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

A hypothetical model of the active site of angiotensin-converting enzyme, based on known chemical and kinetic properties of the enzyme, has enabled us to design a new class of potent and specific inhibitors. These compounds, carboxyalkanoyl and mercaptoalkanoyl derivatives of proline, inhibit the contractile response of guinea pig ileal strip to angiotensin I and augment its response to bradykinin. When administered orally to rats, these agents inhibit the pressor effect of angiotensin I, augment the vasodepressor effect of bradykinin, and lower blood pressure in a model of renovascular hypertension.
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PMID:Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. 19 8

SQ 14,225 (D-3-mercapto-2-methylpropanoyl-L-proline) markedly lowered the blood pressure of the renin-dependent aortic-ligated and two-kidney Goldblatt hypertensive rat and failed to reduce blood pressure in the one-kidney Goldblatt hypertensive rat. In the two-kidney Goldblatt rat, SQ 14,225 (p.o.) was about 10 times as potent as teprotide, the nonapeptide SQ 20,881 (s.c.). Oral doses of SQ 14,225 moderately reduced the blood pressure of the Wistar-Kyoto spontaneously hypertensive rat but not that of the normotensive Wistar-Kyoto rat. Bilateral nephrectomy abolished the antihypertensive activity of SQ 14,225 in the spontaneously hypertensive rat. SQ 14,225 and SQ 20,881 elicited parallel dose-response curves in the two-kidney renal hypertensive rat. Post-treatment of spontaneously hypertensive rats with either agent failed to augment the antihypertensive effect produced by effective doses of the other agent. The results suggest that SQ 14,225 acts primarily by inhibiting the renin-angiotensin system to reduce elevated blood pressure, especially in presumably renin-dependent models of hypertension.
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PMID:Antihypertensive activity in rats for SQ 14,225, an orally active inhibitor of angiotensin I-converting enzyme. 20 93

In two patients with end stage renal disease and dialysis-resistant hypertension, the orally active inhibitor of angiotensin-converting enzyme, captopril (SQ14,225; 2-D-methyl-3-mercaptopropranoyl-L-proline, dramatically lowered blood pressure both before and during dialysis. This agent holds promise as an alternate to bilateral nephrectomy in such patients.
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PMID:Hemodialysis-resistant hypertension: control with an orally active inhibitor of angiotensin-converting enzyme. 21 11

Labelled proline incorporation into collagenous and noncollagenous proteins of aorta or mesenteric arteries was significantly increased in 70-day-old spontaneously hypertensive rats (SHR) at the early stage of hypertension in comparison with normotensive Wistar-Kyoto (WK) rats; however such an increase was not detected in 30-day-old SHR at the prehypertensive stage. Similar increases in the proline incorporation were noted in 70-day-old renal hypertensive rats and in DOCA hypertensive rats in which hypertension had been induced similarly to that om SHR. Furthermore, the decay of the specific activity of noncollagenous and collagenous proteins was studied for 100 days after labelled proline infusion. The dacay of the noncollagenous protein activity was clearly accelerated in the heart, aorta and especially in the mesenteric arteries of SHR compared with WK. The decrease in the hydroxyproline radioactivity of the collagenous protein was significantly faster in the aorta and mesenteric arteries in SHR. These results proved the increased protein metabolism in the arterial walls in the relatively early stage of hypertension in SHR as well as in experimental hypertension, and then suggested its importance in the common pathogenetic mechanisms of hypertension.
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PMID:Vascular protein metabolism in the pathogenesis of hypertension. 96 68

The selectively-bred substrains of spontaneously hypertensive rats with a greater vulnerability to vascular lesions rapidly developed arterial fat deposition within 1 or 2 weeks as well as a greater hypercholesterolemic response when fed on high fat cholesterol diet including 20% of suet, 5% of cholesterol and 2% of cholic acid. The ring-like arterial fat deposition at the branches of superior mesenteric arteries and cerebrobasal arteries, which was found to be good indices for the deposition of intrarenal or coronary arteries, was not observed in normotensive rats fed on high fat cholesterol diet for 3 months, greatly delayed in SHR under antihypertensive treatment and accelerated by 1% salt loading in drinking water. The horseradish peroxidase infused intravenously 1 to 4 hours before sacrifice leaked in ring-like forms which corresponded to the fat deposit in mesenteric arteries. The incorporation of 3H-proline infused 4 hours before sacrifice was enhanced in the mesenteric arteries with the fat deposition. These results clearly indicated that hypertension was a great contributory factor to rapid arterial fat deposition, which was caused by an increased vascular permeability and enhanced the arterial collagen formation, the initiation process of arterio- or atherosclerosis.
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PMID:Pathogenesis of acute arterial fat deposition in spontaneously hypertensive rats. 115 92

Autoradiographic tests carried out on rats with renal hypertension using 3H-proline resulted in an acclerated collagen synthesis by media cells of aorta and coronary arteries. Electronmicroscopically an increased content of collagen fibers and an enrichment of ruthenium-red-positive substances in the extracellular space were found. The 35S-sulfate-incorporation in aorta and coronary arteries of animals with hypertension is also increased. These changes in the extracellular space of the vascular wall have an atherosclerosis promoting effect, probably caused by a distrubance of the permeability.
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PMID:[Expermental contribution on the genesis of arteriosclerosis caused by hypertension]. 123 18

In humans, active renin is generated by the removal of a 43-amino acid prosegment from the zymogen prorenin. This cleavage event is highly specific, occurring at only one of the seven pairs of basic amino acids in the body of preprorenin. This cleavage site selectivity is also displayed by a number of other proteases in vitro and in mouse pituitary AtT-20 cells transfected with a human preprorenin expression vector, suggesting that specificity of cleavage is directed in part by the primary sequence, the higher order structure, or both of prorenin itself. To test this hypothesis, single amino acid mutations were introduced in the region of human preprorenin surrounding the natural cleavage site, and the resultant recombinant proteins were expressed in cultured Chinese hamster ovary and AtT-20 cells. The results suggest that amino acids in addition to the pair of basic amino acids surrounding the cleavage site affect the ability of both trypsin and the endogenous AtT-20 processing enzyme to cleave prorenin. Notably, although a proline at position -4 is essential for processing of prorenin in AtT-20 cells and is correlated with predicted formation of a beta-turn at this position, site-directed mutations suggest that this structural feature in addition to a pair of basic amino acids is not sufficient to lead to proteolytic activation of prorenin. Displacement of sequences surrounding the cleavage site to a position 10 amino acids toward the amino terminus led to partial processing of a mutated prorenin.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Dec
PMID:Molecular determinants of human prorenin processing. 145 93

Incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries in two-kidney, one-clip hypertensive rats was greater than that in normotensive rats. Splanchnicotomy predominantly over the root of mesenteric arteries or intracranioventricular injection of 6-hydroxydopamine prevented the development of hypertension in 2K-1C rats concomitant with the reduction of incorporation of 3H-proline into the non-collagenous protein in mesenteric arteries. The content of norepinephrine in the hypothalamus in 2K-1C rats was lower than that in normotensive control rats. These findings indicate that increased non-collagenous protein synthesis in mesenteric arteries or low level of hypothalamic norepinephrine has facilitative effects on the development of 2K-1C hypertension.
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PMID:Central catecholamine, sympathetic nerve and vascular protein in the acute phase of two-kidney, one-clip renovascular hypertension in rats. 145 31

Endothelin-1 (ET-1), a potent vasoconstrictor peptide synthesized by the vascular smooth muscle endothelium, has been previously shown to produce a sustained, salt-sensitive elevation in mean arterial pressure when chronically infused over a 7-day period into male Sprague-Dawley rats. In addition to other physiological actions, ET-1 has been shown to have potent effects on various renal functions, including renin production. Activation of the renin-angiotensin system, therefore, may contribute to the pressor response induced by ET-1. In this investigation, captopril ([2S]-1-[3-mercapto-2-methylpropionyl]-L-proline), a sulfhydryl-containing angiotensin I converting enzyme inhibitor, was chronically administered to endothelin-infused rats to elucidate the role of the renin-angiotensin system in this animal model of hypertension. Rats were catheterized, housed in metabolic cages, and maintained on a fixed 6.0 meq.day-1 sodium intake throughout the experiment, with daily measurements taken of mean arterial pressure, heart rate, water intake, urine output, and urinary sodium and potassium excretions. Infusion of ET-1 alone at a rate of 5.0 pmol.kg-1.min-1 for 7 days was associated with a significant and sustained increase in mean arterial pressure; concomitant chronic administration of captopril in another group of rats at a rate of 1.0 mg.kg-1.hr-1 prevented the ET-1-induced hypertension. In an additional study, however, increases in plasma angiotensin II concentration were not observed in rats administered ET-1 alone at 5.0 pmol.kg-1.min-1. These results indicate that endothelin-induced hypertension may involve stimulation of the renin-angiotensin system but not an increase in circulating angiotensin II concentration.
Hypertension 1992 Jun
PMID:Captopril prevents chronic hypertension produced by infusion of endothelin-1 in rats. 159 67

Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) are a useful animal model for studying juvenile malignant hypertension. Using M-SHRSP males, the effects of SQ 29,852 [(S)-1-[6-amino-2-[[hydroxy (4-phenylbutyl) phosphinyl]oxy]-1-oxohexyl]-L-proline; 30-40 mg/kg per day], captopril (30-40 mg/kg per day), hydralazine hydrochloride (10-15 mg/kg per day) and a 33% fish meal diet on the prevention and therapy of malignant hypertension were examined. Drugs and diet were given separately, beginning at weaning, maturity or adulthood. Observed effects included antihypertension, prolonged life span and prevention and/or reversal of angionecrosis. Each treatment resulted in an antihypertensive effect, but some adult rats seemed treatment-resistant. SQ 29,852 was the most effective treatment for reducing blood pressure. The life span of animals in the treated groups was extended significantly beyond that of the controls. In particular, those rats treated with either captopril or SQ 29,852 lived in excess of 500 days. This included not only those in which treatment resulted in a lowering of blood pressure, but also those whose severe hypertension was not so reduced. Angionecrosis was observed in the organs of many of the non-treated animals, including the brain, heart, kidneys and testes. Both hydralazine and the fish meal diet had a limited effect, if any, on the prevention or reversal of angionecrosis. In contrast, almost none of the rats given either captopril or SQ 29,852 showed cerebrovascular lesions or angionecrosis of the brain, heart and kidneys; angionecrosis in adult M-SHRSP kidneys disappeared within 10 or 18 days after the initiation of SQ 29,852 or captopril, respectively. This data seems to support a possible role for these two drugs not only in prevention, but also in repair, of angionecrosis independent of markedly high blood pressure in M-SHRSP. Based on our overall observations, SQ 29,852 was seen as the most effective of the treatments studied.
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PMID:Chronic treatment with captopril, SQ29,852, hydralazine and a 33% fish meal diet in malignant stroke-prone spontaneously hypertensive rats. 166 66


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