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

The renin-angiotensin system (RAS) has been demonstrated to be a key element in blood pressure regulation and fluid volume homeostasis. Since angiotensin II (AII) is the effector molecule of the RAS, the most direct approach to block this system is to antagonize AII at the level of its receptor. Therefore, at Du Pont Merck the working hypothesis has been that the identification of metabolically stable and orally effective AII-receptor antagonists would constitute a new and superior class of agents useful in treating hypertension and congestive heart failure. Our program began with a detailed pharmacologic evaluation of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries in Osaka, Japan. They were found to be a series of weak but selective AII-receptor antagonists with a competitive mode of action. We embarked on a program aimed to design and synthesize more potent and orally effective nonpeptide antagonists, while attempting to preserve their selective affinity for the AII receptor. The first major breakthrough in our efforts to increase the potency of these compounds came with the development of a series of N-benzylimidazole phthalamic acid derivatives. Although effective at lowering blood pressure when administered intravenously, the phthalamic acids were devoid of oral activity. The first orally active AII antagonists came with the discovery of the biphenyl carboxylic acids. Although these compounds are absorbed after oral dosing, their bioavailability was less than desired. In the hope of improving the oral absorption of these biphenyls, we investigated a variety of acidic groups as bioisosteric replacements for the carboxylic acid. The key to the discovery of nonpeptide AII-receptor antagonists with improved oral activity and duration of action resulted from replacing the carboxylic acid group with the isosteric but more lipophilic tetrazole ring. Hence, our efforts culminated in the discovery of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly potent angiotensin type 1 (AT1) selective receptor antagonist with a long duration of action. Losartan is currently undergoing clinical investigation for the treatment of hypertension. The history, including the rationale for the design of the compounds, and ensuing structure-activity relationships of losartan and related analogs will be described. Many of the newer compounds exceed the potency of losartan, and the best compounds in the series rival the affinity of the endogenous ligand, AII, for its receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Rationale for the chemical development of angiotensin II receptor antagonists. 129 Jun 16

Losartan, a recently developed nonpeptide angiotensin II (Ang II) receptor antagonist, was administered orally to 10-week-old spontaneously hypertensive rats (SHR) for 2 weeks. Cardiac weight and tissue Ang II, as well as plasma renin activity (PRA) and Ang II, were determined. Treatment with Losartan (10 mg/kg per day) lowered blood pressure markedly. Losartan reduced significantly the left ventricular weight by 11% compared with control rats. The left ventricular Ang II content was lowered by Losartan (18.6 +/- 0.9 pg/tissue; 21.9 +/- 0.9 pg/tissue, control, p less than 0.05), whereas PRA and plasma Ang II concentration were increased by the treatment. With the control and Losartan-treated animals, there was a significant positive correlation between the left ventricular weight and the tissue Ang II content (r = 0.563, p less than 0.05). These results provide evidence that cardiac tissue Ang II, rather than circulating Ang II, plays an important role in the pathophysiology of left ventricular hypertrophy of this animal model of human hypertension.
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PMID:Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats. 138 40

The persistent effects on blood pressure of the angiotensin II receptor antagonist losartan and the converting enzyme inhibitor captopril were compared in the young spontaneously hypertensive rat (SHR). Losartan (DuP753/MK954, 15 mg/kg/day) and captopril (100 mg/kg/day) were given in the drinking water of 3-week-old SHRs for 4- and 10-week durations. Blood pressure was measured during treatment and after treatment was stopped until the age of 30 weeks. Both losartan and captopril given for 4 and 10 weeks prevented the development of hypertension during treatment and redevelopment of hypertension after treatment was stopped. Treatment for 10 weeks was more effective than for 4 weeks in lowering long-term pressure. Four weeks of treatment did not affect the mesenteric resistance artery media/lumen (m1/l1) ratio. In contrast, both losartan and captopril given for 10 weeks resulted in large and significant reductions in m1/l1 [5.3 +/- 0.8 and 5.63 +/- 0.8 vs 7.7 +/- 0.8 x 10(-2) (SD), p less than 0.001]. In losartan-treated rats, plasma renin and angiotensin II concentration were increased between 4- and 7-fold at the end of both treatment periods. These findings show losartan to be an effective antihypertensive agent and support data implicating angiotensin II in the early events leading to hypertension in this model. The abilities of losartan and captopril to affect blood pressure without affecting vascular structure suggest that the latter is a poor predictor of long-term hypertensive levels in the SHR.
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PMID:Angiotensin II receptor antagonist losartan has persistent effects on blood pressure in the young spontaneously hypertensive rat: lack of relation to vascular structure. 138 8

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long-term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.
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PMID:Long-term angiotensin II antagonism in spontaneously hypertensive rats: effects on blood pressure and cardiovascular amplifiers. 138 43

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Sep
PMID:Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. 151 48

Primary and secondary hypertension differ with regard to circadian blood pressure (BP) profiles. To evaluate the contribution of the renin-angiotensin system (RAS) to circadian BP regulation, we studied cardiovascular effects of the angiotensin II (AII) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril in animal models of primary and secondary hypertension after morning and evening dosing. Systolic/diastolic BP (SBP/DBP) and heart rate (HR) were measured telemetrically in spontaneously hypertensive rats (SHR) and transgenic hypertensive rats (TGR[mRen-2]27). Losartan (0.3 to 30 mg/kg) or enalapril maleate (10 mg/kg) were injected intraperitoneally (i.p.) either at 0700 or 1900 h. Baseline SBP/DBP and HR showed significant circadian rhythmicity in both strains. The 24-h means in SBP/DBP were 190/127 mm Hg in SHR and 200/139 mm Hg in TGR. TGR showed a reversed circadian profile in BP, with peaks occurring during the daily resting period, whereas HR peaked at night. Losartan reduced BP dose dependently; reductions in TGR were significantly greater and obtained at 30-fold lower doses than in SHR. Maximum decreases induced by losartan were similar to those induced with enalapril 10 mg/kg. Both drugs reduced BP in TGR more effectively when applied at 0700 than at 1900 h, resulting in a normalized circadian BP profile. Our results demonstrate that the RAS is involved in both the pathomechanism of hypertension and in the inverse circadian BP pressure pattern in TGR.
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PMID:Effects of the angiotensin II receptor antagonist losartan on 24-hour blood pressure profiles of primary and secondary hypertensive rats. 747 45

Fructose feeding induces a moderate increase in blood pressure levels in normal rats that is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. The sympathetic nervous system seems to participate in the alterations of this model. To further explore the mechanisms underlying fructose-induced hypertension, the effects of the AT1 receptor antagonist losartan on blood pressure, insulin resistance, renal function, and vascular reactivity in mesenteric vascular beds were studied. Sprague-Dawley rats were fed for 4 weeks with diets containing 60% fructose or 60% starch (control), and half of each group received losartan (1 mg/kg per day) in the drinking water. Fructose-fed rats showed higher (P < .05) blood pressure levels and plasma concentrations of triglycerides and insulin than those of controls. Losartan treatment prevented both blood pressure elevation and hyperinsulinemia in fructose-fed rats but not elevation of plasma triglycerides. Plasma glucose and insulin levels in response to an oral glucose load were higher (P < .05) in fructose-fed rats than in controls. These exaggerated responses were prevented by losartan treatment. No differences in the constrictor responses of mesenteric vascular beds to KCl (60 mumol), angiotensin II (1 nmol), phenylephrine (10(-5) mol/L), or endothelin-1 (10 pmol) were found between the two groups. Relaxing responses to acetylcholine or sodium nitroprusside in phenylephrine-precontracted mesenteric vascular beds and constrictor response to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (100 nmol) were comparable in both groups. Losartan blunted angiotensin II constriction and reduced (P < .05) responses to phenylephrine in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Dec
PMID:Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. 749 71

The influence of dietary sodium restriction and angiotensin II blockade on hypertension induced by a 25-day period of administration of the inhibitor of nitric oxide synthesis NG-nitro-L-arginine methyl ester (L-NAME: 10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotension II receptor blocker, losartan (30 mg/kg once daily by gavage) was administered prior to and during L-NAME in rats fed the normal sodium diet. Results expressed as mean +/- ESM are presented in the following table: [table: see text] At the end of studies, conscious systolic arterial pressure increased similarly in L-NAME-treated groups maintained on NS or LS intake. Moreover, a 25% reduction in cardiac output due to a decrease in stroke volume was observed in both groups. A slight but significant cardiac hypertrophic response was observed in hypertensive rats irrespective of sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in cardiac output and the cardiac hypertrophy associated with L-NAME treatment in rats on normal sodium intake. In conclusion, hypertension resulting from chronic blockade of nitric oxide synthesis was not affected by dietary sodium restriction. A crucial role for the renin-angiotensin system was demonstrated in this new model of hypertension.
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PMID:[Sodium intake and angiotensin in hypertension induced by chronic NO synthase inhibition in the rat]. 751 Apr 68

The renin angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. For this reason, attempts to specifically block this system have been a pharmacological goal for over 25 years. Blockade of the renin system has been attempted at 3 pivotal sites: the rate limiting angiotensinogen-renin step, conversion of angiotensin I to angiotensin II, and the active receptor sites for the terminal products of angiotensin II and aldosterone. Converting enzyme inhibitors have been successfully studied and utilised in clinical cardiovascular disorders, but questions persist regarding the specificity of their action. Thus, other more specific approaches remain under evaluation. Inhibition of the action of renin on angiotensinogen was demonstrated with early inhibitory peptides and in experimental studies with specific antibodies. Most currently available renin inhibitors are nonpeptides, which nonetheless require intravenous administration. An oral renin inhibitor with clinical effects has been evaluated in early human trials. Like renin inhibitors and converting enzyme inhibitors, specific angiotensin antagonists were studied early in the course of renin system pharmacological blockade. Early angiotensin antagonists were limited, due to the requirement for intravenous administration and because of their short half-lives. They also had the potential for mixed agonist/antagonist physiological and pharmacological effects, which could result in a pressor, rather than a depressor, response. The angiotensin receptor antagonists have the appeal of blocking the specific receptor at its target tissue site, analogous to other well described systems. Newer angiotensin antagonists do not have the limitations of the precursor peptides. Losartan (DUP753) is a specific angiotensin II AT1 receptor antagonist. It is orally effective without agonist activity, and has high receptor binding characteristics. Early studies indicate that it is a specific probe of the renin system, and is providing newer insights into the role of the renin system in cardiovascular disorders. Emerging clinical studies indicate that it is effective for blood pressure reduction and as a vasodilator. Aldosterone antagonists such as spironolactone have been available for decades. Spironolactone is being used in an ongoing trial to assess the impact of combined converting enzyme and aldosterone inhibition. Newer aldosterone antagonists could add to targeted blockade of aldosterone without the adverse effects of the precursor compound, and the potential for combined specific renin system blockade.
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PMID:The clinical potential of renin inhibitors and angiotensin antagonists. 751 58

To compare the effects of an angiotensin II (Ang II)-receptor antagonist and an angiotensin-converting enzyme (ACE) inhibitor on myocardial, vascular structure and reactivity, SHR (5-week-old) were treated with losartan of captoril for 16 weeks. Losartan (10 mg/kg/day, p.o.) and captopril (30 mg/kg/day, p.o.) significantly prevented the development of hypertension with aging, and the effects by these drugs were almost similar. Losartan and captopril significantly reduced the ventricular weight and the thickening of the coronary artery. Maximal coronary flow (MCF) induced by adenosine in the isolated heart was significantly higher in both the losartan and captopril groups. However, MCF in the captopril group was significantly lower than that in the losartan group. The pressor response to exogenous norepinephrine in the mesenteric arterial bed was significantly lower in the losartan group, whereas that in the captopril group was not. These findings suggest that the local Ang II produced by enzymes other than ACE also may play a role in vascular hypertrophy and hyperresponsiveness in SHR.
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PMID:[Effects of chronic losartan treatment on myocardial, vascular structure and reactivity with aging in spontaneously hypertensive rats (SHR): its effects compared with those of captopril]. 755 36


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