using Doppler echocardiography. Transmitral flow velocities showed no significant differences between the two groups. Peak early diastolic flow was 0.79+/-0.12 m/s and 0.79+/-0.13 m/s in the risk group and control group, respectively. Peak late diastolic flow was 0.44+/-0.08 in the risk group and 0.42+/-0.11 m/s in the control group. The ratio of early to late diastolic velocity was 1.85+/-0.32 and 1.94+/-0.37. The deceleration time of the early diastolic flow was identical in both groups: 138+/-24 ms and 138+/-23 ms. There was no significant prolongation of the isovolumic relaxation time in the risk group: 75+/-17 compared to 73+/-17 ms in the control group. Doppler measurements showed no correlation with left ventricular mass. We conclude that, in this cross-sectional study, young normotensive offspring of hypertensive parents do not exhibit Doppler echocardiographic signs of diastolic filling alteration in the absence of increased left ventricular mass.

Effects of angiotensin II-receptor blockade with losartan on insulin sensitivity, lipid profile, and endothelin in normotensive offspring of hypertensive parents.

Humans genetically predisposed to hypertension tend to develop at a prehypertensive stage subtle metabolic and hormonal dysregulations, and certain of these could potentially be angiotensin II dependent. Therefore the aim of this study was to investigate the effects of the angiotensin II-receptor antagonist losartan on insulin sensitivity, lipid profile, and plasma endothelin-1 (ET-1) levels in normotensive offspring of hypertensive parents with a randomized, double-blind, placebo- controlled, crossover design. Insulin sensitivity index (SI), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total and HDL cholesterol, serum triglycerides, and plasma ET-1 levels were assessed in 19 young (26.2 +/- 0.7 years, mean +/- SEM), healthy, lean [body mass index (BMI), 22.6 +/- 0.7 kg/m2] normotensive male offspring of essential hypertensive parents after 14 days of losartan, 50 mg, and 14 days of placebo, respectively. Compared with placebo, losartan administration did not significantly modify SI (12.2 +/- 1.7 vs. 12.7 +/- 1.5 x 10(-4)/min/microU/ml on placebo), fasting plasma insulin and glucose, as well as the areas under the insulin and glucose curves. Plasma ET-1 levels also did not differ significantly between the placebo and losartan administration phases (1.1 +/- 0.06 vs. 1.2 +/- 0.06 pg/ml). However, serum total cholesterol and triglycerides decreased significantly with losartan treatment (3.8 +/- 0.2 vs. 4.1 +/- 0.2 mM and 0.9 +/- 0.1 vs. 1.1 +/- 0.1 mM, respectively; p < 0.01). Body weight, BMI, heart rate (HR), blood pressure (BP), and 24-h urinary sodium, potassium, and creatinine values were stable throughout the study. These findings demonstrate that angiotensin II-receptor blockade with losartan, administered in the therapeutic dose of 50 mg daily, does not alter insulin sensitivity determined by the Minimal Model Method of Bergman and does not affect ET-1 in normotensive offspring of essential hypertensive parents. The normal insulin sensitivity in the subjects studied might explain why losartan did not improve it. However, losartan significantly reduced serum total cholesterol and total triglyceride levels.

Differential activation of cardiac and peripheral sympathetic nervous system by nifedipine: role of pharmacokinetics.

OBJECTIVES: We sought to study the effects of short-acting and long-acting nifedipine on the sympathetic nervous system (SNS), heart rate (HR) and blood pressure (BP) of normotensive subjects under baseline conditions and during SNS stimulation. BACKGROUND: Calcium channel antagonists in different pharmacokinetic formulations are widely used in patients with coronary artery disease or hypertension. Short-acting formulations activate the SNS, an action that may be disadvantageous in patients with coronary disease, especially if left ventricular function is impaired. The effects of slow-release formulations on the SNS are unknown. METHODS: We used microneurography to investigate the influence of nifedipine (5 mg; 10 mg; and slow-release [GITS], 60 mg) on muscle sympathetic nerve activity (MSA) and skin sympathetic nerve activity (SSA) in healthy volunteers. RESULTS: Peak plasma levels after short-acting and slow-release nifedipine were achieved within 60 min and 330 min, respectively. Short-acting (10 mg, n = 10) and slow-release (n = 10) nifedipine, but not placebo, markedly activated MSA and increased plasma norepinephrine; plasma endothelin increased only with slow-release nifedipine. HR increased after short-acting nifedipine, but not after nifedipine GITS. Nifedipine had no effect on SSA (n = 6). Blockade of cardiac sympathetic activity (with esmolol) led to similar decreases in HR with or without nifedipine, whereas parasympatholysis (with atropine) led to similar increases in HR with or without nifedipine. The cold pressor test markedly increased MSA in all treatment groups and further increased MSA beyond the increase induced by nifedipine. CONCLUSIONS: Nifedipine markedly increased MSA, but not SSA, independently of drug release formulation. In contrast, HR increased with short-acting, but not with slow-release, nifedipine. Therefore, nifedipine activates cardiac and peripheral sympathetic nerves differently depending on pharmacokinetics. These effects of nifedipine may be disadvantageous in cardiac patients with increased sympathetic activity or congestive heart failure, or both.

Requirements for antihypertensive therapy in diabetic patients: metabolic aspects.

AIM OF ANTIHYPERTENSIVE TREATMENT IN DIABETICS: Prevention or treatment of hypertensive in diabetic patients reduces the incidence and progression of diabetic complications of retinopathy and nephropathy, cerebro- and cardio-vascular disease, and widespread macroangiopathy. Therefore, in patients with diabetes and hypertension beside good glucose control, the basic and probably major intervention steps is to normalize blood pressure. Antihypertensive treatment usually means life-long use of antihypertensive drugs. METABOLIC EFFECTS OF DIFFERENT DRUG CLASSES: Given the known diabetogenic properties of several antihypertensive drugs and their high rate of use, in probably a substantial proportion of patients with diabetes or prone to develop diabetes, treating arterial hypertension with conventional diuretics and/or beta-blockers might, in the long term, offset the beneficial effects of lowering blood pressure. Furthermore, there are conflicting reports of increased mortality in patients treated with diuretics, beta-blockers or calcium antagonists. Consequently, metabolic aspects and side effects of antihypertensive drugs are key elements in determining the preference for a specific antihypertensive regimen. Although the impact of hyperinsulinemia/insulin resistance on morbidity and mortality is an open question, it is preferable that antihypertensive treatment does not increase insulin resistance and/or hyperinsulinemia. Chronic beta-blocker treatment can be accompanied by an increase in insulin resistance. Calcium antagonists and angiotensin converting enzyme (ACE) inhibitors and alpha(1)-blockers are neutral or might even improve insulin resistance and lipid profile. Thiazides impair glucose tolerance, increase low-density lipoprotein cholesterol and decrease potassium, although these side effects are dose-dependent. Unless diuretics are needed for reasons other than hypertension, treatment of diabetics with thiazides should be avoided until the influence of these agents on prognosis is clarified. If the addition of a diuretic is needed, the metabolically neutral indapamide would seem a reasonable choice. PREFERRED FIRST-LINE TREATMENT: On the basis of favorable pharmacological profiles, ACE inhibitors and certain calcium antagonists have emerged as the preferred first-line drugs in the treatment of the hypertensive diabetic patient. In diabetics with nephropathy, therapy is usually initiated with an ACE inhibitor. Moreover, the combination of an ACE inhibitor and a calcium antagonist that lowers the heart rate (such as verapamil) might offer even greater advantages than either class of drug alone, since they combine metabolic neutrality with added antihypertensive and renal protective efficacy.

Albuminuria in diabetes mellitus: relation to ambulatory versus office blood pressure and effects of cilazapril.

This study aimed to investigate the relationship between microalbuminuria and office blood pressure (BP) as compared with ambulatory BP in patients with diabetes mellitus under everyday practice conditions. It was also undertaken to assess the effect of the angiotensin converting enzyme inhibitor cilazapril on diabetes-associated albuminuria. Ambulatory BP was recorded during daytime in 54 patients with type II diabetes mellitus at the end of a 4-week period during which they received no vasoactive drug. The difference between office and ambulatory BP was unpredictable in the individual patient. There was no significant correlation between either ambulatory or office BP and urinary albumin/p5eatinine ratio. Fifty-one patients underwent a 40-week treatment with 5 mg/day of cilazapril. There was, in the absence of satisfactory BP control, the possibility of adding the calcium antagonist amlodipine (5 mg/day) from the 10th week onward and 12.5 mg/day of hydrochlorothiazide from the 20th week onward. Office mean BP was significantly reduced after 30 to 40 weeks of therapy in patients with normoalbuminuria (n = 19, -14%, P < .001), in those with microalbuminuria (n = 22, -6.6%, P < .01), as well as in those with clinical proteinuria (n = 9, -11.4%, P < .01). During the same time, the urinary albumin/creatinine ratio was not modified in normoalbuminuric patients (n = 19, +24.6%, P = .72) as well as in those with clinical proteinuria (n = 9, -29.4%, P = .09). On the other hand this value was significantly reduced for the group with microalbuminuria (n = 23, -24.3%, P < .05). In the overall population, as well as in hyperalbuminuric patients (patients with microalbuminuria + patients with clinical proteinuria), the reduction of the albumin/ creatinine ratio was also significant (n = 51, -7%, P < .01 and n = 32, -25,7%, P < .01, respectively). In conclusion, the findings of this study performed by practicing physicians show that ambulatory BP may differ greatly from office BP in diabetic patients. They also indicate that urinary albumin excretion is poorly correlated with office and ambulatory BP in type II diabetics. Finally, they demonstrate the antiproteinuric action of prolonged treatment with the angiotensin converting enzyme inhibitor cilazapril, whether given alone or combined with amlodipine.

Metabolic neutrality of perindopril: focus on insulin sensitivity in overweight patients with essential hypertension.

To assess the effects of antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril on insulin sensitivity, plasma insulin, and lipoprotein metabolism in overweight hypertensive patients, we measured the insulin sensitivity index (SI, determined according to the minimal model method of Bergman), fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure (BP) in 30 overweight [mean body mass index (BMI) 30.9 kg/m2], nondiabetic patients with essential hypertension after a 4-week run-in period and after 6 weeks of perindopril (n = 20) or placebo (n = 10) administered in a double-blind fashion. Furthermore, we estimated their state of physical fitness using the Conconi bicycle ergometer test before and after perindopril or placebo administration. SI was low in our study population (3.2 vs. 13.3 10(-4) ml.microU-1.min-1 in normal lean control subjects). It did not differ between the perindopril and placebo group after the placebo run-in period (3.1 vs. 3.3 x 10(-4) ml.microU-1.min-1) and was not influenced by perindopril (3.3 x 10(-4) ml.microU-1.min-1) or placebo (3.6 x 10(-4) ml.microU-1.min-1) treatment. Moreover, no significant changes were apparent in fasting plasma insulin and glucose, the areas under the glucose and insulin curves, the glucose disappearance rates, serum total triglycerides (TG), or cholesterol or lipoprotein cholesterol fractions between run-in and active treatment phases in the perindopril or the placebo group, respectively. Heart rate (HR), body weight, and anaerobic threshold remained stable in both groups. Compliance, assessed by pill counting was > 90% in both groups at all visits. Therefore, the ACE inhibitor perindopril is neutral with regard to insulin sensitivity, plasma insulin and glucose, and lipoprotein metabolism in overweight, nondiabetic patients with essential hypertension.

Metabolic neutrality of combined verapamil-trandolapril treatment in contrast to beta-blocker-low-dose chlortalidone treatment in hypertensive type 2 diabetes.

OBJECTIVE: To investigate the metabolic, antihypertensive and albuminuria-modifying effects of a heart rate-modulating calcium antagonist-angiotensin converting enzyme inhibitor combination compared with those of a beta-blocker-low-dose diuretic combination in non-insulin-dependent diabetic hypertensives. DESIGN: A prospective randomized double-blind study. SUBJECTS AND METHODS: Twenty-four diabetics with diastolic blood pressure 90-115 mmHg without azotemia (plasma creatinine level < 150 mumol/l) were evaluated after 4 weeks receiving placebo and 12 weeks receiving treatment either with combined slow-release verapamil (retard formulation) and trandolapril (mean maintenance doses, 180 and 1.6 mg daily) or with atenolol and chlortalidone (71 and 18 mg daily). Insulin sensitivity (by the minimal model method of Bergman), additional metabolic variables, clinic blood pressure, ambulatory blood pressure profile and renal indices were assessed at the end of the placebo and active treatment phases. RESULTS: Compared with placebo, the two therapies produced similar decreases in mean supine clinic blood pressure [10 +/- 3 versus 11 +/- 3% (means +/- SEM)], upright clinic blood pressure (10 +/- 4 versus 11 +/- 4%) and ambulatory daytime blood pressure (9 +/- 2 versus 12 +/- 3%). However, although the verapamil-trandolapril combination was found to be metabolically neutral, the atenolol-chlortalidone combination aggravated insulin resistance [insulin sensitivity index, from (0.8 +/- 0.2) to (0.3 +/- 0.1) x 10(-4)/min per U per ml], increased the serum triglycerides level and decreased the high-density lipoprotein cholesterol and plasma potassium levels. Although both therapies tended to reduce 24 h albuminuria, this was significant for the verapamil-trandolapril treatment only. CONCLUSIONS: Because the effect of any antihypertensive drug, including diuretics and beta-blockers, on cardiovascular morbidity and on mortality in non-insulin-dependent diabetic patients is not known, rational treatment selection can presently be based only on surrogate end-points. Therefore, the triad of metabolic neutrality with antihypertensive and antiproteinuric efficacy supports combined verapamil-trandolapril as a potentially valuable therapy for hypertension accompanying diabetes mellitus.

Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents.

BACKGROUND: The pathogenesis of essential hypertension is still uncertain, but genetic factors and the sympathetic nervous system are likely to be involved. Sympathetic nerve activity and hormonal circulatory control mechanisms, however, are affected by blood pressure itself. Hence, early functional changes are best investigated in normotensive subjects at risk to develop hypertension, such as normotensive offspring of hypertensive parents. METHODS AND RESULTS: Muscle sympathetic nerve activity (MSA) was measured in the peroneal nerve of 10 normotensive offspring of parents with essential hypertension and 8 offspring of normotensive parents. Measurements were performed under resting conditions, during a 10-minute period of hypoxia (12.5% O2/87.5% N2) and during a 3-minute mental stress test. The tests were separated by a 30-minute resting period. Plasma samples for determination of norepinephrine and endothelin were collected before and after the tests. Baseline values of MSA were comparable in offspring of hypertensive and normotensive parents. During hypoxia, MSA, heart rate, and norepinephrine and endothelin plasma levels increased in offspring of hypertensive and normotensive parents to a comparable degree, whereas no significant changes in blood pressure and plasma norepinephrine levels were observed in either group. During mental stress, MSA and plasma norepinephrine and endothelin increased only in offspring of hypertensive parents (P < .001 to .01). In parallel, blood pressure increased significantly only in offspring of hypertensive parents (P < .001 to .05) but heart rate increased in both groups (P < .001 to .05). CONCLUSIONS: The activity of the sympathetic nervous system and plasma norepinephrine and endothelin levels are increased during mental stress only in offspring of hypertensive parents, whereas the response to hypoxia was similar in offspring of hypertensive and normotensive parents, suggesting a genetically determined abnormal regulation of the sympathetic nervous system to certain stressful stimuli in offspring of hypertensive parents. This may play a role in the pathogenesis of essential hypertension.

Reduced plasma cyclic GMP but normal renal responses to atrial natriuretic factor in pre-hypertension.

The amount of, and response of the kidneys to, endogenous natriuretic factor(s) could be important in the pathogenesis of essential hypertension. Searching for possible disturbance(s) related to atrial natriuretic factor (ANF) and its second messenger, cyclic guanosine monophosphate (c-GMP), we assessed plasma immunoreactive (ir) ANF and c-GMP, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary c-GMP, absolute and fractional (FE) excretions of sodium (Na) and chloride (Cl) before and during infusions of low ANF doses or vehicle (V) in 7 normotensive sons of essential hypertensive parents (SEH) compared with 7 sons of normotensive parents (SN). Each subject was infused at 2-week intervals in a single-blind randomized sequence with 4 different solutions: V only or ANF 0.004, 0.008 and 0.016 microgram/kg/min, infused over 90 min. Plasma irANF was lower in SEH than in SN (p < 0.001) during vehicle infusion. Basal plasma c-GMP levels were, on all 4 different study days lower (p < 0.05 to < 0.01) in SEH in SN. Response of plasma c-GMP to infused ANF was also slightly decreased in SEH (p < 0.05 to < 0.01). BP, ERPF and GFR did not differ between SEH and SN and were unchanged during the 4 infusions. Urinary c-GMP excretion, FENa and FECl increased dose-dependently during ANF (p < 0.05 to < 0.0001) but not V infusions. These findings indicate that at the stage of pre-hypertension a disturbance in the ANF-c-GMP regulatory pathway may occur, which is expressed primarily at the circulatory rather than the renal excretory level.