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

Inhibitors of the renin-angiotensin system lower blood pressure of spontaneously hypertensive rats, although plasma renin is not elevated. To test the hypothesis that the actions of angiotensin II within the kidney may contribute to the high blood pressure in spontaneously hypertensive rats, we infused valsartan, a subtype 1 angiotensin II receptor antagonist, via the suprarenal artery into the right kidney of conscious, freely moving, unilaterally nephrectomized (left) spontaneously hypertensive rats (12 to 14 weeks old). Valsartan (0.3 mg/kg per day for 48 hours) lowered blood pressure (change in blood pressure, -7 +/- 3, -19 +/- 4, and -26 +/- 4 mm Hg, n = 11, at 12, 24, and 48 hours) after intrarenal administration but had no significant effect on blood pressure after intravenous administration (change in blood pressure, 1 +/- 5, -3 +/- 4, and 10 +/- 5 mm Hg, n = 7, at 12, 24, and 48 hours). Infusion of vehicle (0.9% saline) intrarenally had no significant effect on blood pressure (change in blood pressure, 2 +/- 5, -1 +/- 6, and 0 +/- 7 mm Hg, n = 11, at 12, 24, and 48 hours). The maximum fall in blood pressure reached after intrarenal administration of this dose of valsartan was similar to the maximum fall induced after intravenous administration of higher doses (change in blood pressure, -14 +/- 5, -27 +/- 4, and -32 +/- 5 mm Hg, n = 7, at 12, 24, and 48 hours after 3 mg/kg per day i.v.). Thus, endogenous angiotensin II acting within the kidney appears to play an important role in the maintenance of high blood pressure in spontaneously hypertensive rats.
Hypertension 1993 Jun
PMID:Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hypertensive rats. 850 92

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 (10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotensin II receptor blocker losartan (30 mg/kg once daily by gavage) was administered before and during NG-nitro-L-arginine-methyl ester in rats fed the normal sodium diet. At the end of the studies, conscious systolic arterial pressure increased similarly in NG-nitro-L-arginine-methyl ester-treated groups maintained on normal or low sodium 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. At the completion of studies, plasma renin activity was similar to corresponding controls in the hypertensive groups on normal or low sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in stroke volume and cardiac hypertrophy associated with NG-nitro-L-arginine-methyl ester treatment in rats on normal sodium intake. In conclusion, hypertension resulting from long-term 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.
Hypertension 1993 Jun
PMID:Sodium and angiotensin in hypertension induced by long-term nitric oxide blockade. 850 4

A reaction between enzyme renin and its only natural substrate angiotensinogen is the initial and rate-limiting step for producing a potent vasoconstrictor angiotensin II as the final product of the renin-angiotensin system, a contributory factor in the pathogenesis of hypertension. In order to assess the role of the interaction of human renin with human angiotensinogen in the development of high blood pressure, we have constructed the chimeric renin-angiotensin cascade in mice comprising both human renin and human angiotensinogen as well as the endogenous angiotensin-converting enzyme and angiotensin II receptor by cross-mating separate lines of transgenic mice carrying either the human renin or human angiotensinogen genes. Although each single gene carrier did not develop hypertension despite the observed normal tissue-specific expression of the transgenes, dual gene strains exhibited a chronically sustained increase in blood pressure. Administration of a human renin-specific inhibitor (ES-8891) was effective in reducing the elevated blood pressure only against the cross-mated hybrid mice, but treatment of an angiotensin-converting enzyme inhibitor (captopril) and a selective antagonist (DuP 753) directed at the angiotensin II receptor decreased the basal level of blood pressure even in single gene carriers as well as in dual gene mice. These results clearly demonstrated that the sustained increase in blood pressure of the hybrid mice was initiated by the interaction between the products of the two human genes.
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PMID:Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. 850 94

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.
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PMID:Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. 851 25

This study investigated the anti-hypertensive efficacy and tolerability of once-daily losartan potassium (50 mg titrated to 100 mg), an angiotensin II receptor antagonist, compared with once daily felodipine extended release (ER) (5 mg titrated to 10 mg), a calcium channel blocker, after 12 weeks of therapy in elderly hypertensive patients. Following a 4-week, single-blind, placebo baseline period, qualifying patients were randomly allocated to 12 weeks of double-blind treatment with losartan potassium or felodipine ER. After 6 weeks, patients with a 24 h post-dose sitting diastolic blood pressure > or = 90 mm Hg had their dose doubled for the remaining 6 weeks. At 6 weeks, there was a greater BP response for felodipine ER than losartan potassium in elderly patients with mild to moderate hypertension. However, after 12 weeks of therapy, losartan potassium reduced BP as effectively as felodipine ER with no differences in mean BP reduction or anti-hypertensive response category between treatment groups. In this study, both treatments were well tolerated; felodipine ER was associated with a numerically higher incidence of headache and oedema while the incidence of asthenia was numerically higher in losartan-treated patients.
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PMID:Randomised, double-blind, parallel study of the anti-hypertensive efficacy and safety of losartan potassium compared with felodipine ER in elderly patients with mild to moderate hypertension. 855 92

Losartan, on orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two-period, placebo-controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13-day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6-day period after both warfarin doses for the measurements of R- and S-warfarin concentrations and prothrombin times. The pharmacokinetics of R- and S-warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.
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PMID:Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin. 856 8

Spectral analysis was recently chosen to characterize the fast oscillations depending on the autonomic nervous system. Humoral stimuli could impinge on low frequency (LF) domain of blood pressure (BP) since the time lag to humoral systems activation is larger. This study was designed to analyse LF components of short-term variability of BP of conscious rats in conditions where humoral systems were activated. We studied rats with two-kidney Goldblatt hypertension in which the BP level was dependent upon the renin-angiotensin and kallikrein-kinin systems. Spectral powers of the systolic and diastolic BP and heart rate (HR) were computed in the high (respiratory, HF), mid (0.2-0.6 Hz, MF) and low (0.02-0.2 Hz, LF) frequency bands, as detected by the Fast Fourier Transform technique on consecutive 102-s stationary periods. Renal hypertension by a two-kidney one clip procedure was associated with a marked rise in SBP (+47 mmHg) and no significant change in HR. Renal hypertension selectively increased the LF component of SBP (+86%) when hypertensive rats were compared to sham operated animals. First, administration of losartan, a selective nonpeptide angiotensin II receptor antagonist, to sham rats resulted in a moderate SBP decrease, a significant tachycardia (+47 batt/min) with no change in BP and HR spectra profiles. Losartan determined in the hypertensive group a marked fall in SBP (-25 mmHg) with a significant tachycardia (+50 batt/min). Interestingly, losartan reduced the LF component of SBP (-26%). In a second series of normotensive and hypertensive rats, Hoe 140, a bradykinin B-2 receptor antagonist, did not affect the BP and HR levels of the two groups of rats. Hoe 140 decreased the LF component of SBP variability (-28%). Losartan, added after Hoe 140, decreased the BP (-17 mmHg) in association with a tachycardia (+59 batt/min) and induced a supplementary decrease of the LF component of SBP variability (-60%) in hypertensive rats. After the combined blockade, the LF component of SBP of the hypertensive rats was equivalent to that of the sham rats. Thus, an increase in the LF component of BP variability was observed in a model of hypertension where the BP is dependent upon humoral factors. The contribution of the renin-angiotensin and kallikrein-kinin systems in the slow fluctuations of BP was demonstrated using two specific antagonists losartan and Hoe 140.
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PMID:[Hormonal contribution to short-term variability of blood pressure in a renovascular hypertension model]. 857 74

This 12-week, open-label study was conducted to gain experience with losartan potassium, an angiotensin II receptor antagonist, in patients with severe hypertension. Patients were either untreated or withdrawn from current therapy for at least 48 h before initiation of losartan 50 mg once daily. Patients were titrated to 100 mg as needed to achieve a goal of sitting diastolic blood pressure (SiDBP) 90 or 95 mm Hg. Hydrochlorothiazide (12.5 mg once daily titrated to 25 mg) was added and followed by either a dihydropyridine calcium channel blocker (CCB) and/or atenolol, if BP was not controlled. A total of 179 patients with a pretreatment mean baseline BP of 172 +/- 17/112 +/- 18 mm Hg enrolled in the trial and BP was recorded 24 h after dosing at baseline and weeks 2, 4, 8 and the final week (10-12 weeks). The mean reductions in SiDBP from baseline were 7.3, 9.3, 15.9 and 18.9 mm Hg, respectively, and these changes from baseline were statistically significant, P < 0.001. At the end of the trial, 22% of patients remained on losartan monotherapy, 30% required the addition of hydrochlorothiazide (HCTZ) and 31% required both HCTZ and a CCB; 11% required HCTZ and atenolol while 4% required HCTZ, a CCB and atenolol; 2% of patients were on regimens not specified by the protocol. SiDBP < 90 mm Hg was achieved in 68 patients by the final visit; 24% of these patients were treated with losartan monotherapy (50 or 100 mg), 41% achieved control with the addition of HCTZ (12.5 or 25 mg) and 24% required triple therapy which included losartan, HCTZ and a CCB. As assessed by the investigator, 25% of the patients in the study had drug-related clinical adverse experiences. Headache was the most frequently reported clinical adverse event (26% of patients). No clinically significant changes in laboratory parameters were observed. It is concluded that losartan potassium can be used as initial therapy for patients with severe hypertension and can be administered concurrently with hydrochlorothiazide, calcium channel blockers and atenolol.
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PMID:Losartan potassium as initial therapy in patients with severe hypertension. 858 62

Lessons learned from ambulatory blood pressure (BP) monitoring strongly influence the development of new anti-hypertensive drugs. Efficacy should be demonstrated not only in the conventional clinical setting, but also throughout the full 24 h day, including the important early morning hours near the end of dosing intervals. Preservation of the circadian pattern, including appropriate day/night BP differences, may be a further important goal of therapy. The reproducibility of ambulatory monitoring measurements, together with the absence of placebo effects with this technique, adds greatly to its power and efficiency. Moreover, the use of ambulatory monitoring to accurately diagnose hypertension and exclude non-confirmed or white coat hypertensives from clinical trials adds further sensitivity to quantifying drug action. This technique was recently applied to the evaluation of the new angiotensin II receptor antagonist losartan. Hypertensive patients diagnosed by ambulatory monitoring were divided into four groups: placebo, losartan 50 mg once daily, 100 mg once daily or 50 mg twice daily. Compared with placebo, which had no effect, all three losartan regimens decreased SBP and DBP significantly. There was no difference in efficacy between the two once daily regimens, although 50 mg twice daily was slightly more effective than 50 mg once daily but not statistically significantly different from 100 mg once daily. However, all losartan groups exhibited sustained BP reductions throughout the 24 h dosing interval and preserved the circadian BP patterns. Ambulatory monitoring was thus able to accurately quantity the efficacy and the key chronobiological aspects of anti-hypertensive therapy with losartan in an efficient and cost-effective manner.
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PMID:Controlling blood pressure throughout the day: issues in testing a new anti-hypertensive agent. 858 78

The past few decades have seen a remarkable development in the field of pharmacological therapy, one of the most notable examples being the treatment of arterial hypertension. Some of the early anti-hypertensive agents were relatively crude by today's standards, but gradually efficacy, tolerability, or both, of blood pressure-lowering (BP) drugs have been improved. It is presently possible to choose from a number of effective and well-tolerated compounds for the treatment of hypertension. The latest additions to the anti-hypertensive armamentarium are the angiotensin II receptor antagonists, the most advanced of these being losartan. It is perhaps most relevant to compare losartan to the angiotensin converting enzyme (ACE) inhibitors, another class of anti-hypertensive agents which acts mainly by interfering with the renin-angiotensin-aldosterone system (RAAS). Studies have shown that losartan lowers BP at least as effectively as ACE inhibitors. However, the side-effect profile of losartan is more favourable. In particular cough, a relatively common side-effect of ACE inhibitors, has been shown to be significantly less common during losartan treatment. This is probably because losartan does not interfere with bradykinin metabolism, unlike the ACE inhibitors. Regarding the reversal of left ventricular hypertrophy (LVH), a powerful risk indicator for cardiovascular disease, we have shown that losartan is more effective in this regard than treatment with the beta-blocker atenolol. It appears, based on these and other findings, that interference with the RAAS is particularly useful in causing reversal of the cardiovascular hypertrophic changes. The prognostic implications remain to be demonstrated, but it would be logical to expect a benefit from this effect. It was recently shown that polymorphism of the ACE gene is associated with increased risk of coronary heart disease even in the absence of conventional risk factors. If these findings are confirmed the interest in interfering with the RAAS as a therapeutic modality in hypertension would obviously be strengthened. It is not easy to predict the future role of any new therapeutic modality. The positive relation between efficacy and tolerability of losartan, as well as the fact that several observations suggest that interference with the RAAS could be favourable from a prognostic point of view, suggest that losartan may come to play an important role in the future treatment of hypertension.
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PMID:The future role of losartan. 858 83


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