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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This multicentre, randomized, controlled clinical trial assessed the effects of candesartan cilexetil (cand.cil.), a novel angiotensin II antagonist selective for the AT1 receptor with long-lasting antihypertensive activity, compared to placebo on glucose homeostasis and serum lipid profile in mild hypertensives with type II diabetes. A total of 161 men and women, 30-75 years old, with mild hypertension (sitting diastolic blood pressure 90-100 mmHg) and type II diabetes (HbA1c 5.5-9.0%), both measured after a 4-week placebo run-in period, were randomized to double-blind treatment with cand.cil. 8 mg o.i.d. (n = 83) or placebo (n = 78). Dose was increased to 16 mg o.i.d. if diastolic blood pressure remained >90 mmHg. At randomization and after 12 weeks of treatment HbA1c (primary effect variable), blood glucose and the serum lipid profile (including total cholesterol, HDL and LDL cholesterol, triglycerides) were assessed. The statistical analysis of the differences between treatments was based on changes from randomization to the end of the study. Cand.cil. had no significant effect on HbA1c, blood glucose and serum lipids compared to placebo. The median HbA1c both at baseline and after 12 weeks was 7.1% in patients on cand.cil., and 7.2% and 7.1% in patients on placebo. The 95% confidence interval for the median difference in change between the groups was narrow (-0.25; 0.16), including zero, which excluded any clinically important difference. The same held true for blood glucose (-1.10; 0.20), total cholesterol (-0.40; 0.20) and the other lipid parameters. More than 60% of the patients reached a diastolic blood pressure <90 mmHg; adverse events and withdrawals were similar in both groups. Thus, in patients with mild hypertension and type II diabetes, cand.cil. 8-16 mg o.i.d. for 12 weeks does not affect glucose homeostasis and serum lipids. Blood pressure was controlled in most patients, and cand.cil. was well tolerated.
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PMID:Antihypertensive treatment with candesartan cilexetil does not affect glucose homeostasis or serum lipid profile in patients with mild hypertension and type II diabetes. 975 87

In a multicenter, randomized, double-blind, placebo-controlled clinical trial the effects of candesartan cilexetil (cand.cil.), a novel angiotensin II antagonist selective for the AT1 receptor with long-lasting antihypertensive activity, on glucose homeostasis--and the serum lipid profile--were assessed in patients with mild hypertension and stable type II diabetes mellitus. A total of 161 men and women, 30-75 years old, with mild hypertension (sitting diastolic blood pressure 90-100 mmHg) and type II diabetes (HbA1c 5.5-9.0%), both measured after a 4-week placebo run-in period, were randomized to double-blind treatment with cand.cil. 8 mg o.i.d. (n = 83) or placebo (n = 78). Dose was increased to 16 mg o.i.d., if diastolic blood pressure remained > or = 90 mmHg. At randomization and after 12 weeks of treatment HbA1c (primary effect variable), blood glucose and the serum lipid profile (including total cholesterol, HDL and LDL cholesterol, triglycerides) were assessed. The statistical analysis of the differences between treatments was based on changes from randomization to the end of the study. Cand.cil. had no significant effect on HbA1c, blood glucose, and serum lipids compared to placebo. The median HbA1c both at baseline and after 12 weeks was 7.1% in patients on cand.cil., and 7.2% and 7.1% in patients on placebo. The 95% confidence interval for the median difference in change between the groups was narrow (-0.25; 0.16), including zero, which excluded any clinically important difference. The same held true for blood glucose (-1.10; 0.20), total cholesterol (-0.40; 0.20), and the other lipid parameters. More than 60% of the patients reached a diastolic blood pressure < 90 mmHg; adverse events and withdrawals were similar in both groups. Thus, in patients with mild hypertension and type II diabetes, cand.cil. 8 to 16 mg o.i.d. for 12 weeks does not affect glucose homeostasis respectively serum lipids. Blood pressure was controlled in most patients and cand.cil. was well tolerated.
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PMID:Effects of candesartan cilexetil on glucose homeostasis. Multicenter Study Group. 983 77

Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others presented a mild impairment of pre-existent anemia. No interactions with cyclosporine or FK-506 were described. These results indicate that losartan is effective in reducing BP in hypertensive patients with a renal transplant. It has a good tolerance profile and does not interfere with immunosuppressive therapy.
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PMID:Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients. 983 98

We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT1 receptors, the present experiments were designed to determine the participation of AT1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33% of the initial values, P < 0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a non-peptide antagonist of angiotensin II with AT1-receptor type specificity (1.63 mumol/100 g body weight as a bolus, i.v., plus a 30-min infusion of 0.018 mumol 100 g body weight-1 min-1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P < 0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 +/- 0.28 mM, angiotensin II, N = 9 vs 6.4 +/- 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT1-type.
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PMID:The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors. 987 9

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.
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PMID:Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. 1008 42

It has been shown that glomerular angiotensin II (ANG II) receptors are downregulated and protein kinase C (PKC) is activated under diabetic conditions. We, therefore, investigated ANG II receptor and PKC isoform regulation in glomerular mesangial cells (MCs) under normal and elevated glucose concentrations. MCs were isolated from collagenase-treated rat glomeruli and cultured in medium containing normal or high glucose concentrations (5.5 and 25.0 mM, respectively). Competitive binding experiments were performed using the ANG II antagonists losartan and PD-123319, and PKC analysis was conducted by Western blotting. Competitive binding studies showed that the AT1 receptor was the only ANG II receptor detected on MCs grown to either subconfluence or confluence under either glucose concentration. AT1 receptor density was significantly downregulated in cells grown to confluence in high-glucose medium. Furthermore, elevated glucose concentration enhanced the presence of all MC PKC isoforms. In addition, PKCbeta, PKCgamma and PKCepsilon were translocated only in cells cultured in elevated glucose concentrations following 1-min stimulation by ANG II, whereas PKCalpha, PKCtheta, and PKClambda were translocated by ANG II only in cells grown in normal glucose. Moreover, no changes in the translocation of PKCdelta, PKCiota, PKCzeta, and PKCmu were detected in response to ANG II stimulation under euglycemic conditions. We conclude that MCs grown in high glucose concentration show altered ANG II receptor regulation as well as PKC isoform translocation compared with cells grown in normal glucose concentration.
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PMID:Regulation of angiotensin II receptors and PKC isoforms by glucose in rat mesangial cells. 1033 51

Insulin responsiveness was studied in isolated adipocytes from the normotensive Wistar Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). The effect of insulin (0.1 to 5 nmol/L) on glucose uptake (glucose transport and lipogenesis) was measured, and the maximal effect of insulin (Emax) and the dose of insulin required to elicit 50% of the maximal response (EC50) were calculated. A diminished Emax on lipogenesis without changes in the EC50 was detected in SHRs. The Emax was 0.49 +/- 0.09 (SHR) and 1.16 +/- 0.14 (WKY) micromol/10(5) cells (P < .05), and the EC50 was 0.13 +/- 0.03 and 0.11 +/- 0.02 nmol/L for WKY and SHR, respectively. Similar results were obtained when measuring insulin-stimulated glucose transport. A 30-day long-term treatment with enalapril (20 mg/kg/d) normalized insulin responsiveness in adipocytes from SHRs. The effect of enalapril was suppressed when SHRs were pretreated with enalapril and 150 microg/kg/d of the bradykinin (BK) B2-receptor blocker Hoe 140. Pretreatment with losartan (40 mg/kg/d) did not improve insulin action in the SHR. Since these results were obtained with isolated cells in which glucose availability was not a function of blood flow, and the effect of insulin in the SHR was improved by pretreatment with an angiotensin-converting enzyme (ACE) inhibitor but not with the AT1-receptor blocker, it appears that the insulin resistance linked to the hypertension is not related to changes in blood flow.
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PMID:Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan. 1045 71

Although angiotensin AT1 receptor antagonist(AT1 A) improves insulin sensitivity in insulin resistant models, its effect on spontaneously hypertensive rats(SHR) has not been elucidated. We investigated the effects of AT1 A, candesartan on insulin sensitivity in SHR/Izm and the role of sympathetic activity in its mechanism. In 9-week-old SHR/Izm, candesartan(10 mg/kg/day) was given orally for 5 days. A control group received vehicle. On the 6th day, mean arterial pressure (MAP), heart rate(HR), plasma norepinephrine (PNE), plasma epinephrine(PE) and plasma dopaminc(PDA) were measured in both groups (n = 11 in each group). In the separate groups of rats, fasting blood glucose (FBG), serum sodium, serum potassium and insulin sensitivity by steady state blood glucose (SSBG) were assessed (n = 16 in the Candesartan group and n = 8 in the Control group). MAP and SSBG were significantly lower in the Candesartan group (117 +/- 2 mmHg and 138 +/- 5 mg/dl) than those in the Control group(155 +/- 6 mmHg and 164 +/- 10 mg/dl). Body weight, HR, FBG, PNE, PE, PDA, sodium and potassium were the same between the groups. In conclusion, since AT1 A, candesartal lowers blood pressure and improves insulin sensitivity irrespective of sympathetic activity in SHR/Izm, it is useful in treating hypertension associated with insulin resistance.
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PMID:[Effects of angiotensin II receptor antagonist on insulin sensitivity and sympathetic activity in spontaneously hypertensive rats]. 1057 94

To determine whether myocyte death and angiotensin II (AT II) formation are implicated in the development of diabetic cardiomyopathy, rats were injected with streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days. Expression of the components of the renin-angiotensin system (RAS) and AT II levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the number and distribution of AT II sites in myocytes were measured at 3 and 10 days. The effects of AT1 blockade on local RAS and cell death were examined at 3 days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and decreased at 10 and 28 days, in spite of high concentrations of blood glucose. Cell necrosis was absent throughout. Angiotensinogen, renin, and AT1 receptor increased in myocytes from diabetic rat hearts, while angiotensin-converting enzyme and AT2 remained constant. AT II quantity increased severalfold, as did the fraction of AT II positive cells and the number of AT II sites per myocyte. However, AT II labeling decreased at 10 days, which paralleled the reduction in myocyte death. AT1 antagonist inhibited upregulation of this receptor and angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy may be viewed as an AT II-dependent process in which that peptide plays a critical role in myocyte death and hypertrophy.
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PMID:Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. 1078 Jun 68

Simultaneous blockade of systemic AT1 and AT2 receptors or converting enzyme inhibition (CEI) attenuates the hypoglycemia-induced reflex increase of epinephrine (Epi). To examine the role of brain AT1 and AT2 receptors in the reflex regulation of Epi release, we measured catecholamines, hemodynamics, and renin during insulin-induced hypoglycemia in conscious rats pretreated intracerebroventricularly with losartan, PD-123319, losartan and PD-123319, or vehicle. Epi and norepinephrine (NE) increased 60-and 3-fold, respectively. However, the gain of the reflex increase in plasma Epi (Deltaplasma Epi/Deltaplasma glucose) and the overall Epi and NE responses were similar in all groups. The ensuing blood pressure response was similar between groups, but the corresponding bradycardia was augmented after PD-123319 (P < 0.05 vs. vehicle) or combined losartan and PD-123319 (P < 0.01 vs. vehicle). The findings indicate 1) brain angiotensin receptors are not essential for the reflex regulation of Epi release during hypoglycemia and 2) the gain of baroreceptor-mediated bradycardia is increased by blockade of brain AT2 receptors in this model.
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PMID:Brain angiotensin receptors and sympathoadrenal regulation during insulin-induced hypoglycemia. 1124 40


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