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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Losartan potassium (Cozaar) is an angiotensin II receptor antagonist (AT1 selective) which has undergone extensive clinical trials for the treatment of hypertension. This literature survey will review some of the pre-clinical findings with losartan in models of heart failure, and where appropriate, we will compare the haemodynamic findings in animals with similar studies completed in patients. The major conclusion from these trials is that losartan has clear haemodynamic benefits in patients in heart failure and that the drug appears to be well tolerated, with a low incidence of adverse experiences related to impaired renal function.
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PMID:Losartan in heart failure: preclinical experiences and initial clinical outcomes. 771 3

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic functions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1A(-/-) mice were born in expected numbers, and the histomorphology of their kidneys, heart, and vasculature was normal. AT1 receptor-specific angiotensin II binding was not detected in the kidneys of homozygous Agtr1A(-/-) mutant animals, and Agtr1A(+/-) heterozygotes exhibited a reduction in renal AT1 receptor-specific binding to approximately 50% of wild-type [Agtr1A(+/+)] levels. Pressor responses to infused angiotensin II were virtually absent in Agtr1A(-/-) mice and were qualitatively altered in Agtr1A(+/-) heterozygotes. Compared with wild-type controls, systolic blood pressure measured by tail cuff sphygmomanometer was reduced by 12 mmHg (1 mmHg = 133 Pa) in Agtr1A(+/-) mice and by 24 mmHg in Agtr1A(-/-) mice. Similar differences in blood pressure between the groups were seen when intraarterial pressures were measured by carotid cannulation. These studies demonstrate that type 1A angiotensin II receptor function is required for vascular and hemodynamic responses to angiotensin II and that altered expression of the Agtr1A gene has marked effects on blood pressures.
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PMID:Regulation of blood pressure by the type 1A angiotensin II receptor gene. 772 93

Recent developments in angiotensin II receptor research are discussed in the context of our knowledge in preceding years. Cloning of non-mammalian angiotensin II receptors without high affinity for non-peptide antagonists has permitted a new approach to the delineation of ligand-binding domains. Cloning of the second major isoform of angiotensin II receptor, AT2, and identification as a seven transmembrane domain receptor with only 32% sequence homology with the first isoform, AT1, provide the first concrete step toward our understanding of the roles of AT2. The discovery of phospholipase C-mediated pathway for AT1 in vascular smooth muscle cell signaling introduces an entirely unexpected angle to future research. New aspects of AT1 gene regulation and receptor desensitization and internalization are evolving. Molecular mechanisms and physiological implications of the differential expression of AT1A and AT1B are being clarified. The recent discovery of human AT1B may make studies on animal models interesting and more meaningful. The first paper on the genetic role of the AT1 gene in human hypertension has just been published. A promising future is expected in the further development of angiotensin-receptor research in relation to cardiac, renal, and vascular function by employing techniques of molecular biology.
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PMID:Recent progress in molecular and cell biological studies of angiotensin receptors. 774 57

The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (P < or = .01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Jun
PMID:A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. 776 85

This study was performed to examine the effects of blockade of the renin-angiotensin system on the development of hypertension and renal damage in stroke-prone spontaneously hypertensive rats (SHR-sp), using a non-peptide angiotensin II receptor antagonist, CV-11974. We examined changes in blood pressure, urinary protein excretion, creatinine clearance and renal morphology in CV-11974-treated SHR-sp rats and compared these variables with those in non-treated SHR-sp and Wistar Kyoto (WKY) rats, as well as in hydralazine-treated SHR-sp rats. CV-11974 lowered systolic blood pressure in a manner similarly to hydralazine (CV-11974 204 +/- 3, hydralazine 200 +/- 3, non-treated SHR-sp 284 +/- 9, WKY 155 +/- 5 mmHg), but reduced urinary protein excretion more than hydralazine (p < 0.01). There were no significant differences in creatinine clearance among experimental groups. The glomerulosclerosis index was greater in non-treated and hydralazine-treated SHR-sp rats than in CV-11974 treated SHR-sp and WKY rats (p < 0.01). Hydralazine-treated SHR-sp rats had a lower glomerulosclerosis index than the non-treated SHR-sp rats (p < 0.01). No significant differences were found in glomerulosclerosis index between CV-11974-treated SHR-sp and WKY rats. Tubular atrophy, tubular casts and interstitial fibrosis were observed in non-treated SHR-sp rats and, occasionally, in hydralazine-treated SHR-sp rats, but not in CV-11974-treated SHR-sp rats or WKY rats. These results indicate that the angiotensin II receptor antagonist was superior to hydralazine as far as renal protection was concerned. This suggests that renal damage in SHR-sp rats is associated not only with hypertension but also with activation of the renin-angiotensin system.
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PMID:Renal protective effects of angiotensin II receptor I antagonist CV-11974 in spontaneously hypertensive stroke-prone rats (SHR-sp). 788 3

Endothelium-derived nitric oxide (EDNO) and angiotensin II play a role in the regulation of vascular tone and sodium handling. The objective of this study was to determine the role played by angiotensin II in mediating the arterial pressure and renal response to increments in sodium intake during chronic EDNO inhibition. Six groups of Wistar rats were studied; they were fed either a normal sodium diet (groups I, II, and III) or a high sodium diet (groups IV, V and VI). Rats in groups II, III, V and VI were placed on oral L-N-nitroarginine-methyl ester (L-NAME) for 4 weeks. In groups III and VI, the angiotensin II receptor antagonist, TCV-116, was administered. A significant increase in blood pressure was observed in group V compared with group II at the end of the experimental period. TCV-116 attenuated the L-NAME-induced hypertension in both group III and group VI. Urinary protein excretion and the glomerular sclerotic injury score in group V were greater than in group II. TCV-116 attenuated the proteinuria and glomerular injury induced by chronic EDNO inhibition in the groups with normal (group III) and high sodium intake (group IV). Systemic hypertension and glomerular injury were enhanced by salt loading during EDNO inhibition, and the angiotensin II receptor antagonist, TCV-116, attenuated this salt-induced increase in blood pressure and renal injury, suggesting that EDNO may counteract the renal effects of angiotensin II.
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PMID:Enhancement of hypertension and renal injury by salt-loading during chronic nitric oxide inhibition. Effects of TCV-116, a novel angiotensin II receptor antagonist. 788 7

To determine whether an angiotensin II receptor antagonist (AT antagonist) could improve the impaired coronary circulation as well as induce regression of cardiac hypertrophy in the hypertensive heart, and to elucidate whether the nitric oxide system in the coronary artery was involved in this mechanism, the AT1 antagonist, TCV-116 (10 mg/kg), was administered orally to spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY), and coronary flow was measured in the isolated hearts. High systolic blood pressure in SHR was significantly reduced by a 2-week treatment with TCV. Left ventricular (LV) hypertrophy in SHR regressed after TCV treatment, while LV weight in WKY was not reduced. Total minimum coronary vascular resistance (MCVR) obtained with adenosine (10(-5) M) infusions in a Langendorff apparatus was significantly greater in SHR than in WKY. Increased MCVR in SHR was reduced after TCV treatment. Coronary perfusion with NG-monomethyl-L-arginine monoacetate (L-NMMA) increased coronary vascular resistance (CVR) in WKY, while it failed to increase CVR in SHR. TCV treatment restored the responses to L-NMMA in SHR. These findings suggest that the AT1 antagonist, TCV-116, lowered the high blood pressure in SHR, concomitantly improving the impaired coronary circulation, and that it induced regression of the cardiac hypertrophy. The suppressed nitric oxide (NO) system in the coronary vessels in SHR appeared to be activated by TCV treatment.
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PMID:Effect of an angiotensin II receptor antagonist, TCV-116, on cardiac hypertrophy and coronary circulation in spontaneously hypertensive rats. 788 11

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.
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PMID:Captopril increases skin microvascular blood flow secondary to bradykinin, nitric oxide, and prostaglandins. 789 12

We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.
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PMID:Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. 793 34

The angiotensin II type 1 (AT1) receptor in murine species exists as two isoforms (AT1A and AT1B) encoded by two different genes. Both subtypes have a 9/10 homology in the coding sequence of their mRNA. We examined organs of adult rats (liver, pituitary gland, adrenal gland, kidney, heart, and lung) to study the differential expression of these two genes in target tissues for angiotensin II. AT1A and AT1B mRNAs were detected by in situ hybridization using specific riboprobes for the 3' noncoding region of the mRNAs that have the lowest homology (approximately 6/10). Only AT1A was expressed in the liver, heart, and lung, and only AT1B was expressed in the anterior pituitary, where most cells were positive. In the adrenal gland, AT1A mRNA was detected in the zona glomerulosa and medulla and AT1B in the glomerulosa. In the kidney, AT1A mRNA was the predominant isoform (mesangial and juxtaglomerular cells, proximal tubules, vasa recta, and interstitial cells), but AT1B was also detected in mesangial and juxtaglomerular cells and in the renal pelvis. The results of this in situ detection suggest a tissue-selective regulation of AT1A and AT1B mRNAs. This tissue specificity may constitute a prerequisite condition if the two angiotensin II receptor subtypes, which are pharmacologically similar, are to selectively modulate the various effects of angiotensin II in the different target tissues.
Hypertension 1994 Nov
PMID:Tissue-specific expression of type 1 angiotensin II receptor subtypes. An in situ hybridization study. 796 11


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