Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development and evolution of hypertensive vascular lesions affecting the arterial supply of (a) the kidney and (b) organs other than the kidney were studied in rats developing either malignant (MHY) or benign (BHY) hypertension 3, 6, 9 and 12 days after aortic ligation between the renal arteries. Vascular disease evolved into two distinct patterns which suggested acute renal damage to be the determinant for the development of either the malignant or benign form of hypertension. Three days after aortic ligation MHY and BHY animals showed widespread fibrinoid deposition in vascular territories above the aortic ligature. However, in MHYs these lesions were much more severe and, in the kidney, they were accompanied by the development of focal parenchymal atrophy, microinfarcts and hyalin droplet degeneration of cells of the Bowman capsule. The degree of renal damage correlated with elevations in blood urea nitrogen (BUN) and plasma creatinine; however, there was no correlation with rises in blood pressure, plasma renin activity (PRA), aldosterone or corticosterone which were similarly elevated in 3-day MHY and 3-day BHY animals. Between 6 and 12 days a marked clearance of fibrinoid took place in all organ beds of BHYs, but in the non-renal vasculature of MHY animals fibrinoid remained prominent and served as the central core for necrotising arterial lesions. In the kidney of MHYs some reduction in the fibrinoid content was observed, but the parenchymal damage perpetuating from the earlier stages had exacerbated leading to collagen deposition and a marked increase in the collagen concentration of the renal cortex. These features were accompanied by further elevations in PRA and corticosteroids and a progressive deterioration of renal function. By contrast, in 12-day BHY animals, despite sustained hypertension, PRA and corticosteroids were falling from their previously higher levels and normal renal function was maintained. These studies warrant inference that extensive parenchymal damage of the kidney due in part to severe arterial fibrinoid deposition is one of the initial events in the development of malignant hypertension.
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PMID:Acute arterial fibrinoid deposition and ischaemic parenchymal damage of the kidney. Pathogenic factors in the development of malignant hypertension. 636 44

The short chemical half-life limits the potential therapeutic value of Prostacyclin (PGI2). Replacement of the acid-labile enolether structure of PGI2 by a beta-thia-imino group resulted in the orally active and chemically stable analogue Hoe 892. Incubation of rabbit platelet rich plasma with PGI2 and Hoe 892 caused a dose dependent inhibition of collagen and arachidonic acid (AA) induced platelet aggregation with ID50 of 4.2 and 20.1 ng/ml for PGI2 respectively 43.3 and 170.2 ng/ml for Hoe 892. These effects could be potentiated by the phosphodiesterase inhibitor theophylline. Single oral administration of Hoe 892 in conscious rabbits inhibited platelet aggregation for more than 3 hrs with an ID50 of 0.2 mg/kg using collagen and 1.5 mg/kg using AA. These doses were without influence on systemic blood pressure (BP) in conscious rabbits. Intravenous injection of Hoe 892 induced a dose dependent decrease of systemic BP in anesthetized rats (ED25 of 2.2 micrograms/kg) and in the rats with acute renal hypertension. Hoe 892 stimulated renin release in anesthetized rats. The hemodynamic profile in anesthetized dogs (0.5 micrograms/kg/min i.v.) was characterized by a decrease of systemic BP, left ventricular pressure, pulmonary artery pressure, total peripheral resistance and in increase in heart rate, cardiac output and dp/dt max, thus demonstrating arteriolar vasodilation. In conscious dogs with two kidney, two wrapped hypertension oral treatment for 1 or 5 days resulted in a marked reduction of BP.
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PMID:The orally active thia-imino-prostacyclin Hoe 892: antiaggregatory and cardiovascular activities. 640 94

The potent converting enzyme inhibitor (CEI) SQ14,225, which is known to prevent the formation of angiotensin II (AII) has been used to evaluate the role of AII in the development and reversal of cardiac hypertrophy. The present study describes the effect of CEI on blood pressure (BP) and myocardial hypertrophy (prevention and reversal) in the spontaneously hypertensive rat (SHR). A group of 3-week- and 8-week-old male SHR was treated with CEI (30 mg/kg in drinking water) for 6 weeks. An additional group of SHR was also treated with a combination of CEI and a diuretic (hydrochlorothiazide, 500 mg/liter). Heart weight, BP, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), hydroxyproline, myocardial catecholamines, and plasma renin activity (PRA) were determined. In the prevention study, we found a significant reduction in the ratio of heart weight to body weight along with the prevention of hypertension (200 vs 145 mm Hg, p less than 0.001). Similar reductions in BP and heart weights were obtained with the reversal group. A better BP control was noted in the CEI and hydrochlorothiazide group. The reduction of heart weight was associated with a reduction in RNA and hydroxyproline content. In all groups, we found a significant increase in PRA (p less than 0.001) and a slight increase in tissue catecholamine concentration. No change in kidney weight was found in any group. Data clearly showed that oral administration of CEI prevented and reversed cardiac hypertrophy in SHR. Reversal was associated with a decrease in myocardial collagen content. These data indicate that prevention of AII formation in combination with BP control can prevent and reverse cardiac hypertrophy in SHR. Of course, whether or not CEI acts only through the renin angiotension system is still speculative.
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PMID:Effect of converting enzyme inhibitor (SQ14,225) on myocardial hypertrophy in spontaneously hypertensive rats. 644 75

Captopril 12.5 to 50 mg as a single dose was given to six patients with pulmonary hypertension secondary to collagen vascular disease. Total pulmonary resistance was decreased in four patients from 19% to 39%, but mean pulmonary artery pressure (63 +/- 15 mm Hg) was not decreased, probably because of the concurrent increase in cardiac output from 21% to 52% (2p less than 0.05). The systemic arterial pressure was slightly decreased due to the decrease in total systemic resistance. Control plasma renin activity ranged from 0.15 to 16 ng/ml/hr and was increased during captopril from 19% to 356%. These results, although preliminary, suggest that captopril may be beneficial in certain patients with pulmonary hypertension secondary to collagen vascular disease.
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PMID:Hemodynamic effects of captopril in pulmonary hypertension of collagen vascular disease. 675 Oct 58

Epidemiologic and experimental data suggest an antiatherothrombotic potential of omega-3 polyunsaturated fatty acids. Therefore, the Western diet, which supplies predominantly omega-6 polyunsaturated fatty acids, was supplemented with 40 ml/day of cod liver oil, which provides about 10 g of omega-3 polyunsaturated fatty acids daily, for 25 days in eight volunteers. The omega-3 polyunsaturated fatty acids were incorporated in platelet and erythrocyte membrane phospholipids at the expense of omega-6 polyunsaturated fatty acids. Bleeding time increased (p less than 0.01) and platelet count (p less than 0.05), platelet aggregation upon ADP and collagen (p less than 0.01-0.05), and associated thromboxane B2 formation (p less than 0.01) decreased. Blood pressure (p less than 0.05) and blood pressure response to norepinephrine (p less than 0.01) and angiotensin II (NS) fell, without major changes in plasma catecholamines, renin, urinary aldosterone, kallikrein, prostaglandins E2 and F2 alpha and red cell cation fluxes. Biochemical and functional changes were reversed 4 weeks after cod liver oil was discontinued. Formation of prostaglandins derived from eicosapentaenoic acid and interference of eicosapentaenoic acid with formation and action of prostaglandins derived from arachidonic acid were evident in vitro. Whatever the mechanism, this moderate supplement of omega-3 polyunsaturated fatty acids markedly changed membrane phospholipids, which was associated with a shift toward less reactive platelets and a blunted circulatory response to pressure hormones.
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PMID:Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil. 682 92

Chronic hypertension was induced in rats by application of a clip for 17 or 20 weeks to the unilateral renal artery and leaving the contrarenal vessel intact (two-kidney one clip hypertension, 2K-1C hypertension). Some of the rats received antihypertensive treatment with phenoxybenzamine (POB). 3H-proline was injected into all rats in the 17th experimental week to observe the in vivo incorporation rates of 3H-proline into vascular non-collagenous protein and vascular collagen. Plasma renin activity (PRA) of decapitated rats was assayed in the terminal stage of the experiment. Significant differences were noted between 2K-1C hypertensive rats and sham-operated normotensive rats, the former rats having significantly higher incorporation rates of 3H-proline into non-collagenous protein (p less than 0.001) and collagen of testicular (p less than 0.05) or mesenteric artery (p less than 0.01). The 3H-proline incorporated into each fraction of vascular protein was reduced by antihypertensive treatment with POB either in sham-operated rats (p less than 0.05) or 2K-1C rats (p less than 0.001), except for the aorta and heart. Positive correlations were noted between blood pressure and incorporated 3H-proline into non-collagenous protein of testicular arteries (r = 0.78, p less than 0.001) and mesenteric arteries (r = 0.90, p less than 0.001), in all animals. Similar positive correlations were also noted between blood pressure and tritiated collagen, to lesser extents, in testicular arteries (r = 0.67, p less than 0.001) and mesenteric arteries (r = 0.73, P less than 0.001). A rapid turnover of 3H-proline incorporated into non-collagenous protein was characteristically observed in the testicular arteries, mesenteric arteries and aorta of 2K-1C hypertensive rats 3 weeks after the proline injection. Though magnitude was low, the turnover of 3H-proline was also noted in each collagen fraction of the equivalent vessels of the same hypertensive rats. PRA of 2K-1C hypertensive rats was similar to that of sham-operated normotensive rats at the 20th week. Levels of PRA of the former or the latter rats treated with POB were 2.4-fold (p less than 0.001) or 2.5-fold (p less than 0.001) higher than those of non-medicated corresponding controls. These results indicate that (1) increased synthesis of vascular non-collagenous protein as well as collagen, especially of small arteries, plays a major role for the pathogenesis of chronic hypertension in 2K-1C rats, and (2) renin does not contribute to elevation of the blood pressure in the maintenance phase of this type of experimental hypertension.
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PMID:The role of vascular protein and renin in chronic two-kidney, one clip Goldblatt hypertension. 704 32

To study the possible role of catecholamines in platelet activation, platelet aggregation stimulated by ADP, collagen, arachidonic acid and L-epinephrine, thromboxane B2 (TXB2) formation and plasma levels of catecholamines and renin were studied in healthy men both before and after 6 days of propranolol treatment (40 mg three times daily) under control conditions and during sympathoadrenergic stimulation by physical exercise (200 W) or smoking. Exercise markedly increased plasma norepinephrine from 128 +/- 28 to 998 +/- 418 pg/ml (+/- SD), and plasma renin activity from 1.0 +/- 0.5 to 4.2 +/- 1.8 ng AI/ml . hour. Smoking predominantly increased plasma epinephrine, from 47 +/- 25 to 154 +/- 76 pg/ml. Propranolol did not consistently influence these variables, but blunted the circulatory response to exercise and smoking. Despite the marked increases of plasma catecholamines after both stimuli with and without beta blockade, platelet aggregation stimulated by ADP, 1-epinephrine, collagen and arachidonic acid and associated TXB2 formation were not enhanced. Moreover, as already suggested by a trend toward reduced aggregability in these settings, plasma norepinephrine levels in the same range (745 +/- 368 pg/ml) due to infusion (5 micrograms/min) significantly reduced platelet aggregation with low-dose collagen (0.25-0.75 micrograms/ml), I-epinephrine (0.2-1.0 microM) and ADP (0.5-1.5 microM). These data do not support a role of endogenous catecholamines in initiating platelet activation and TXB2 formation.
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PMID:Plasma catecholamines, platelet aggregation and associated thromboxane formation after physical exercise, smoking or norepinephrine infusion. 704 12

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. 748 84

From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. a) In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and NG-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis. 749 60

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. 749 21


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