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

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

This study examines the effects of angiotensin II on hypertrophy and proliferation of aortic smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats and the receptor subtypes mediating these effects. In quiescent confluent cells, angiotensin II induced a dose-dependent increase in thymidine and leucine incorporation without stimulating cell proliferation. In nonconfluent cells, angiotensin II stimulated cell proliferation only in combination with a submaximal concentration of fetal calf serum. These effects were enhanced in cells from spontaneously hypertensive rats compared with Wistar-Kyoto rats. The effects of angiotensin II could be blocked by the AT1 receptor antagonist DuP 753 but not by the AT2 receptor ligand PD 123177. In receptor binding studies with cells derived from both rat strains, AT1-typical binding was observed. These data show that the angiotensin II receptors present in vascular smooth muscle cells in culture from both rat strains are of the AT1 receptor subtype. This receptor subtype appears to mediate vascular smooth muscle cell hypertrophy and proliferation as well as vasoconstriction. Although no difference in the receptor profile was detectable between the two rat strains, the affinity for the ligands to the receptor and the receptor density tended to be greater in cells from spontaneously hypertensive rats than in cells from Wistar-Kyoto rats. These results may partly explain the greater hypotensive response to angiotensin II receptor blockade in spontaneously hypertensive rats than in Wistar-Kyoto rats, although both rat strains have the same plasma concentrations of angiotensin II.
Hypertension 1992 Dec
PMID:Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. 145 90

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V1-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.
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PMID:Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence. 149 64

Angiotensin II is a potent pressor hormone and a primary regulator of aldosterone secretion. It acts through at least two types of receptors termed AT1 and AT2. We analyzed cDNA and genomic clones encoding the human angiotensin II type-1 receptor, AT1. The human AT1 gene was mapped to chromosome 3q by polymerase chain reaction analysis of DNA from a panel of human-hamster somatic cell hybrids. The predicted amino acid sequence is 95% identical to the corresponding rat and bovine receptors and 25% and 22% identical, respectively, to the receptors encoded by the RTA and MAS genes. Characterization of several human cDNA clones demonstrated the existence of two alternate 5'-untranslated regions (UTRs) that contain a common initial sequence but differ by the presence or absence of an insertion of 84 base pairs. In the genomic sequence, the coding sequences are contained in a single exon, with an intron occurring in the 5'-UTR at the position of insertion of the 84-base pair sequence. The exons encoding the alternate 5'-UTRs are located at least 3.8 kilobases away from the exon encoding the protein. Reverse transcription-polymerase chain reaction analysis showed that both forms of 5'-UTR are present in approximately equal abundance in a range of tissues expressing AT1. The reagents developed in this work may be useful in testing the hypothesis that genetic variations in angiotensin II receptor function are associated with a tendency to develop hypertension.
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PMID:Genetic analysis of the human type-1 angiotensin II receptor. 150 24

The goal of the present study was to compare the hemodynamic and biochemical effects of the renin inhibitor Ro 42-5892, the angiotensin converting enzyme inhibitor cilazapril, and the angiotensin II receptor blocker EXP132, the aldehyde derivative of DuP 753. The three drugs were evaluated in guinea pigs, previously treated with furosemide, using their maximal effective doses. Cilazapril decreased arterial blood pressure more than Ro 42-5892 and EXP132. In contrast, Ro 42-5892 and EXP132 had similar effects. The larger decrease of arterial pressure induced by cilazapril was not due to a larger decrease of angiotensin II in plasma and was not influenced by cyclooxygenase inhibition with indomethacin or by bradykinin antagonism with Hoe 140. After binephrectomy, most of the blood pressure-lowering effect of Ro 42-5892 disappeared. In contrast, cilazapril was still markedly effective, pointing to extrarenal effects. We conclude that in furosemide-treated guinea pigs, as opposed to previously published animal models, the decrease of arterial pressure induced by angiotensin converting enzyme inhibitors may be partly due to extrarenal effects not related to the renin-angiotensin system.
Hypertension 1992 Mar
PMID:Effects of renin-angiotensin system blockade in guinea pigs. 153 64

Previous studies have shown that the anterior hypothalamic area participates in the centrally mediated pressor response to exogenous angiotensin II. The current study was designed to test the hypothesis that endogenous anterior hypothalamic angiotensin II plays a significant role in blood pressure control. Type 1 angiotensin II receptors in the anterior hypothalamic area were blocked by local microinjection of DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist. DuP 753 (20 or 40 micrograms; in 100 nl artificial cerebrospinal fluid) or vehicle alone was microinjected into the anterior hypothalamic area of conscious NaCl-sensitive spontaneously hypertensive rats and Wistar-Kyoto controls. DuP 753 caused significant dose-related decreases in mean arterial pressure (maximal decrease, 22.5 +/- 1.8 mm Hg) with unchanged heart rate in NaCl-sensitive spontaneously hypertensive rats but effected no change in Wistar-Kyoto rats. Injections of equal volumes of artificial cerebrospinal fluid into the anterior hypothalamic area had no effect in either strain. Further, microinjection of DuP 753 into the posterior hypothalamic area produced no significant effect on blood pressure or heart rate in NaCl-sensitive spontaneously hypertensive rats. Microinjection into the anterior hypothalamic area of the selective type 2 angiotensin II receptor antagonist PD 123319 did not affect blood pressure or heart rate in NaCl-sensitive spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 May
PMID:Depressor effect of blocking angiotensin subtype 1 receptors in anterior hypothalamus. 156 66

Oral administration of the angiotensin II receptor subtype 1 (AT1) antagonist DuP 753 causes long-lasting lowering of mean arterial pressure in spontaneously hypertensive rats. We examined whether the antihypertensive action of DuP 753 is a result of inhibition of brain angiotensin II. In normal spontaneously hypertensive rats, we found that intracerebroventricular DuP 753 (10 micrograms) blocked the pressor action of intracerebroventricular angiotensin II (100 ng); however, intracerebroventricular DuP 753 (10 micrograms) had no effect on the pressor response to 300 ng/kg angiotensin II administered intravenously (48 +/- 3 mm Hg in the presence of intracerebroventricular DuP 753 versus 49 +/- 4 mm Hg in its absence). In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 micrograms caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours. In contrast to its central effects, we found that oral DuP 753 (10 or 30 mg/kg) in normal spontaneously hypertensive rats resulted in sustained mean arterial pressure decreases of up to -74 mm Hg. These data suggest that, although the pressor effect of brain angiotensin II is mediated by the AT1 receptor, blockade of these receptors does not lower blood pressure in spontaneously hypertensive rats. In the spontaneously hypertensive rat, DuP 753 depresses blood pressure by blockade of peripheral, not central, AT1 receptors.
Hypertension 1992 Jun
PMID:Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats. 159 65

A transgenic rat line, TGR(mREN2)27, was established by introducing the murine Ren-2 gene into the genome of rats by microinjection techniques. These rats exhibit severe hypertension, making them an interesting model in which to study the role of renin in the pathophysiology of hypertension. However, although the additional renin gene is the only genetic difference compared with control rats, the exact mechanism of hypertension in TGR(mREN2)27 rats is still unclear. It cannot be attributed to a stimulation of the endocrine renin-angiotensin system or to an overexpression of renin in the kidney, since plasma and kidney renin and renin gene expression in the kidney are low in these animals. Here we describe recent progress made toward elucidating mechanisms of hypertension in TGR(mREN2)27 rats. 1) TGR(mREN2)27 rats were bred to homozygosity. The development of high blood pressure in homozygous rats is accelerated compared with that of heterozygous rats. This is paralleled by a higher mortality rate in homozygous TGR(mREN2)27 rats. Blood pressure and mortality rate of homozygous transgenic rats were effectively reduced by 10 mg captopril per kilogram body weight. 2) Treatment of 8-week-old heterozygous TGR(mREN2)27 rats with 10 mg/kg body wt per day of the angiotensin II receptor antagonist DuP 753 for 4.5 weeks normalized blood pressure. After withdrawal of the drug, blood pressure increased rapidly, reaching control levels after 3 weeks. In another group of TGR(mREN2)27 rats treated with 0.5 mg/kg per day, there was no change in blood pressure. Plasma renin and plasma angiotensin II were significantly higher in the high-dose group compared with the low-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats. 159 68

We have previously demonstrated that loss of renal functional reserve (renal response to protein loading) in two-kidney, one clip Goldblatt hypertension is characterized by no change in glomerular filtration rate or single nephron glomerular filtration rate and decreased absolute proximal tubular reabsorption during glycine administration. Captopril restores proximal reabsorption and renal functional reserve in this condition. Because captopril suppresses angiotensin II generation and increases bradykinin, prostaglandins, and potentially nitric oxide, we have investigated the role of angiotensin II blockade in restoring proximal reabsorption and renal functional reserve by comparing captopril with DuP 753, an angiotensin II receptor antagonist, in Goldblatt rats. One month after clipping, two period micropuncture studies (control and glycine) were performed on the unclipped kidney. Normal rats and three groups of clipped rats were studied: an untreated group (HYP), a group treated with captopril (CEI), and a group treated with DuP 753 (DuP) 5 days before micropuncture. Glycine increased glomerular filtration rate, nephron plasma flow, and single nephron glomerular filtration rate in normal rats. Systemic and glomerular hypertension in HYP rats was associated with loss of renal functional reserve and a decrease in absolute proximal reabsorption during glycine. Captopril and DuP 753 normalized systemic and glomerular capillary pressure and prevented the decrease in proximal reabsorption during glycine; however, only CEI rats increased single nephron glomerular filtration rate and glomerular filtration rate after glycine. In conclusion, abnormal responses of both glomerular and tubular function are responsible for the loss of renal functional reserve in Goldblatt rats. Inhibitory angiotensin II activity is responsible for decreasing proximal reabsorption during glycine; however, factors other than angiotensin II limit the glomerular response to glycine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:Angiotensin II and renal functional reserve in rats with Goldblatt hypertension. 159 82

Clinical states in which angiotensin II is increased are often associated with increases in mineralocorticoids. To determine the effects of mineralocorticoids on angiotensin II action, we examined the effects of aldosterone on angiotensin II receptor expression and function in cultured rat vascular smooth muscle cells. Incubation with aldosterone resulted in concentration- and time-dependent increases in angiotensin II receptor number, without changes in binding affinity. For example, incubation with 1 microM aldosterone for 40 hours resulted in 59% increases in angiotensin II receptor number. Increases in angiotensin II receptors were dependent on protein synthesis as evidenced by the time dependency of upregulation and inhibition by cycloheximide. Incubation with aldosterone resulted in enhanced angiotensin II-stimulated phospholipase C activation, as demonstrated by increases in angiotensin II-induced inositol phosphate responses in proportion to the increases in receptor number. In addition, aldosterone prevented angiotensin II-induced downregulation of angiotensin II surface receptors and angiotensin II desensitization of inositol phosphate formation. In summary, aldosterone 1) directly increased angiotensin II receptor number, 2) increased angiotensin II-stimulated inositol phosphate responses, and 3) prevented angiotensin II-induced downregulation and desensitization. In conclusion, aldosterone may potentiate the pressor responses of angiotensin II via effects on angiotensin II receptors.
Hypertension 1992 Jul
PMID:Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses. 161 54


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