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)

In the pentobarbital sodium-anesthetized rat, dehydration for 24 h increased ion and water absorption from the jejunum. Dehydration also elevated plasma concentrations of angiotensin peptides and plasma renin activity but did not significantly alter plasma aldosterone concentrations. Infusion of tyramine, norepinephrine, and angiotensin II (AII) also stimulated jejunal absorption in a manner similar to dehydration. The elevation of jejunal absorption in response to dehydration is totally inhibited by the converting enzyme inhibitor captopril and the angiotensin receptor antagonist [lle7]AIII. Thus, increased jejunal absorption following dehydration is mediated by the renin-angiotensin system and is not secondary to either aldosterone or to antidiuretic hormone release. Further experiments demonstrated that the increase in jejunal absorption in response to dehydration was unaffected by propranolol but was totally abolished by phentolamine, prazosin, and peripheral sympathectomy. It is proposed that AII stimulates jejunal absorption by enhancing transepithelial transport processes and/or by altering the balance of Starling forces governing fluid absorption across enteric capillaries. Angiotensin thus appears to be a physiologically important mediator of jejunal absorption in states characterized by extracellular volume depletion.
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PMID:Modulation of jejunal ion and water absorption by endogenous angiotensin after dehydration. 674 21

We studied the renal effects of the cyclooxygenase inhibitor sodium meclofenamate (M) (5 mg/kg, iv) in the pentobarbital-anesthetized dog that had been maintained on an elevated (100 meq/day) or on a reduced (< meq/day) sodium intake, and during the administration of antiotensin II in the sodium-replete dog, or the angiotensin receptor blocker [Sar1-Ala8]angiotensin II in the sodium-deprived dog. In the sodium-replete dog, M did not affect mean arterial blood pressure (MABP), renal blood flow (RBF), glomerular filtration rate, (GFR), or urine volume (V), but reduced the urinary excretion of sodium (UNaV) by 47%, and of immunoreactive PGE2 (iPGE2) by 90%. However, in the sodium-replete dog during angiotensin II infusion (3 ng . kg-1 . min-1, iv), M reduced RBF by 35%, GFR by 24%, V by 72%, and iPGE2 by 94%. Similarly, in the sodium-deprived dog M reduced RBF by 34%, GFR by 28%, and iPGE2 excretion by 89%. However, M did not affect RBF or GFR in the sodium-deprived dog during infusion of [Sar1-Ala8]angiotensin II (6 microgram . kg-1 . min-1, iv), although iPGE2 excretion was reduced by 84%. This study demonstrates that the effects of M on renal hemodynamics in the dog vary with the state of sodium balance and suggests that a prostaglandin(s) contributes to maintenance of renal blood flow during activation of the renin-angiotensin system.
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PMID:Differential renal effects of cyclooxygenase inhibition in sodium-replete and sodium-deprived dog. 699 17

The mechanism of the hypotensive response to captopril was investigated in pithed and urethane anesthetized rats. Cumulative intravenous doses of captopril produced dose-dependent hypotensive responses which were correlated with blockade of the pressor response to angiotensin I. Angiotensin II responses were unaffected. Infusions of saralasin, an angiotensin receptor antagonist, inhibited the hypotensive action of captopril, the degree of antagonism being correlated with inhibition of angiotensin II pressor responses. Bilateral nephrectomy lowered blood pressure to approximately the same level as captopril and completely abolished the hypotensive effect of captopril. No evidence was obtained for the involvement of endogenous bradykinin or prostaglandins in the hypotensive action of captopril. It is concluded that in pithed and urethane anesthetized rats, captopril mediates its hypotensive response by removing the renal renin-angiotensin system, most probably via inhibition of angiotensin I - converting enzyme. The results contrast with similar studies conducted in anesthetized dogs. In this species, the mechanism of action of captopril remains for further resolution.
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PMID:Studies on the mechanism of captopril induced hypotension in rats. 702 11

1 Indomethacin treatment of postural hypotension in four patients with chronic autonomic failure increased their pressor supersensitivity to intravenous noradrenaline without causing fluid retention. 2 All patients were supersensitive to angiotensin II in spite of normal levels of plasma renin activity in the supine position and therefore (by inference) of angiotensin II. This suggests that in autonomic failure, the degree of angiotensin receptor occupancy by endogenous angiotensin II is not important in determining pressor sensitivity to exogenous angiotensin II. Indomethacin increased the pressor supersensitivity to angiotensin II in all patients. 3 Indomethacin treatment decreased supine plasma renin activity to 50% of the level present before indomethacin treatment. 4 Indomethacin increased the lying but not the standing blood pressure. The failure to raise the standing pressure may be the result of the additional postural stress overcoming any vasoconstriction resulting from the increased sensitivity of vascular receptors to noradrenaline. The decrease in plasma renin activity could also contribute to the failure of indomethacin to prevent a fall in blood pressure on standing. 5 In our patients the excretion of the main urinary metabolite (PGFM) of prostaglandin F2 alpha was higher than recorded previously in normal controls. During treatment with indomethacin, plasma indomethacin levels were in the range at which inhibition of prostaglandin synthesis occurs and the excretion of PGFM was decreased. 6 Indomethacin was not effective in the treatment of postural hypotension in these patients with autonomic failure.
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PMID:The pressor actions of noradrenaline and angiotension II in chronic autonomic failure treated with indomethacin. 743 38

Activation of the renin-angiotensin system by sodium deficiency is associated with reciprocal changes in the expression of angiotensin II receptors in adrenal glomerulosa and vascular smooth muscle cells. The effects of dietary sodium changes on the expression of brain angiotensin receptor subtype 1 (AT1) mRNAs were examined in rats maintained on normal, low, and high sodium intake for 3 weeks. Plasma aldosterone and renin activity were elevated in rats maintained on a low salt diet compared with normal rats and were reduced in rats maintained on a high salt diet. These results are consistent with previous findings on the effects of altered dietary sodium on the renin-angiotensin system. The expression of AT1A and AT1B receptor subtype mRNAs was determined by quantitative reverse transcriptase-polymerase chain reaction during changes in sodium intake. The results revealed that sodium deprivation enhanced the expression of AT1B receptors in decorticated brains by 164% compared with high sodium intake. Conversely, high sodium diet increased the expression of AT1A receptors by 155% in the brain compared with low sodium intake. These data suggest that AT1A and AT1B receptors play reciprocal roles in central mechanisms for the control of fluid homeostasis. Further analysis of the molecular biology of angiotensin II receptor regulation in the brain may provide new insights into the interplay between the renin-angiotensin system and blood pressure regulation and also into the role of angiotensin II in the pathogenesis of essential hypertension.
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PMID:Regulation of angiotensin II receptors in rat brain during dietary sodium changes. 750 98

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.
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PMID:Role of angiotensin in pressure overload-induced hypertrophy in rats: effects of angiotensin-converting enzyme inhibitors, an AT1 receptor antagonist, and surgical reversal. 751 60

The renin angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. For this reason, attempts to specifically block this system have been a pharmacological goal for over 25 years. Blockade of the renin system has been attempted at 3 pivotal sites: the rate limiting angiotensinogen-renin step, conversion of angiotensin I to angiotensin II, and the active receptor sites for the terminal products of angiotensin II and aldosterone. Converting enzyme inhibitors have been successfully studied and utilised in clinical cardiovascular disorders, but questions persist regarding the specificity of their action. Thus, other more specific approaches remain under evaluation. Inhibition of the action of renin on angiotensinogen was demonstrated with early inhibitory peptides and in experimental studies with specific antibodies. Most currently available renin inhibitors are nonpeptides, which nonetheless require intravenous administration. An oral renin inhibitor with clinical effects has been evaluated in early human trials. Like renin inhibitors and converting enzyme inhibitors, specific angiotensin antagonists were studied early in the course of renin system pharmacological blockade. Early angiotensin antagonists were limited, due to the requirement for intravenous administration and because of their short half-lives. They also had the potential for mixed agonist/antagonist physiological and pharmacological effects, which could result in a pressor, rather than a depressor, response. The angiotensin receptor antagonists have the appeal of blocking the specific receptor at its target tissue site, analogous to other well described systems. Newer angiotensin antagonists do not have the limitations of the precursor peptides. Losartan (DUP753) is a specific angiotensin II AT1 receptor antagonist. It is orally effective without agonist activity, and has high receptor binding characteristics. Early studies indicate that it is a specific probe of the renin system, and is providing newer insights into the role of the renin system in cardiovascular disorders. Emerging clinical studies indicate that it is effective for blood pressure reduction and as a vasodilator. Aldosterone antagonists such as spironolactone have been available for decades. Spironolactone is being used in an ongoing trial to assess the impact of combined converting enzyme and aldosterone inhibition. Newer aldosterone antagonists could add to targeted blockade of aldosterone without the adverse effects of the precursor compound, and the potential for combined specific renin system blockade.
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PMID:The clinical potential of renin inhibitors and angiotensin antagonists. 751 58

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal. 2. The fetal RAS plays a role in maintenance of arterial pressure. The extent to which it does so depends on the level of activity of the system. 3. The distribution of renin within the fetal rat kidney is much more widespread than in the adult. The fetal kidney, like other vascular beds has high levels of the AT2 angiotensin receptor subtype. With maturation the proportion of the AT1 receptor subtype increases. 4. Blockade of the fetal RAS with angiotensin converting enzyme (ACE) inhibitors or with the non-peptide AII antagonist (losartan) caused a fall in fetal glomerular filtration rate (GFR) and a rise in renal blood flow (RBF). AII reverses the fall in GFR even though RBF decreases. 5. The fraction of the filtered sodium load reabsorbed by the proximal tubule was not affected when the fetal RAS was blocked by captopril or losartan. High doses of infused AII had no effect on renal reabsorption of sodium, in the short term, but in the long term depressed fractional proximal reabsorption. 6. Only in high doses does AII stimulate the secretion of aldosterone from the fetal adrenal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functions of the renin-angiotensin system during development. 758 4

The brain GABAergic system was previously shown to influence blood pressure (BP) maintenance in rats which may in part be accomplished by disruption of the central renin-angiotensin system (RAS). We examined the potential role of GABA in sustaining the high BP exhibited by the spontaneously hypertensive rat (SHR) model of human essential hypertension. Intracerebroventricular (i.c.v.) infusion of GABA produced decreases in BP in members of three rat strains, including Wistar-Kyoto (WKY) and Sprague-Dawley normotensive controls and SHR. The SHR were significantly more sensitive to GABA than the normotensive strains. Next, the GABA receptor antagonist bicuculline (BMI) was infused i.c.v. and produced increases in BP in members of each strain. Finally, i.c.v. pretreatment with the specific angiotensin receptor antagonist [Sar1, Thr8]AII (sarthran), blocked subsequent GABA-induced decreases in BP in members of all three strains, and there was a trend toward sarthran attenuation of BMI-induced increases in BP. These results encourage the hypothesis that the hypotensive effects produced by central application of GABA are mediated by the brain angiotensin system.
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PMID:GABA and bicuculline-induced blood pressure changes in spontaneously hypertensive rats. 767 72

Extrahepatic synthesis and localization of angiotensinogen have been described in animals, thus establishing the tissue renin-angiotensin system. We examined angiotensinogen messenger RNA synthesis by northern blotting. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies using a specific antibody to angiotensinogen revealed a stronger reaction in the endocardial layer of the human left ventricle, than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Furthermore, our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. We examined the participation of the collagen in the occurrence and progression of cardiomyopathy. The acetic acid solubility of collagen and reducible crosslink decreased in cardiomyopathic hamsters as the fibrosis progressed, but was unchanged in controls. These findings indicate that in the early phase of cardiomyopathy the extracellular matrix of the myocardium is similar to immature tissues. In the later phase, the matrix resembles that of hard tissues, and is insoluble. Furthermore, we examined the relationship between angiotensin II and collagen synthesis. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6-fold greater than that in Wistar-Kyoto rats. The responsiveness of collagen production to Ang II was significantly enhanced in SHR. This effect was angiotensin receptor-specific, because it was blocked by the competitive inhibitor. These results indicate angiotensin II may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.
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PMID:Renin-angiotensin system in failing heart. 776 Mar 44


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