Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orthostatic cardiovascular reflexes were evaluated in conscious cynomolgus monkeys during interruption of the renin-angiotensin system with the renin inhibitor: RIP (Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys-OH). RIP was synthesized via solid phase techniques and purified to homogeneity. In vitro studies indicated that it exhibited classical competitive inhibition of renin with a KI of 2.3 microM. In vivo, RIP at 2 mg/kg per min inhibited renin and angiotensin I pressor responses indicating that it was not a specific renin inhibitor at this dose. However, in spite of the nonspecificity, RIP did not affect the supine blood pressure of sodium-replete monkeys, but did evoke hypotension in supine sodium depleted monkeys. RIP did not elicit significant orthostatic hypotension in either sodium-replete or sodium depleted monkeys. The cardiovascular effects of RIP described in this study appear to be due to inhibition of the renin-angiotensin system.
 ...
PMID:Cardiovascular effects of a renin inhibitor in relation to posture in nonhuman primates. 298 82

Numerous studies have suggested that a functional relationship exists between the renal kallikrein-kinin and renin-angiotensin systems. We used an in vitro preparation of isolated glomeruli to study the effect of kinins on renin release. Glomeruli were harvested from the dissected cortices of rat kidneys by a passive sieving technique. They were then placed in chambers and superfused with aerated modified Krebs buffer, and the chamber effluent was collected during two sequential 10-min periods. Bradykinin at 10(-6) M increased renin release from 2.17 +/- 0.34 to 4.05 +/- 0.72 ng ANG I/min, and 10(-5) M bradykinin increased renin release from 3.51 +/- 0.64 to 8.94 +/- 1.27 ng ANG I/min. With albumin-modified buffer, 10(-5) M bradykinin stimulated renin release from 7.11 +/- 0.79 to 14.03 +/- 2.36 ng/min. Lys-bradykinin at 10(-5) M also increased renin release from 5.69 +/- 1.11 to 14.50 +/- 2.65 ng ANG I/min. However, neither of the inactive kinin analogues, [Tyr8]bradykinin or des-Arg9-bradykinin, had any effect on renin release. We found that isolated glomeruli were relatively free of kininase activity, in contrast to the high activity found in the kidney slice preparation or in rat plasma. These results suggest that biologically active kinins can stimulate renin release in an in vitro preparation that is free of degradative kininases and independent of hemodynamic and neural influences.
 ...
PMID:Kinin stimulation of renin release in isolated rat glomeruli. 298 45

The acute hemodynamic and hormonal effects of the oral angiotensin-converting enzyme (ACE) inhibitor lisinopril (MK-521) were assessed over a period of 96 hours in 12 patients with heart failure. This compound is the lysine analogue of enalaprilat (MK-422), is biologically active following absorption, and is cleared via the urine without any known metabolic transformation. Single doses of lisinopril, ranging from 1.25 mg to 10 mg, were administered on days 1 and 3, each followed by 48 hours of intensive hemodynamic observation. Across all doses, maximal reductions in mean arterial pressure (17.2%), mean pulmonary capillary wedge pressure (28%), and systemic vascular resistance (25.6%) were observed compared to baseline values. No significant changes in heart rate were recorded. Arterial blood was sampled at frequent intervals for angiotensin II, ACE activity, plasma renin activity, renin substrate, plasma aldosterone, and serum drug levels. Right atrial blood was sampled simultaneously for angiotensin I, thus permitting assessment of the degree of pulmonary conversion to angiotensin II. The results indicate potent inhibition of the renin-angiotensin-aldosterone system along with hemodynamic efficacy over a period exceeding 24 hours. Frequent clinical follow-up on long-term chronic therapy has revealed no adverse experience.
 ...
PMID:Acute hemodynamic and hormonal effects of lisinopril (MK-521) in congestive heart failure. 301 50

Lisinopril (MK521), a lysine analogue of enalaprilic acid, the bioactive metabolite of enalapril, has a longer half-life than enalaprilic acid, and is excreted unchanged in the urine. Its kinetic profile and antihypertensive and hormonal effects have been investigated in an open study in 3 groups each of 6 hypertensive patients, with normal, moderate and severe impairment of renal function. Serum drug level, blood pressure, converting enzyme activity (CEA), plasma renin activity (PRA), aldosterone concentration (PAC), and serum potassium and creatinine were measured during 1 week following a single oral dose and subsequently following 8 daily doses of 5 mg lisinopril. Accumulation of lisinopril was found in the severe renal failure group. CEA was suppressed to less than 10% of its initial value from 4 to 24 h after the initial dose in all three groups, and the suppression was more marked and lasted longer in patients with severe renal failure. An inverse correlation was found in all patients between log serum lisinopril concentration and log CEA. Lisinopril lowered blood pressure in all three groups over 24 h. PRA rose and PAC fell similarly in the groups. Serum potassium increased in the renal failure groups and creatinine remained unchanged in all groups. Thus, when lisinopril 5 mg is given daily to patients with severe renal failure it may accumulate. The high serum lisinopril concentration does not cause an excessive antihypertensive effect. In patients with severe renal failure, adjustment of the dose or the dosing frequency to the degree of renal failure is recommended to avoid administration of doses in excess of those required to achieve adequate inhibition of converting enzyme.
 ...
PMID:Lisinopril in hypertensive patients with and without renal failure. 303 22

Effects of the pentapeptide renin inhibitor (RI-78; Phe(4Cl)-Phe-Val-Tyr-Lys-NH2) and the angiotensin converting enzyme (ACE) inhibitor (teprotide) on mean arterial pressure (MAP) were examined in conscious monkeys (M. fascicularis). In salt depleted normotensive monkeys with a MAP of 95 +/- 4 mmHg and plasma renin activity (PRA) of 15.9 +/- 2.7 ngAI/ml/h, a bolus injection of a dose of 375 micrograms/kg of RI-78 caused a prompt hypotensive effect. Maximal hypotensive action was seen within 1 min, and MAP returned to the basal level within 15 min. With this dose, MAP was reduced by 20 +/- 6 mmHg. Teprotide (1 mg/kg) decreased MAP and reached a nadir after 13 min. There was no significant difference between maximal hypotensive responses seen with RI-78 (375 micrograms/kg) and with teprotide (1 mg/kg). Hypotensive effects of RI-78 and teprotide were also examined in acute renal hypertensive monkeys with a MAP of 125 +/- 5 mmHg and a PRA of 27.1 +/- 5.7 ngAI/ml/h. Again, similar hypotensive effects were observed. We conclude that antihypertensive effect of RI-78 is comparable to that seen with teprotide.
 ...
PMID:Hypotensive effects of the renin inhibitor (RI-78) and the converting enzyme inhibitor (teprotide) in conscious monkeys. 303

The effects of a new somatostatin analogue SMS 201-995 (H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol), Sandostatin) on the orthostatic stimulation of plasma renin activity (PRA) following head-up tilting and on angiotensin II (Ang-II) induced aldosterone (PA) release were studied under placebo controlled conditions in separate groups of healthy volunteers consisting of six and 10 subjects, respectively. Head-up tilting (by 60 degrees) produced the characteristic increases in PRA and PA. Administration of SMS 201-995 significantly (P less than 0.05) inhibited this PRA elevation from 30 min on. Throughout the study period, PA levels were not consistently altered by this analogue. Furthermore, SMS 201-995 failed to inhibit the stimulation of PA secretion induced by exogenous angiotensin-II (2-10 ng/kg/min). Results presented here are at variance with data collected with natural somatostatin showing an inhibitory effect on stimulated PA. This discrepancy can be explained by the recently described absence of SMS 201-995 binding sites in primate adrenal cortex and in human aldosteronomas.
 ...
PMID:Effect of a new somatostatin analogue SMS 201-995 (Sandostatin) on the renin-aldosterone axis. 304 92

1. In order to study the role of the kidney in the elimination of endogenous plasma renin, renin was measured in the plasma and urine of female mice. 2. The renin concentration was two orders of magnitude lower in urine than in plasma, but it increased after intraperitoneal injection of submandibular mouse renin. No correlation between the plasma renin concentration and the urinary renin concentration and renin excretion rate could be demonstrated. 3. Blockade of the tubular reabsorption of proteins by intraperitoneal injection of the basic amino acid lysine increased the urinary renin concentration, renin excretion rate and renin clearance two to three orders of magnitude, without affecting the plasma renin concentration. 4. This finding demonstrates that ultrafiltered renin is reabsorbed almost completely in the renal tubules and that the mechanism most likely is the same as for other filtered proteins. 5. The large renal renin clearance obtained after intraperitoneal lysine is in accordance with a major role of the kidneys in the elimination of renin from the circulation, by a glomerular ultrafiltration and tubular reabsorption and metabolization of renin.
 ...
PMID:Ultrafiltration of renin in the mouse kidney studied by inhibition of tubular protein reabsorption with lysine. 313 59

Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibitors of renin, with Boc-Phe-Pro psi[CH2O]Phe-His-Leu psi[CH(OH)CH2]Val-Ile-(2-aminomethyl) pyridine (17) having an IC50 of 1.6 X 10(-9) M.
 ...
PMID:Renin inhibitors containing psi[CH2O] pseudopeptide inserts. 327 10

The specificity of action of bovine brain cortex cathepsin D (EC 3.4.23.5) and high-Mr aspartic endopeptidase (EC 3.4.23.-) was studied with the vasoactive peptides renin substrate tetradecapeptide (RSTP), substance P (SP), and angiotensins I and II, and with model peptides--Lys-Pro-Ala-Glu-Phe-Phe (NO2)-Ala-Leu (I), Gly-Gly-His-Phe (NO2)-Phe-Ala-Leu-NH2 (II), and Abz-Ala-Ala-Phe-Phe-pNA (III). Cerebral aspartic peptidases show identical substrate specificity, cleaving the Leu10-Leu bond in RSTP and Phe-Phe in SP and peptide I-III, and not splitting angiotensins I and II. Because of the higher catalytic efficiency of cathepsin D (Kcat value), the specificity constants (Kcat/Km) for cathepsin D-catalyzed hydrolysis of substrates 1-111 are much higher than those for the high-Mr enzyme. High-Mr aspartic peptidase shares a number of properties with cathepsin D (sensitivity to pepstatin, substrate specificity, pH activity profile) and shows partial immunological identity; however, high-Mr aspartic peptidase has a specific activity 7-10 times lower than that of cathepsin D. The kinetic parameters of proteolysis of model peptides presented indicate that the high-Mr enzyme may be a complex of a single-chain cathepsin D with another polypeptide, although the possibility that it is an independent aspartic peptidase cannot be excluded.
 ...
PMID:Substrate specificity of cerebral cathepsin D and high-Mr aspartic endopeptidase. 328 13

The synthesis and in vitro renin inhibitory potencies of angiotensinogen (ANG) analogues having amide (CONH) bond replacements at P1-P1', the Leu-Val cleavage site, corresponding to Leu psi[CH2SO]Val, and the trans olefinic analogue of statine (Sta), 4(S)-amino-6-methyl-2(E)-heptenoic acid (dehydrostatine, Dhs), are reported. These are compared to P1-P1' Leu psi[CH2NH]Val-, Sta-, or Phe-Phe-substituted analogues of the same template. The Dhs pseudodipeptide was found to be an adequate mimic of a trans CONH bond and gave a peptide, H-Pro-His-Pro-Phe-His-Dhs-Ile-His-D-Lys-OH, approximately equal in potency to a Phe-Phe-containing inhibitor, but 200-fold less potent than its Sta-substituted congener. That the enhanced potency of the Sta-containing peptide most likely depends on hydrogen bonding as well as tetrahedral geometry is indicated by the 50-100-fold lower potency of the tetrahedral Leu psi[CH2S]Val and Leu psi[CH2SO]Val analogues as compared to the Leu psi[CH2NH]Val-containing congener.
 ...
PMID:Synthesis and renin inhibitory activity of angiotensinogen analogues having dehydrostatine, Leu psi [CH2S]Val, or Leu psi [CH2SO]Val at the P1-P1' cleavage site. 329 Apr 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>