Drugs online research references
J Biol Chem. 1993 Dec 5;268(34):25748-54.
Mutations in two specific residues of testicular angiotensin-converting enzyme change its catalytic properties.
Sen I, Kasturi S, Abdul Jabbar M, Sen GC.
Department of Cardiovascular Biology, Cleveland Clinic Foundation, Ohio 44195.
Chemical modifications of 2 specific residues present in angiotensin-converting enzyme (ACE) result in its inactivation, thereby suggesting that these 2 residues may be important for its enzyme activity. We directly tested this hypothesis by substituting Tyr-236 with Phe and Lys-154 with Glu in rabbit testicular ACE (ACET) using site-directed mutagenesis of the corresponding cDNA. Wild type ACET, the two single mutants, and the double mutant were expressed in HeLa cells using the vaccinia virus-T7 polymerase expression system. The rate of synthesis, post-translational modifications, and cleavage secretion pattern of all four proteins were indistinguishable. The enzymatic properties of the two single mutants and the wild type enzyme were also very similar. In contrast, the double mutant had about a 20-fold lower specific activity although its Km was only 6-fold higher than that of the wild type protein. The double mutant also had a 100-fold higher Ki for lisinopril, a competitive inhibitor of ACET, and was 17-fold less sensitive to stimulation by NaCl, an activator of ACET. These results directly demonstrate that Tyr-236 and Lys-154 are indeed critical for the catalytic activity, lisinopril inhibition, and NaCl activation of ACET.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7902354&dopt=Abstract
word match zestril online literature
Circulation. 2000 Feb 29;101(8):844-6.
Maximally recommended doses of angiotensin-converting enzyme (ACE) inhibitors do not completely prevent ACE-mediated formation of angiotensin II in chronic heart failure.
Jorde UP, Ennezat PV, Lisker J, Suryadevara V, Infeld J, Cukon S, Hammer A, Sonnenblick EH, Le Jemtel TH.
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
BACKGROUND: The added benefits of angiotensin II type I receptor (AT(1)) blockers (ARBs) to ACE inhibition suggests that recommended doses of ACE inhibitors provide only partial inhibition of ACE in chronic heart failure (CHF). Accordingly, the level of ACE inhibition was assessed by the pressor response to angiotensin (Ang) I in patients who had been treated with recommended doses of ACE inhibitors. METHODS AND RESULTS: Forty-two patients with CHF receiving 40 mg/d of a long-acting ACE inhibitor or 150 mg of captopril were studied. Radial artery systolic pressure (RASP, mm Hg) was monitored noninvasively. The pressor response to ascending doses of Ang I was evaluated in all patients before and after administration of the ARB valsartan. The pressor response to Ang I before and after valsartan was also reevaluated in 11 patients after the dose of ACE inhibitor was doubled for 1 week. RASP increased linearly with significantly ascending doses of Ang I despite treatment with ACE inhibitors. The pressor response to Ang I was blunted significantly by valsartan. Ang I-induced increase in RASP did not correlate with duration of ACE inhibitor therapy. After the dose of ACE inhibitors was doubled, the pressor response to Ang I was no longer different from that noted after valsartan. CONCLUSIONS: Recommended doses of ACE inhibitors do not fully inhibit ACE in CHF. The level of ACE inhibition achieved is not related to duration of ACE inhibitor therapy. Greater ACE inhibition is also achieved at twice the recommended doses of ACE inhibitors.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10694521&dopt=Abstract
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Kidney Int. 1994 Jun;45(6):1614-21.
Regulation of the renal angiotensin II receptor gene in acute unilateral ureteral obstruction.
Pimentel JL Jr, Wang S, Martinez-Maldonado M.
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
We have shown that acute (24-hr) unilateral ureteral obstruction (UUO) induces the genes encoding for renin, in juxtaglomerular apparatuses and in tubules, for angiotensin converting enzyme in vascular endothelial cells, and for angiotensinogen in perivascular fat. These molecular changes occur in temporal association to marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR), suggesting that angiotensin II (Ang II) is at least partly responsible for the renal vasoconstriction. We tested the hypothesis that down-regulation of the Ang II type-1 receptor (AT1-R) gene occurs in UUO in response to Ang II, by examining the effects of an ACE inhibitor [lisinopril (Li), 5 mg/kg/day] and of the specific nonpeptidic AT1-R blocker, losartan (Lo) (10 mg/kg/day). UUO or sham operated (which included manipulation but not obstruction of the ureter) rats (S) were studied. Northern blot analysis of the steady state concentration of AT1-R mRNA corrected for GAPDH mRNA showed a marked decrease in receptor expression (-77%, N = 4, P < 0.01) in the obstructed kidney (UUO) compared to S; sham diminished gene expression modestly compared to the contralateral kidneys (C) of UUO. In situ hybridization for AT1-R mRNA also showed diminished expression in UUO compared to C kidneys (N = 4). Treatment of UUO rats (N = 4) with Lo increased AT1-R mRNA five times above the levels in UUO rats receiving vehicle; the increase induced by Li was 50% that of Lo; S (N = 4) and C (N = 4) did not change. Losartan, but not vehicle treatment increased RBF (sixfold) and GFR (fivefold) in the UUO kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7933808&dopt=Abstract
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