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)

Renal hemodynamics in heart failure and the effects of angiotensin converting enzyme (ACE) inhibition on renal function are reviewed. The incidence of renal dysfunction in patients with congestive heart failure is relatively high; however, the incidence of progression of renal dysfunction during treatment with ACE inhibitors is low. The mild reduction in renal function initially observed represents the physiologic expression of blocking both the systemic and the intrarenal compensatory activities of the renin-angiotensin system. Despite small changes in blood urea nitrogen and serum creatinine noted following initiation of enalapril therapy in the two studies described, there was no further clinically significant increase in blood urea nitrogen and serum creatinine noted during continued treatment in the majority of patients, irrespective of baseline renal function. The use of enalapril as adjunctive therapy with digitalis and diuretics in patients with congestive heart failure, with appropriate adjustment of the dosages of these agents, may benefit many patients.
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PMID:Effect of angiotensin converting enzyme inhibition on renal function in the treatment of heart failure. 267 17

The conformation of the synthetic renin inhibitor CP-69,799, bound to the active site of the fungal aspartic proteinase endothiapepsin (EC 3.4.23.6), has been determined by X-ray diffraction at 1.8 A resolution and refined to the crystallographic R factor of 16%. CP-69,799 is an oligopeptide transition--state analogue inhibitor that contains a new dipeptide isostere at the P1-P1' position. This dipeptide isostere is a nitrogen analogue of the well-explored hydroxyethylene dipeptide isostere, wherein the tetrahedral P1' C alpha atom has been replaced by trigonal nitrogen. The inhibitor binds in the extended conformation, filling S4 to S3' pockets, with hydroxyl group of the P1 residue positioned symmetrically between the two catalytic aspartates of the enzyme. Interactions between the inhibitor and the enzyme include 12 hydrogen bonds and extensive van der Waals contacts in all the pockets, except for S3'. The crystal structure reveals a bifurcated orientation of the P2 histidine side chain and an interesting relative rotation of the P3 phenyl ring to accommodate the cyclohexyl side chain at P1. The binding of the inhibitor to the enzyme, while producing no large distortions in the enzyme active site cleft, results in small but significant change in the relative orientation of the two endothiapepsin domains. This structural change may represent the action effected by the proteinase as it distorts its substrate towards the transition state for proteolytic cleavage.
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PMID:High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme. 267 15

Changes in blood, serum, and urine parameters that are usually associated with fluid and electrolyte balance were studied in 45 volunteers who ran the 1987 Pittsburgh Marathon. There were 39 males and 6 females. The mean age was 39.3 years. Their mean fluid intake was 1650 cc and the mean finishing time was 4 hours and 1 minute. The race was run in the rain with a temperature of 46 degrees F. When the prerace and postrace values of the runners were compared, significant increases were noted in the serum sodium, potassium, blood urea nitrogen (BUN), creatinine, uric acid, creatine phosphokinase (CPK), protein, plasma renin, vasopressin, and urinary potassium. Significant decreases were found in weight, blood pressure, and urinary sodium. No significant differences were noted in serum chloride, serum glucose, and hemoglobin/hematocrit. The mean weight loss of 1.9 kg was less than weight losses reported in marathons run under warmer conditions.
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PMID:Fluid and electrolyte balance during a cool weather marathon. 269 76

The aims of this study were to investigate the potential effects of captopril (CPT)-induced chronic hyperreninemia on atherogenesis, and to describe and quantitate the morphological changes which occur in the juxtaglomerular (JG) apparatus of drug-treated rabbits. Four groups of normotensive New Zealand rabbits were used. Drug control groups were fed regular rabbit chow (Group I), or regular chow supplemented with cholesterol (Group III). Group II animals were fed regular chow and treated with captopril, and Group IV animals were fed the cholesterol-diet and treated with captopril. Daily captopril administration for a period of six months resulted in significantly (p less than 0.001) increased levels of plasma renin activity and blood urea nitrogen. Mean systemic arterial pressure, plasma aldosterone levels, and hematocrits were significantly reduced in the CPT-treated animals as compared to untreated control groups. No effect on atherogenesis was found. Morphometric analysis showed no difference in the size of the glomeruli between the untreated and the CPT-treated, normal-diet groups, however, significant (p less than 0.001) hypertrophy and hyperplasia of the JG complex were observed in all CPT-treated animals. It is concluded that captopril-induced reductions in systemic arterial blood pressure and perfusion pressure, in concert with a blocked renin-angiotensin system which interferes with the normal autoregulation of renal blood flow and glomerular filtration, leads to significant morphologic and functional alterations in the kidney of normotensive animals.
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PMID:Captopril-induced hyperreninemia in cholesterol-fed rabbits. 298 51

Acute and 1-month toxicity studies with SCH 31846, a nonsulfhydryl anti-hypertensive agent which acts by inhibiting angiotensin-converting enzyme, were initiated to evaluate its toxicity. The oral LD50s in mice and rats were approximately 1.8 and 2.5 g/kg, respectively, while the iv LD50 was approximately 450 mg/kg in mice and 150 mg/kg in rats. Signs of acute toxicity in rats and mice included salivation, hypoactivity, ataxia, prostration, and convulsions. In a 1-month dog study at oral doses of 25, 75, or 150 mg/kg, there was a dose-related increase in emesis between 1 and 2 hr after dosing. Absorption studies showed peak blood concentrations occurring in dogs between 0.3 and 1 hr after dosing. No other noteworthy antemortem changes were observed. In a 1-month rat study at oral doses of 30, 180, or 600 mg/kg, the hematocrit and hemoglobin values of the 600 mg/kg-dosed female rats were slightly but significantly (p less than 0.05) decreased and the blood urea nitrogen was slightly but significantly (p less than 0.05) increased in all SCH 31846-dosed male rats and the 600 mg/kg-dosed female rats. Absorption studies in male rats at doses of 30, 180, and 600 mg/kg indicate that SCH 31846 is well absorbed in rats. The 150 mg/kg-dosed dogs and the 180- and 600 mg/kg-dosed rats had a slight increase in the number of renin-containing granules in the renal juxtaglomerular cells. No other compound-related microscopic changes were observed. These data are similar to data reported for Captopril and suggest that in the dog and rat the toxicity of ACE inhibitors is not dependent upon the presence or absence of a sulfhydryl group.
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PMID:Acute and subchronic toxicity of a nonsulfhydryl angiotensin-converting enzyme inhibitor. 300 64

The present study was made to clarify the mechanisms of the antinephritic action of SA-446, an angiotensin I converting enzyme inhibitor, on crescentic-type anti-GBM nephritis in rats as compared to the actions of spironolactone (an antialdosterone agent), kallidinogenase (a kallikrein agent) and saralasin (an angiotensin II antagonist). SA-446 (25 mg/kg/day, p.o.) had a tendency to reduce the urinary protein excretion and plasma urea nitrogen content. In addition, this drug remarkably inhibited not only glomerular histopathological changes (i.e., crescent formation, the adhesion of capillary walls to Bowman's capsule and fibrinoid necrosis) but also the elevation of blood pressure. Spironolactone (25 mg/kg/day, p.o.) and kallidinogenase (25 KU/day, i.m.) also showed beneficial effects on glomerular histopathological changes and hypertension, although both drugs were not as effective as SA-446. However, saralasin (72 micrograms/day, s.c.) caused a marked aggravating action on this nephritis. This nephritic model showed a marked low activity of plasma renin all through the 40 day experimental period. In this model, the urinary aldosterone excretion was increased, in spite of the decrease in plasma renin activity. SA-446 and kallidinogenase significantly inhibited the decrease in plasma renin activity and the increase in urinary aldosterone excretion. Spironolactone inhibited only the increase in the aldosterone excretion. However, saralasin decreased the plasma renin activity under the control level and strongly increased the urinary aldosterone excretion (about 1.8 times the control level on the 20th day). These results suggest that the antinephritic effect of SA-446 may be related to the antihypertensive action and the increase in renal blood flow through activation of the kallikrein-kinin and prostaglandins systems.
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PMID:Studies on mechanisms of antinephritic action of SA-446 an angiotensin I converting enzyme inhibitor (1). A comparison with actions of spironolactone, kallidinogenase and saralasin. 302 37

The response to angiotensin-converting enzyme inhibitors (ACEIs) can be of considerable help in the diagnosis of human renovascular hypertension (RVH) in three settings. First, a particularly dramatic antihypertensive response or a decline in glomerular filtration rate (GFR), as indexed by a rise in serum creatinine or blood urea nitrogen concentrations, are useful clues to the presence of renovascular hypertension. Second, an exaggerated rise in plasma renin activity (PRA) after short-term captopril administration is a very promising screening test for this condition. Third, ACEI-induced changes in single-kidney hemodynamics (assessed by renography) may be helpful in confirming the diagnosis and offers the prospect of localizing the ischemic kidney.
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PMID:Diagnostic uses of angiotensin-converting enzyme inhibitors in renovascular hypertension. 305 43

Both the antihypertensive efficacy and side effects of nifedipine were investigated in hypertensive patients with impaired renal function (n = 44) in short-term (7 days) and long-term (6 months) therapeutic trials. Comparable hypotensive effects were obtained in both the short- and long-term studies (from 184 +/- 4.6/108 +/- 2.8 to 166 +/- 4.6/97 +/- 3.2 mmHg, and from 178 +/- 4.2/108 +/- 2.1 to 157 +/- 4.4/95 +/- 2.4 mmHg, respectively). In the short-term study (n = 20), the antihypertensive effect was significantly related to the pretreatment blood pressure (r = 0.51) and inversely related to the plasma renin activity (PRA) (r = -0.61; p less than 0.05). However, it was not related to age or reciprocal value of the pretreatment serum creatinine. In the long-term study (n = 24), blood-pressure-lowering effects of nifedipine were found to depend on the reciprocal value of the serum creatinine but not on PRA. The blood urea nitrogen and creatinine were not changed significantly during the observation period. Side effects occurred in 8 of the 44 patients, but severe side effects necessitating termination of administration were observed in only 2 patients. These results indicate that nifedipine is effective in both the short- and long-term treatment of hypertensives patients with impaired renal function. Impaired renal function is a key factor in the hypotensive effects of nifedipine in long-term therapy.
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PMID:Short- and long-term efficacy of nifedipine in hypertensive patients with impaired renal function, with special reference to influencing factors. 313 14

Hypernatremia has occasionally been observed in patients with myotonic muscular dystrophy (MyD). To elucidate the possibility of osmoregulatory dysfunction, we investigated hypothalamo-posterior pituitary function as well as serum electrolytes in eight patients with MyD. Blood samples were obtained early in the morning after overnight dehydration. Renal function was estimated by blood urea nitrogen, serum creatinine and creatinine clearance. Posterior pituitary function was evaluated by direct measurement of plasma vasopressin (AVP) during a 5% hypertonic saline infusion. Plasma AVP concentrations were determined by sensitive radioimmunoassay. In five patients, circulating blood volume (CBV), plasma renin activity (PRA) and serum aldosterone (S-Aldo.) were also measured. The mean serum sodium level (143.9 +/- 1.7mEq/1: Mean +/- SD) was significantly higher than in the controls (139.4 +/- 2.2mEq/1). A 5% hypertonic saline infusion showed a subnormal increase in AVP and diminished thirst, despite sufficient elevation of plasma osmolality, in all patients as compared with healthy adults. Renal function was intact. Biochemical evidence of dehydration, estimated by PRA, S-Aldo and CBV, was unremarkable in four of the five patients. These findings suggest that patients with MyD have neurogenic disorders of osmoregulation in addition to previously reported endocrine abnormalities. Impaired AVP secretion in response to osmotic stimuli and reduced thirst might be responsible for such failure.
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PMID:[Impaired vasopressin secretion in patients with myotonic dystrophy]. 328 99

Stereoselective syntheses of several nonpeptide fragments that function as Leu10-Val11 scissile bond replacements in human angiotensinogen are presented. The opening of N-protected aminoalkyl epoxide 3 with a variety of sulfur, oxygen, nitrogen, and carbon nucleophiles is a key reaction in the preparation of these novel fragments 4-8. The coupling of these fragments to protected dipeptides that mimic positions 8 and 9 in angiotensinogen produces inhibitors of human renin even though the molecules contain no functionality beyond what is formally the Val11 side chain of angiotensinogen. R groups that closely resemble that of the Val side chain are preferable; thus, isopropyl greater than or equal to higher alkyl greater than phenyl greater than substituted phenyl. Sulfur is the best X group; oxidation leads to slight (X = SO2) and significant (X = SO) decreases in inhibitory potency. One such inhibitor, 60, has an IC50 of 13 nM when tested with purified human renin at pH 6.0. The significant activity of these small inhibitors is thought to be due in part to the hydroxyl group of the fragment functioning as a transition-state analogue. Of these, the inhibitors that contain histidine show marked selectivity toward renin over a related aspartic proteinase, pepsin.
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PMID:New inhibitors of human renin that contain novel Leu-Val replacements. 330 46


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