Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study.

Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P

Renal effects of CO2 and iodinated contrast media in patients undergoing renovascular intervention: a prospective, randomized study.

PURPOSE: CO2 gas has been proposed for use instead of iodinated contrast media in angiographic examinations in patients at risk of developing renal failure from contrast media. The influence of intraarterial injection of CO2 with small added amounts of ioxaglate (200 mgI/mL) or ioxaglate alone on renal function in patients with suspected renal artery stenosis was studied in a prospective, randomized study. MATERIALS AND METHODS: One hundred twenty-three patients underwent renovascular intervention (n = 83) and/or renal angiography (n = 40) for suspected renal artery stenosis. Patients with a serum creatinine concentration less than 200 micromol/L (n = 82) were randomized prospectively to receive CO2 with small added amounts of ioxaglate (n = 37) or only ioxaglate (n = 45). Patients with serum creatinine levels greater than 200 micromol/L (n = 41) were not randomized and initially received CO2. Serum creatinine concentrations were measured within 1 day before and 1 day, 2 days, and 2-3 weeks after the procedure. RESULTS: The amount of injected CO2 did not relate to an increase in serum creatinine level. In the randomized groups, and also when the whole patient sample was considered, the amount of injected iodine was significantly correlated (P = .011) with an increase in serum creatinine level and a decrease in estimated creatinine clearance after 2 days. Among the randomized patients, one in the CO2 group and three in the ioxaglate group had a more than 25% increase in serum creatinine level within the first 2 days after the intervention. CONCLUSION: The risk of impairment of renal function is lower after injection of CO2 with small amounts of added ioxaglate compared with injection of a larger amount of ioxaglate alone. The larger the amount of administered iodinated contrast medium, the greater the risk of development of renal failure.

Endothelium-dependent vasodilation in normotensive subjects with a familial history of essential hypertension and in young subjects with borderline hypertension.

OBJECTIVE: To investigate if young normotensive subjects with a familial history of essential hypertension (FHH) or young borderline-hypertensive (BHT) subjects have a defect endothelial function. METHODS: Fifteen young (26 +/- 4 years) healthy normotensive (115 +/- 8/71 +/- 6 mmHg) subjects with a FHH, 31 matched healthy normotensive subjects without FHH and seven BHT (143 +/- 12/92 +/- 2 mmHg), otherwise healthy, young males underwent evaluation of endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV), by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV) in the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. RESULTS: Although there was no significant difference between normotensive subjects with and without a FHH regarding FBF during vasodilation induced by MCh or SNP, the subjects with a FHH presented a significantly suppressed endothelial function index, calculated as the ratio between EDV and EIDV, when compared to subjects without FHH (1.04 +/- 0.15 vs. 1.24 +/- 0.23, p < 0.01). Also in the group of BHT subjects, the endothelial function index was suppressed (1.01 +/- 0.18, p < 0.01), in this case due to a significantly attenuated EDV (p < 0.05), when compared to male subjects without a FHH. CONCLUSION: The present findings suggest an early occurrence of endothelial dysfunction in the development of essential hypertension.

Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.

BACKGROUND: Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS: After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS: The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.

Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.

BACKGROUND: Our aim was to determine if gene polymorphisms in the renin-angiotensin-aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. METHODS AND RESULTS: Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (-23 +/- 31SD g/m2 for TM and +0.5 +/- 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (-0.1 +/- 19 g/m2 for AA and -18 +/- 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. DISCUSSION: The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

Hemodynamic Results of Perorally Administered Converting Enzme Inhibitors in Congestive Heart Failure.

The acute hemodynamic response to captopril (8 patients) and enalapril (8 patients) was evaluated in congestive heart failure patients in NYHA functional class III. All patients had a history of congestive heart failure for more than six months. The results show marked interindividual variations but average values for cardiac output increase and decrease in filling pressures agree with findings in the literature. 6 patients in the captopril group and five in the enalapril group were started on maintenance therapy. One patient in the captopril group deteriorated and underwent a successful heart transplantation and one patient in the enalapril group returned with arrhytmias and hypertension (probably not drug-related) after 48 h of therapy. Our data indicate that activation of the renin-angiotensin system through excessive administration of loop-diuretics is associated with a risk of hypovolemia and thus drug-induced hypotension that deserves special attention when considering converting enzyme inhibitor therapy in congestive heart failure.