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AII was a weak contractile agent of detrusor strips, with no significant differences in potency between child and adult bladder samples. These data show the presence of functional AT1 but not AT2 receptors in child detrusor smooth muscle.
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In time-varying covariate analysis of clinical survival data, it is often of interest to estimate the proportion of treatment effect (PTE), along with its confidence intervals, explained by a surrogate marker. The conventional procedure for such an analysis fits data into two working models separately to estimate the treatment effects before and after adjustment of the covariate. The construction of confidence intervals for the PTE under the conventional procedure lacks support by standard statistical software such as SAS, and could be very computationally demanding even after the support is available in the future. To overcome this problem, we propose a new procedure to simplify the computation. Under the new procedure, the treatment effects before and after adjustment of the covariate are simultaneously estimated from a single model. More important than saving computational effort, the new procedure can also be effectively applied to multiple-covariate models for the decomposition of overall treatment effect and for the comparison of PTE among several surrogate markers. The new procedure is applied to the motivating data example from the LIFE study, and demonstrates flexibility that the conventional procedure currently lacks.
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A 64-year-old woman, suffering from hypertension, developed a widespread and rapidly evolving bullous and pustular eruption without any other clinical sign. Leucocytoclastic vasculitis and junctional blisters were present with deposits of both IgA and IgG at these sites. Withdrawal of losartan, which was the only drug taken by the patient, and tapered corticotherapy cleared the lesions. The rash left a prominent mottled hyperpigmentation. It did not recur during the following months despite the presence of antineutrophil cytoplasmic antibodies.
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Unilateral ureteral obstruction in pigs is associated with an enhanced, de novo generation of angiotensin II from the ipsilateral kidney. In order to further investigate the role of this system during unilateral ureter obstruction, the renal hemodynamic response to the non-peptide angiotensin II antagonist losartan was investigated. Danish land race pigs were operated on under general anesthesia. Catheters were placed in both renal veins by x-ray and ultrasonic flow probes were mounted on the renal arteries. Losartan (2 mg/kg/h) was administered intravenously to an experimental group ( n=9) continuously over 8 h of unilateral ureteral occlusion. This group was then compared to a matched control group which received only saline ( n=6). Ipsilateral pelvic pressure, renal blood flow using ultrasound transit time, glomerular filtration rate, mean arterial pressure and heart rate were measured. Renal handling of angiotensin II was examined by determining the renal extraction and secretion rates of immunoreactive angiotensin II. The anticipated reduction in ipsilateral renal blood flow after the onset of obstruction was attenuated in the losartan treated pigs, but the ipsilateral glomerular filtration rate was unaffected as compared with the controls. In the losartan group, the increase in renal vascular resistance was significantly reduced compared with un-treated controls (141+/-25% vs 217+/-24%, P<0.05). Plasma immunoreactive angiotensin II increased significantly from all three sample locations in both groups after the onset of obstruction, being more pronounced in the losartan treated group in which immunoreactive angiotensin II from the ipsilateral renal vein increased from 5.1+/-0.5 pmol/l to 41.6+/-19.6 pmol/l, P=0.027. In the controls immunoreactive angiotensin II increased from 2.7+/-0.3 pmol/l to 24.8+/-10.2 pmol/l. Furthermore, plasma aldosterone was significantly reduced after losartan administration (from 80.4 pmol/l to 36.0 pmol/l, P=0.005), indicating effective blockade of the angiotensin II type-1 receptor. The results from the present study suggest that continuous intravenous administration of losartan blocks the angiotensin II receptor mediated effects in the pig. Losartan is able to reduce ipsilateral vasoconstriction in the obstructed kidney during unilateral ureter obstruction supporting the view that angiotensin II is an important mediator of vasoconstriction during unilateral ureter obstruction in the pig model with acute unilateral occlusion of the ureter.
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Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects.
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The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.
Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC).
once daily candesartan cilexetil is effective and well tolerated when used once daily (as monotherapy or in combination with other antihypertensive agents) in patients with mild, moderate or severe hypertension. Initially, however, the drug is likely to be used as an alternative to other agents in patients not responding to or intolerant of their current drug therapy.
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Both impaired glucose tolerance and diabetes are associated with substantially increased prevalence of hypertension, cardiovascular and renal disease. The goal for hypertension treatment in diabetic patients is in evolution, because of recent clinical trials. For example, the results of the recent Action to Control Cardiovascular Risk in Diabetes-BP Arm (ACCORD BP) trial failed to show an additional benefit on cardiovascular event reduction at a mean systolic BP of 119 mm Hg. A post hoc analysis of 6,400 patients with type 2 diabetes from the International Verapamil-Trandolapril Study (INVEST) also failed to show additional cardiovascular risk reduction among patients who achieved a BP <130/80 mm Hg. While the evidence fails to support a lower BP goal to reduce coronary events, there was a risk reduction in stroke events both in ACCORD and the Appropriate Blood Pressure Control in NIDDM (ABCD) trial. A number of other clinical trials also demonstrate that when systolic pressures fall to less than 130 mm Hg, a reduction in stroke but not coronary disease events occurs. Thus, the precise BP goal for diabetic patients remains unresolved. We would posit that a BP goal of 135/85 mm Hg may be a reasonable compromise when viewing the impact of BP reduction on composite stroke and coronary artery disease in extant trials.
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Recent studies have revealed angiotensin II subtype 1 (AT1) receptors on macula densa cells, raising the possibility that angiotensin II (Ang II) could enhance tubuloglomerular feedback (TGF) by affecting macula densa cell function. We hypothesized that Ang II enhances TGF via activation of AT1 receptors on the luminal membrane of the macula densa.
The effects of DuP 753 and EXP 3174, nonpeptide angiotensin II type 1 antagonists, on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Responses to the peptide were stable with respect to time, did not exhibit tachyphylaxis, and 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl]methyl]methyl]imidazole (DuP 753) in doses of 1 and 2.5 mg/kg decreased vasoconstrictor responses to angiotensin II in a competitive manner, with a longer duration of action at the higher dose. DuP 753 had no significant effect on vasoconstrictor responses to vasopressin, norepinephrine, neuropeptide Y or 11 alpha,6 alpha-epoxymethano-9 alpha,11 alpha-dideoxy-prostaglandin F2 alpha, on biphasic responses to endothelin-1, or on vasodilator responses to acetylcholine. 2-n-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]im idazole-5-carboxylic acid (EXP 3174) also decreased responses to angiotensin II without altering responses to norepinephrine, vasopressin, U46619 or endothelin-1. The inhibitory effect of EXP 3174 was surmountable; however, large doses of angiotensin II were required, and the blockade was long in duration. The effects of DuP 753 and EXP 3174 on responses to angiotensin II and angiotensin III were similar, and when EXP 3174 was administered in doses of 0.1 and 0.05 mg/kg i.v., the blockade was overcome and the dose-response curves for angiotensin II were shifted to the right in a parallel manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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Multicenter randomized, double-blind, placebo-controlled clinical trial.
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response was achieved in 40/55 (73%) of patients, 24 (44%) with complete response and 16 (29%) with partial response. No EC-MPS discontinuation has been observed due to adverse events, except for one case of transient interruption of medication for 2 weeks.
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The release of arginine vasopressin (AVP) from the magnocellular neurosecretory cells (MNCs) in the supraoptic nucleus (SON) is crucial for body fluid homeostasis. The MNC activity is modulated by synaptic inputs and humoral factors. A recent study demonstrated that an N-terminal splice variant of the transient receptor potential vanilloid type 1 (TRPV1) is essential for osmosensory transduction in the SON. In the present study, we examined the effects of mannitol and angiotensin II on miniature EPSCs (mEPSCs) in the supraoptic MNCs using whole-cell patch-clamp recording in in vitro slice preparation. Mannitol (60 mm) and angiotensin II (0.1 microm) increased the frequency of mEPSCs without affecting the amplitude. These effects were attenuated by pre-exposure to a nonspecific TRPV channel blocker, ruthenium red (10 microm) and enhanced by pre-exposure to cannabinoid type1 receptor antagonist, AM251 (2 microm). Mannitol-induced potentiation of mEPSCs was not attenuated by angiotensin II receptor antagonist, losartan (10 microm), indicating independent pathways of mannitol and angiotensin II to the TRPV channels. The potentiation of mEPSCs by mannitol was not mimicked by a TRPV1 agonist, capsaicin, and also not attenuated by TRPV1 blockers, capsazepine (10 microm). PKC was involved in angiotensin II-induced potentiation of mEPSCs. The effects of mannitol and angiotensin II on the supraoptic MNCs in trpv1 knock-out mice were significantly attenuated compared with those in wild-type mice counterparts. The results suggest that hyperosmotic stimulation and angiotensin II independently modulate mEPSCs through capsaicin-insensitive TRPV1 channel in the presynaptic terminals of the SON.
In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.
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Vascular hypertrophy occurs during chronic hypertension and contributes to the elevation of peripheral vascular resistance in hypertension. In this study, we examined whether acute pressure overloading of the vascular wall produces activation of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in isolated perfused rat aortae, and examined whether the mechanical overloading-induced MAP kinase activation is mediated via the vascular angiotensin system. Aortae were perfused with Tyrode solution. Increases in perfusion pressure caused a pressure-dependent increase in MAP kinase activity in endothelium-intact aortae and in endothelium-denuded aortae. The increase in MAP kinase activity induced by pressure loading was inhibited by the angiotensin receptor antagonist, losartan, the renin inhibitor, pepstatin A, and the angiotensin-converting enzyme inhibitor, captopril. Ca(2+) depletion and the Ca(2+) channel antagonist, nifedipine, did not affect the pressure loading-induced MAP kinase activation. The results of the present study suggest that pressure loading of the vascular wall per se can activate MAP kinases in the vasculature and that the MAP kinase activation is mediated at least partly via the vascular angiotensin system. It seems unlikely that the pressure loading-induced increase in MAP kinase activity is mainly mediated via increases in Ca(2+) influx in vascular cells.
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Acute inhibition (1 h) of nitric oxide synthase (NOS) with L-NAME causes leukocyte recruitment in the rat mesenteric postcapillary venules that is angiotensin-II (Ang-II) dependent. Since 4-h exposure to Ang-II provokes arteriolar leukocyte adhesion, this study was designed to investigate whether subacute (4-h) NOS inhibition also causes this effect.
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Pancreatic cancer is one of the leading causes of cancer death, and represents a challenging chemotherapeutic problem. The crucial role of angiogenesis in tumor growth has been widely recognized, and several reports have revealed that the combination treatment of the conventional chemotherapeutic drugs and anti-angiogenic agents exerted synergistic anti-cancerous effects. It has been reported that the clinically used angiotensin type-1 receptor blocker (ARB) exerted potent anti-angiogenic activity. The aim of our current study was to examine the combination effect of gemcitabine (GEM), a widely used conventional chemotherapeutic drug against pancreas cancer, and losartan (Lo), an ARB, on murine pancreatic tumor growth, especially in conjunction with angiogenesis. When used individually, GEM and Lo at clinically comparable low doses moderately suppressed pancreatic tumor development. The combination treatment with GEM and Lo exerted a marked inhibitory effect as compared with single agent treatments even after the tumor was fully established. Neovascularization and the expression of the vascular endothelial growth factor (VEGF), a central angiogenic factor, in the tumor were both markedly suppressed in a magnitude similar to the inhibitory effects against the tumor growth. Since both agents are widely used in the clinical practice, the combination regimen of GEM and Lo may represent a potential new therapeutic strategy for pancreatic cancer in the future.
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Losartan, a commonly used angiotensin II receptor blocker (ARB) for blood pressure control, also impairs cutaneous wound healing. Our current study will analyze how Losartan affects wound healing in the muscle and fascia from both biomechanical and histological aspects.
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At the tissue level, Ang II may still be generated in a patient receiving systemic ACE inhibitor therapy. Ang II blockade at the receptor level may thus be more efficient than ACE inhibition in blocking the undesirable cardiovascular actions of Ang II.
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Elevated urinary albumin excretion is a common feature of essential hypertension which may be reduced by ACE-inhibition through independent reductions of both systemic and intraglomerular pressure. A concurrent inhibition of bradykinin breakdown may be involved.
Randomized, open-label, crossover, bioavailability studies were conducted separately in healthy Asian Indian and Japanese volunteers. One tablet either of test or of reference product was administered after 10 hours of overnight fasting. After dosing, serial blood samples were collected for a period of 48 hours for both the studies. Plasma samples were analyzed for losartan, losartan carboxylic acid and hydrochlorothiazide by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax, and other pharmacokinetics parameters were determined from plasma concentration-time profiles for both test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablets. Statistical evaluations were done to evaluate bioequivalence between generic test formulation (EPR0001) and Japanese reference product (Preminent®).
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Over 50 percent of deaths in patients who survive an acute myocardial infarction are due to fatal ventricular tachyarrhythmias. Patients who survive an episode of sustained ventricular arrhythmia are at highest risk of recurrent cardiac arrest. Electrophysiologic studies have been found to be useful in guiding therapy and reducing mortality in these patients and in patients with syncope due to arrhythmic etiology. Evaluation and treatment of nonsustained ventricular tachycardia post infarction remains somewhat controversial. A recently published trial (MADIT), however, showed improved survival with an implanted defibrillator in patients with coronary disease and asymptomatic nonsustained ventricular tachycardia. Asymptomatic patients post infarction at high risk include those who have significant left ventricular dysfunction, late potentials, high-grade ventricular ectopy, and abnormal heart rate variability. These tests individually, however, have a low positive predictive accuracy. This, combined with the fact that antiarrhythmic drugs are frequently not effective and can be proarrhythmic, leaves the best treatment for these patients uncertain. It is known, however, that beta-adrenoreceptor blocking agents do reduce mortality after an acute myocardial infarction. Early studies have shown mixed results relating to sudden death and total mortality with amiodarone. To date, no other antiarrhythmic drug has shown benefit, while several have been shown to be harmful. Recent studies have also shown some beneficial effects of angiotensin-converting enzyme inhibitors, carvedilol, a third-generation beta-blocking agent with vasodilator properties, and the angiotensin II receptor antagonist losartan. However, their precise role in reducing sudden death needs to be defined further.
The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in the United States were included in this double-masked, randomized, parallel-group, active- and placebo-controlled study, with stratification according to sex. After a challenge phase with lisinopril and a placebo washout phase, patients were randomly allocated to receive losartan 50 mg once daily, lisinopril 20 mg once daily, or placebo for a maximum of 8 weeks. The primary efficacy end point of the study was the presence or absence of dry cough during the double-masked period, as rated by the patient at each visit using a validated symptom assessment questionnaire. A secondary end point was the frequency of dry cough, as measured at each visit using a visual analogue scale (VAS). The incidence of dry cough was significantly higher in the lisinopril group than in the losartan and placebo groups (87.5% vs 36.7% and 31.4%, respectively) at the end of the double-masked treatment period; there was no statistically significant difference between the losartan and placebo groups. Mean VAS scores showed that patients treated with lisinopril rated themselves as having a significantly higher frequency of cough than did patients treated with losartan or placebo (4.0 vs 1.2 and 1.5, respectively). Again, the difference between the losartan and placebo groups was not statistically significant. All treatments were otherwise well tolerated, and no serious clinical or laboratory adverse events were reported during the double-masked phase of the study. These results demonstrate that the incidence, severity, and frequency of dry cough in patients with a history of ACE inhibitor-induced dry cough are significantly lower in those treated with losartan than in those treated with lisinopril and are similar to the incidence, severity, and frequency of dry cough in those receiving placebo.
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The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group.