Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to investigate whether angiotensin II, by increasing extracellular matrix synthesis, contributed to the vascular wall thickening observed in hypertension. Thus, we examined the direct effects of angiotensin II on collagen and fibronectin synthesis in cultured rat vascular smooth muscle cells by measuring 3H-proline incorporation. Angiotensin II, in a concentration of 10 mumol/l, increased collagen synthesis in a dose-dependent manner up to 1.8-fold. This increase occurred within 24 h after the addition of angiotensin II and the time required to reach maximum stimulation was approximately 48 h. This increase was receptor-mediated and correlated with an increase in its specific messenger RNA. A closer study of the collagen increase demonstrated a relatively greater increase in type V collagen than type I or type III collagen. Fibronectin synthesis was also increased 1.5-fold with 10 mumol/l angiotensin II. These data suggest that angiotensin II induces vascular wall thickening by acting directly on smooth muscle cells and enhancing the production of extracellular matrix proteins.
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PMID:Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. 184 53

The hypotensive effects of N-[8-amino-1(S)-carboxyoctyl] -L-alanyl-L-proline (AB-47, CAS 120008-53-9) were examined in normotensive rats and various hypertensive rat models. The hemodynamic effect of AB-47 was also examined in anesthetized spontaneously hypertensive rats (SHR). In 2-kidney, 1-clip renal hypertensive rats (2K, 1C-RHR) and SHR, the single administration of AB-47 (10 mg/kg, p.o.) induced potent and long-lasting hypotensive effects. The repeated administration of AB-47 (1 to 10 mg/kg, p.o.) to SHR for 29 days produced a dose-dependently and sustained hypotensive effect of 20 to 70 mmHg. AB-47 (10 mg/kg, p.o.) had a weak hypotensive effect in DOCA-salt hypertensive rats but no effects in normotensive and 1-kidney, 1-clip renal hypertensive rats (1K, 1C-RHR). AB-47 (3 mg/kg, p.o.) reduced blood pressure in intact SHR but not in bilateral nephrectomized SHR. The single intravenous injection of AB-47 (10 to 100 micrograms/kg) dose-dependently lowered systemic blood pressure, left ventricular systolic pressure (LVSP) and dp/dtmax without affecting heart rate (HR) and these effects of AB-47 were more potent than those of captopril and enalaprilat. These results suggest that AB-47 is a potent and long-lasting hypotensive agent and may be useful for the therapy of both hypertension and congestive heart failure.
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PMID:Hypotensive and hemodynamic effects of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline. 209 26

Streptozotocin (STZ)-induced diabetes depresses the rate of vascular collagen synthesis in the spontaneously hypertensive rat (SHR), but it also reduces arterial pressure (SAP) in this strain. We investigated this phenomenon further by comparing the SHR with the renovascular hypertensive (RVH) rat, because diabetes does not affect SAP in the latter model of hypertension. Renovascular hypertension was induced by clipping the left renal artery of Wistar-Kyoto (WKY) rats; sham-operated WKY were included as normotensive controls. Collagen synthesis of arterial tissue in vitro was quantified as prolyl hydroxylase activity and the rate of radioactive proline incorporation into collagen. Arterial collagen synthesis of nondiabetic SHR and RVH animals was elevated compared to that of the nonhypertensive WKY controls. STZ-induced diabetes (8 weeks) reduced SAP of SHR, but had no effect on SAP of either RVH or normotensive WKY rats. However, diabetes significantly depressed vascular collagen synthesis of both SHR and RVH rats, and, less consistently, of the WKY. The results strongly suggest that STZ-induced diabetes in SHR impairs arterial collagen synthesis independent of associated changes in arterial pressure.
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PMID:STZ-induced diabetes in SHR and renovascular hypertensive rats: dissociation between changes in arterial pressure and vascular collagen synthesis. 224 11

We evaluated the processes controlling the accumulation of collagen and elastin in main pulmonary arteries of rats during an episode of hypoxic pulmonary hypertension. Explant cultures of main pulmonary arteries were incubated with [3H]proline to measure collagen and protein synthesis and percent collagen synthesis. Elastin synthesis was measured by [14C]valine incorporation into insoluble elastin. Relative collagen synthesis increased twofold (from 1.1 +/- 0.2 x 10(3) to 2.0 +/- 1.0 x 10(3) disintegrations per minute [14C]hydroxyproline/vessel/hr/mg protein), relative collagen synthesis doubled (from 2% to 4-5% of total protein synthesis), and elastin synthesis increased ninefold (from 0.4 +/- 0.2 x 10(4) to 3.6 +/- 0.6 x 10(4) dpm [14C]valine/vessel/hr/mg protein) in early hypertension. The level of pro alpha l(I) collagen RNA paralleled the relative collagen synthetic rate during the study period. Within 7 days of recovery from hypoxia, collagen and elastin contents were normal. We conclude that collagen and elastin in main pulmonary arteries are synthesized rapidly during an episode of hypoxic pulmonary hypertension and that collagen and elastin are rapidly removed from the hypertensive vessel during normoxic recovery.
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PMID:Collagen and elastin metabolism in hypertensive pulmonary arteries of rats. 231 97

We have shown that administration of the antifibrotic agent cis-4-hydroxy-L-proline (cHyp) to rats at the onset of exposure to hypoxia prevents collagen accumulation in pulmonary arteries and the rise in pulmonary blood pressure. In this experiment, we tested whether cHyp is effective when administered after hypertension was already established. Rats were exposed to hypoxia (10% O2) for 21 days. Groups were hypoxic animals treated with cHyp (200 mg/kg sc twice daily) on days 10-21 (hypoxic cHyp) and saline-injected hypoxic animals (hypoxic). On day 21, we measured mean right ventricular pressure, hematocrit, collagen content of main and intrapulmonary arteries, and wall thickness of arterioles. Treatment reduced right ventricular pressure from 21 +/- 1 to 17 +/- 1 mmHg (P less than 0.05), hematocrit from 66 +/- 1 to 56 +/- 1% (P less than 0.05), hydroxyproline content of intrapulmonary arteries from 30 +/- 3 to 11 +/- 2 micrograms/vessel (P less than 0.05), and wall thickness from 27 +/- 3 to 16 +/- 2 microns (P less than 0.05). These results show that vascular collagen content is increased in established pulmonary hypertension and that cHyp treatment is effective in partially preventing the hemodynamic, structural, and biochemical changes if started after pulmonary hypertension is established. cHyp may also affect the rheological properties of blood.
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PMID:An antifibrotic agent reduces blood pressure in established pulmonary hypertension in the rat. 234 93

The molecular structures of two potent inhibitors of angiotensin converting enzyme (ACE, EC 3.4.15.1, dipeptidyl carboxypeptidase), ketoace, (5S)-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline, and (1S,2R)-1-[[2-(benzoylthio)-cyclopentyl]carbonyl]-L-proline were determined by X-ray diffraction methods. The distances between the binding functions in both crystal structures are in agreement with the experimental results for the hypertension drug captopril and the enzyme substrate hippuryl-L-histidyl-L-leucine. The modified peptide skeletons of both inhibitors adopt extended conformations with the proline amide bond trans. Crystallographic data have been used to determine the coordination geometry for zinc-sulfhydryl and zinc-carbonyl interactions. Coordination distances and bond angles are found to be different from values assumed in models of the angiotensin converting enzyme active site. No preferred torsion angles for a zinc-sulfhydryl inhibitor interaction can be identified. Superposition of the crystallographic structures of four ACE ligands shows that the observed extended conformations place the pharmacophores, zinc atom ligand, carbonyl oxygen atom, and carboxyl group, in juxtaposition and provide an alternative model for the interaction of ligands with the ACE active site.
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PMID:Crystallographic studies of angiotensin converting enzyme inhibitors and analysis of preferred zinc coordination geometry. 236 74

Hypertension in various experimental models, including spontaneously hypertensive rats (SHR), is associated with elevated rates of vascular collagen synthesis. The sympathetic nervous system is an important factor in the etiology of hypertension in SHR. The primary purpose of this study was to determine the effects of the alpha 1-adrenergic receptor antagonist doxazosin on aortic collagen synthesis and on systolic arterial pressure in SHR. Doxazosin was administered either short-term (20 or 200 mg/kg/day by gavage over 5 days) or long-term (0.02 or 0.20 g/L in the drinking water over 8 weeks). Rates of collagen synthesis were determined by incubating aortic segments with 14C-proline in vitro and then measuring either the formation of 14C-hydroxyproline by means of high-performance liquid chromatography, or the amount of radioactivity liberated by collagenase digestion. Systolic arterial pressure was monitored with the standard tail-cuff technique. Both doses of doxazosin depressed aortic collagen synthesis at 8 weeks of treatment, but neither dose had any effect at 4 weeks. In the short-term study only the higher acute dose of doxazosin significantly reduced aortic collagen synthesis; the lower dose had no effect. In the short-term study doxazosin reduced systolic arterial pressure, with a maximum effect at 1-2 days. Tolerance to the depressor effect developed over the remaining 3-4 days, especially with the higher dose. In the 8-week study, the lower doxazosin dose had no effect on systolic arterial pressure, and the higher dose exerted a biphasic effect, moderately but significantly reducing systolic arterial pressure at 1 and 8 weeks of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of doxazosin on vascular collagen synthesis, arterial pressure and serum lipids in the spontaneously hypertensive rat. 244 37

The novel compound BW A575C, N-(1-(S)-carboxy-5-[4-(3-isopropylamino-2-(R,S)-hydroxypropoxy)-indole-2 - carboxamido]pentyl)-(R,S)-alanyl-(S)-proline, is a potent angiotensin converting enzyme (ACE) inhibitor and beta-blocker in vitro. It was therefore of considerable interest to establish whether this novel pharmacological profile was maintained in vivo. In conscious instrumented normotensive rats and dogs, intravenous and oral administration of BW A575C causes a dose-dependent rightward displacement of the pressor dose-response curve to angiotensin I (dose ratio of 29.5 and 16.1 in rats and dogs, respectively, at 1.0 mg/kg i.v.) and the tachycardia dose-response curve to isoprenaline (dose ratio of 3.1 and 8.0 in rats and dogs, respectively, at 1.0 mg/kg i.v.). In these experiments BW A575C is approximately 2-10 times more active as an ACE inhibitor than as a beta-blocker. In conscious instrumented acute renovascular hypertensive dogs, where plasma renin activity is elevated 10-fold, BW A575C (1.0 mg/kg i.v.) causes a reduction in blood pressure of 35% within 10 min of injection, which is sustained for up to 4 h. This reduction in blood pressure is accompanied by a consistent, but nonsignificant, reduction in heart rate. These results confirm the novel pharmacological profile of BW A575C in vivo and demonstrate that this compound is an effective antihypertensive agent in a renin-dependent model of hypertension.
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PMID:BW A575C: pharmacological profile in vivo of a novel angiotensin converting enzyme inhibitor and beta-blocker. 245 71

To assess metabolic functions of the pulmonary circulation during lung injury and subsequent recovery from injury, we measured angiotensin-converting enzyme (ACE) activity by means of benzoyl-phenylalanyl-alanyl-proline (BPAP) hydrolysis and 5-hydroxytryptamine (5-HT) removal in vivo in three groups of anesthetized rabbits. One group was treated with 30 micrograms/kg/day phorbol myristate acetate (PMA) intravenously 10 times over 14 days (PMA group). A second group received the same PMA treatment but was not studied until 14 days after the last treatment (PMA/recovery group). A third group was treated with vehicle alone. At the end of PMA treatment, rabbits had an elevated pulmonary artery pressure and depressed ACE activity, expressed as the ratio Vmax/Km. Decreased Vmax/Km for ACE was due to a significant reduction in apparent Vmax for BPAP (control = 235 +/- 37, PMA = 139 +/- 12 nmol/s). Km was unchanged (control = 25 +/- 4, PMA = 31 +/- 7 microM). Uptake of 5-HT was unaffected by PMA treatment. After 2 wk of recovery (PMA/recovery group), pulmonary hypertension had resolved. In this group, Vmax for BPAP hydrolysis was not significantly different from control (280 +/- 18 nmol/s), but Km was significantly increased (48 +/- 5 microM). We conclude that repeated exposure of rabbits to PMA results in lung injury manifested as depressed pulmonary ACE activity and pulmonary artery hypertension. Although much of these alterations were reversible within 2 wk after discontinuing PMA, an increase in apparent Km of ACE may be a more persistent alteration in vascular endothelial cell dysfunction.
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PMID:Resolution of impaired pulmonary function and pulmonary hypertension after phorbol ester administration in rabbits. 255 Dec 5

Rats had been given intraventricular injection of 6-hydroxydopamine (6-OHDA) before clipping the unilateral renal artery (2K-1C) that caused selective ablation of the central noradrenergic neurons. Central catecholamines and the in vivo incorporation of 3H-proline into vascular non-collagen protein were determined in 2K-1C rats in the acute hypertensive stage. It is suggested that increased non-collagen protein synthesis in the mesenteric artery and the low level of hypothalamic norepinephrine concentration may participate in the development of 2K-1C hypertension in rats.
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PMID:Central noradrenergic neurons and vascular non-collagen protein in the initial phase of two-kidney, one-clip renovascular hypertension. 290 47


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