Drugs online research references
Am J Physiol Renal Physiol. 2000 Nov;279(5):F841-50.
Pathways for angiotensin-(1---7) metabolism in pulmonary and renal tissues.
Allred AJ, Diz DI, Ferrario CM, Chappell MC.
Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Two of the primary sites of actions for angiotensin (ANG)-(1---7) are the vasculature and the kidney. Because little information exists concerning the metabolism of ANG-(1---7) in these tissues, we investigated the hydrolysis of the peptide in rat lung and renal brush-border membrane (BBM) preparations. Radiolabeled ANG-(1---7) was hydrolyzed primarily to ANG-(1---5) by pulmonary membranes. The ANG-converting enzyme (ACE) inhibitor lisinopril abolished the generation of ANG-(1---5), as well as that of smaller metabolites. Kinetic studies of the hydrolysis of ANG-(1---7) to ANG-(1---5) by somatic (pulmonary) and germinal (testes) forms of rat ACE yielded similar values, suggesting that the COOH-domain is responsible for the hydrolysis of ANG-(1---7). Pulmonary metabolism of ANG-(1---5) yielded ANG-(3---5) and was independent of ACE but may involve peptidyl or dipeptidyl aminopeptidases. In renal cortex BBM, ANG-(1---7) was rapidly hydrolyzed to mono- and dipeptide fragments and ANG-(1---4). Aminopeptidase (AP) inhibition attenuated the hydrolysis of ANG-(1---7) and increased ANG-(1---4) formation. Combined treatment with AP and neprilysin (Nep) inhibitors abolished ANG-(1---4) formation and preserved ANG-(1---7). ACE inhibition had no effect on the rate of hydrolysis or the metabolites formed in the BBM. In conclusion, ACE was the major enzymatic activity responsible for the metabolism of ANG-(1---7) in the lung, which is consistent with the ability of ACE inhibitors to increase the half-life of circulating ANG-(1---7) and raise endogenous levels of the peptide. An alternate pathway of metabolism was revealed in the renal cortex, where increased AP and Nep activities, relative to ACE activity, promote conversion of ANG-(1---7) to ANG-(1---4) and smaller fragments.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11053044&dopt=Abstract
Exp Nephrol. 2001;9(1):21-7.
ACE inhibition preserves heparan sulfate proteoglycans in the glomerular basement membrane of rats with established adriamycin nephropathy.
Wapstra FH, Navis GJ, van Goor H, van den Born J, Berden JH, de Jong PE, de Zeeuw D.
Division of Nephrology, Groningen University Institute for Drug Exploration, Nijmegen, The Netherlands.
The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM staining was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage. Copyright 2000 S. Karger AG, Basel.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11053977&dopt=Abstract
J Biol Chem. 2001 Feb 16;276(7):4998-5004. Epub 2000 Nov 06.
Angiotensin I-converting enzyme transition state stabilization by HIS1089: evidence for a catalytic mechanism distinct from other gluzincin metalloproteinases.
Fernandez M, Liu X, Wouters MA, Heyberger S, Husain A.
Enzyme Research Unit, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
Angiotensin (Ang) I-converting enzyme (ACE) is a member of the gluzincin family of zinc metalloproteinases that contains two homologous catalytic domains. Both the N- and C-terminal domains are peptidyl-dipeptidases that catalyze Ang II formation and bradykinin degradation. Multiple sequence alignment was used to predict His(1089) as the catalytic residue in human ACE C-domain that, by analogy with the prototypical gluzincin, thermolysin, stabilizes the scissile carbonyl bond through a hydrogen bond during transition state binding. Site-directed mutagenesis was used to change His(1089) to Ala or Leu. At pH 7.5, with Ang I as substrate, k(cat)/K(m) values for these Ala and Leu mutants were 430 and 4,000-fold lower, respectively, compared with wild-type enzyme and were mainly due to a decrease in catalytic rate (k(cat)) with minor effects on ground state substrate binding (K(m)). A 120,000-fold decrease in the binding of lisinopril, a proposed transition state mimic, was also observed with the His(1089) --> Ala mutation. ACE C-domain-dependent cleavage of AcAFAA showed a pH optimum of 8.2. H1089A has a pH optimum of 5.5 with no pH dependence of its catalytic activity in the range 6.5-10.5, indicating that the His(1089) side chain allows ACE to function as an alkaline peptidyl-dipeptidase. Since transition state mutants of other gluzincins show pH optima shifts toward the alkaline, this effect of His(1089) on the ACE pH optimum and its ability to influence transition state binding of the sulfhydryl inhibitor captopril indicate that the catalytic mechanism of ACE is distinct from that of other gluzincins.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11067854&dopt=Abstract
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