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)

To determine whether or not rat plasma inactive renin is prorenin, specific antibodies were raised against two 15-amino acid peptides, Pro-NH2 and Pro-COOH, which contained the NH2-terminal and COOH-terminal sequences, respectively, of the prosegment of rat prorenin. Inactive renin was measured after trypsin treatment. Immunoaffinity chromatography of normal rat plasma on anti-Pro-NH2 and anti-Pro-COOH immunoglobulin G (IgG)-Sepharose showed that about one-half the amount of inactive renin was prorenin, whereas the rest was neither prorenin nor renin. Thus trypsin treatment of the unfractionated plasma does not provide measurement of the concentration of prorenin. However, fractionation of plasma by high-performance liquid chromatography on G3,000SW columns followed by trypsin treatment led to the measurement of prorenin. Prorenin and active renin concentrations in the normal plasma of conscious rats were 44.3 +/- 5.8 and 13.3 +/- 1.4 (SE) ng ANG I.h-1.ml-1, respectively (n = 10). On the other hand, plasma inactive renin from rats at 24 h after bilateral nephrectomy bound to neither anti-Pro-NH2 nor anti-Pro-COOH IgG immunoaffinity columns, and the enzymatic activity after trypsin treatment was not inhibited by anti-mature renin IgG. These results demonstrate that inactive renin from nephrectomized rats was not prorenin. Thus the kidney is the primary source of circulating prorenin in rats.
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PMID:Immunological evidence that kidney is primary source of circulating inactive prorenin in rats. 201 18

The nonapeptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-NH2 containing the retroviral Tyr-Pro cleavage site is a good substrate for the proteinase of human immunodeficiency viruses but it is not readily hydrolyzed by other nonviral proteinases including the structurally related pepsin-like aspartic proteinases. Replacing the Pro by L-pipecolic acid (2-piperidinecarboxylic acid) converted the substrate into an effective inhibitor of HIV-1 and HIV-2 proteinases with IC50 of approximately 1 microM. This compound showed a high degree of selectivity in that it did not inhibit cathepsin D and renin.
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PMID:Substitution of proline with pipecolic acid at the scissile bond converts a peptide substrate of HIV proteinase into a selective inhibitor. 219 May 54

The synthesis of five amino phosphorus derivatives, 1a-e, is described. The derivatives were incorporated into a series (18) of analogues of the 5-14 portion of angiotensinogen, in most cases at the scissile Leu-Val bond. The resultant compounds were tested in vitro for their ability to inhibit human plasma renin. Replacement of the scissile bond with the phosphinic analogue of Leu10-Val11 (1b) gave the most potent inhibitors, having IC50 = 7.5 x 10(-8) M for H-Pro-His-Pro-Phe-His-(1b)-Ile-His-Lys-OH and IC50 = 1.0 x 10(-7) M for Z-Arg-Arg-Pro-Phe-His-(1b)-Ile-His-NH2. The shorter phosphonic acid sequence Z-Pro-Phe-His-(1d) retained biological activity with an IC50 = 6.4 x 10(-6) M.
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PMID:Renin inhibitors. Synthesis of transition-state analogue inhibitors containing phosphorus acid derivatives at the scissile bond. 266 20

Mean arterial blood pressure (MAP) was 100 +/- 4 mmHg in a group (n = 3) of conscious sodium-deficient dogs. A 3-day infusion of the renin inhibitor isovaleryl -His-Pro-Phe-His-Sta-Leu-Phe-NH2 (SCRIP) lowered MAP to an average of 79 +/- 4 mmHg. Termination of the infusion resulted in a prompt rise in MAP to 100 +/- 5 mmHg but plasma renin activity (PRA), which was 22 +/- 2 ng angiotensin (Ang) l/ml per h before the infusion, recovered only to 5 +/- 1 ng Ang l/ml per h during the same time (4 h after infusion). In other experiments in sodium-deficient dogs, a direct comparison was made between inhibition of PRA and the reduction of blood pressure. Over the dose range 0.1-2 micrograms/kg per min, PRA was inhibited in a dose-related manner, but MAP was not reduced. At dose levels beginning an order of magnitude higher (e.g. 20-160 g/kg per min), PRA was completely inhibited and there was a dose-related fall in MAP. These data suggest that there is no correlation between inhibition of PRA and the reduction in blood pressure in chronically sodium-deficient dogs. In other studies comparing renin inhibition with angiotensin converting enzyme (ACE) inhibition, there was evidence for greater efficacy of ACE inhibition in conscious sodium-deficient dogs, but no evidence of any difference in one-kidney, one clip hypertensive dogs.
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PMID:Characteristics of the blood pressure lowering action of renin inhibition and comparison with angiotensin converting enzyme inhibition. 266 14

Pro-His-Pro-Phe-His-Statine-Ile-Phe-NH2 (R-Pep-27), a potent renin inhibitory peptide, was infused into the conscious, sodium-depleted Macaca fascicularis at doses of 0, 0.1, 1, 4, 16, and 32 micrograms/kg/min for 10 minutes. At all doses greater than 0.1 microgram/kg/min, there was a parallel decrease in mean arterial pressure (MAP), plasma renin activity, and plasma angiotensin II (Ang II) concentration. On the other hand, assays with monoclonal antibodies specific for total renin and active renin demonstrated that the peptide's inhibition of circulating active renin stimulated the release of both. The maximal effective R-Pep-27 dose was approximately 16 micrograms/kg/min, which reduced MAP by an average of 15.8 +/- 1.4 mm Hg (n = 14) and plasma renin activity and plasma Ang II concentration to 3% (n = 9) and 15% (n = 5), respectively, of the pretreatment values. At 0.1 microgram/kg/min, there was no significant decrease in MAP; however, measurement of plasma renin activity showed an average decrease in activity of 42% (n = 3). No significant change in the heart rate was observed at all the doses studied. For comparison, intravenous captopril (400 micrograms/kg bolus) was administered after the MAP of the monkeys had recovered from the peptide experiments, and it reduced MAP by 25.1 +/- 2.4 mm Hg (n = 10) without significantly changing plasma renin activity. As anticipated, injection of angiotensin I (80-160 ng/kg bolus) into sodium-depleted monkeys during peptide infusion caused a transient rise in MAP of 14.8 +/- 5.4 mm Hg (n = 4) above the mean pretreatment value.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of renin inhibition in the conscious primate Macaca fascicularis. 268 Sep 62

Tissue and secreted forms of rat prosomatostatin and its cleavage products were characterized immunochemically using high performance liquid chromatography and sequence-specific radioimmunoassays directed against somatostatin-14 (S-14), S-28-(1-12), and S-28-(1-14). Acetic or hydrochloric acid extracts of hypothalamus, pancreas, stomach, and jejunum contained seven molecular forms of Mr = 10,400 (corresponding to prosomatostatin (pro-S], Mr = 6,800 (7-kDa peptide, consisting of an NH2-terminally truncated form of pro-S), Mr = 7,600 (8-kDa peptide, corresponding to pro-S-(1-76), i.e. pro-S minus the COOH-terminal -Arg-Lys-S-14), Mr = 5,600 (5-kDa peptide, corresponding to pro-S-(33-76)) and three peptides co-chromatographing with synthetic S-14, S-28, and S-28-(1-12). Acid/ethanol extracts of these tissues contained pro-S, 8-kDa peptide, S-28, S-14, and S-28-(1-12) forms, but not the 7- and 5-kDa species. Pepstatin inhibited 7- and 5-kDa peptide formation in acetic acid extracts of tissues. The secreted forms consisted of the same five forms present in acid/ethanol or acetic acid plus pepstatin tissue extracts. The 7- and 5-kDa peptides were not secreted and appeared to be derived artifactually, presumably through the action of renin- and cathepsin D-like acid proteases. Accurate quantitation of the 8-kDa peptide by acid/ethanol extraction revealed a variable tissue distribution. Since the presence of the 8-kDa form provides evidence for direct processing of pro-S----S-14 + 8-kDa peptide, the present data suggest that pro-S----S-14 conversion is important for S-14 synthesis in the hypothalamus and pancreas, tissues rich in the 8-kDa form, but not in the stomach and jejunal mucosa, which contain low concentrations of this peptide.
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PMID:Peptides derived from cleavage of prosomatostatin at carboxyl- and amino-terminal segments. Characterization of tissue and secreted forms in the rat. 289 3

This paper summarizes the results of our recent studies in a group of healthy subjects on the endocrine effects of the new potent opioid peptide, dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), originally isolated from amphibian skin. Intravenous infusion (5.5 microgram/kg/min for 30 min) of dermorphin (D) significantly increased plasma levels of prolactin (PRL), growth hormone (GH), thyrotropin (TSH) and renin activity (PRA), but decreased plasma levels of cortisol. D produced a small decrease in ACTH, and a small increase in plasma aldosterone. Pretreatment with the opioid receptor antagonist naloxone (N) suppressed the PRL and TSH response to D, blunted the D-induced GH and PRA increase, and completely prevented the D-induced plasma cortisol decrease, but enhanced plasma cortisol and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that: (1) D, a new opioid peptide, can stimulate PRL, GH and TSH release in humans; (2) D increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; (3) D suppresses plasma cortisol levels, by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.
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PMID:The effects of dermorphin on the endocrine system in man. 300 18

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.
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PMID:Hypotensive effects of the renin inhibitor (RI-78) and the converting enzyme inhibitor (teprotide) in conscious monkeys. 303

Because several well-studied strains of rats manifest spontaneous hypertension, we set out to design a renin inhibitor suitable for use in this species. On the basis of the sequence of the renin substrate, a series of substrate analogue inhibitory peptides were synthesized by systematically modifying the P5, P3, P2, P1P1', P2', P3', and P4' positions. In assays against rat plasma renin, we found that modifications at the C-terminal segment have a marked influence on potency, and that a secondary butyl side chain at the P2' position is important for obtaining optimal activity. The structure at the P3' position, however, could vary considerably without significant effect. The steric effect of the P2 position was important; there an isopropyl side chain provided optimal binding between the inhibitor and the enzyme. At the P3 and P5 positions, potency appeared to depend on aromatic side chains. The effects at the P1P1' position of the transition-state residue (3S,4S)-4-amino-3-hydroxy -6-methylheptanoic acid (statine) and its congeners (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoic acid (ACHPA) were found to depend on the sequence of the C-terminal segment. For peptides with an unfavorable C-terminal segment (-Ile-Phe-NH2), AHPPA and ACHPA resulted in a surprising retention of potency. For peptides with a favorable C-terminal segment (-Leu-Phe-NH2), the effect of AHPPA was mild, even though ACHPA still significantly enhanced potency. The hypotensive and plasma renin inhibitory effects of three of the analogues were then studied in anesthetized sodium-depleted rats. One of the compounds, acetyl-His-Pro-Phe-Val-Statine-Leu-Phe-NH2 (IC50 against rat plasma renin of 30 nM at pH 7.4), proved to be a potent hypotensive agent and a potentially useful probe for the study of the renin-angiotensin system in rats.
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PMID:Design of rat renin inhibitory peptides. 304 20

A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.
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PMID:Synthesis and biological activity of some transition-state inhibitors of human renin. 313 45


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