Drugs online research references
Am J Hypertens. 1994 Jan;7(1):52-8.
Treatment with lisinopril normalizes serum concentrations of procollagen type III amino-terminal peptide in patients with essential hypertension.
Laviades C, Mayor G, Diez J.
Department of Medicine, San Jorge General Hospital, Huesca, Spain.
Procollagen type III amino-terminal peptide (PIIIP) is cleaved off procollagen type III during the biosynthesis of type III collagen. Thus, to assess the synthesis of collagen type III in essential hypertension, we determined the serum concentrations of PIIIP in 24 patients with never-treated essential hypertension and in 30 normotensive controls. In addition, serum concentrations of PIIIP were measured in 15 patients after receiving lisinopril during 6 months. Serum PIIIP was higher in hypertensives than controls (11.20 +/- 0.76 v 8.47 +/- 0.77 ng/mL, mean +/- SEM, P < .01). A direct correlation was found between serum PIIIP and plasma renin activity (r = 0.54, P < .01) in the group of hypertensives. In addition, serum PIIIP was correlated inversely with maximal early transmitral flow velocity measured during diastole by Doppler echocardiography (r = -0.74, P < .001) in the group of hypertensive patients. The serum PIIIP levels decreased significantly in patients treated with lisinopril (11.76 +/- 0.84 v 8.47 +/- 0.66 ng/mL, P < .01). A significant increase of plasma renin activity and a significant decrease of plasma aldosterone was observed in these patients after treatment with lisinopril. These results suggest that increased collagen type III synthesis is present in patients with essential hypertension. Abnormal synthesis of collagen type III in essential hypertension may be related to the activity of circulating renin-angiotensin-aldosterone system. Whether an excessive synthesis of myocardial collagen type III is responsible for increased serum PIIIP present in essential hypertension deserves further investigation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8136111&dopt=Abstract
J Biol Chem. 1992 Jul 5;267(19):13398-405.
The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors.
Wei L, Clauser E, Alhenc-Gelas F, Corvol P.
Institut de la Sante et de la Recherche Medicale Unite 36, Paris, France.
The endothelial angiotensin I-converting enzyme (ACE; EC 3.4.15.1) has recently been shown to contain two large homologous domains (called here the N and C domains), each being a zinc-dependent dipeptidyl carboxypeptidase. To further characterize the two active sites of ACE, we have investigated their interaction with four competitive ACE inhibitors, which are all potent antihypertensive drugs. The binding of [3H] trandolaprilat to the two active sites was examined using the wild-type ACE and four ACE mutants each containing only one intact domain, the other domain being either deleted or inactivated by point mutation of the zinc-coordinating histidines. In contrast with all the previous studies, which suggested the presence of a single high affinity inhibitor binding site in ACE, the present study shows that both the N and C domains of ACE contain a high affinity inhibitor binding site (KD = 3 and 1 X 10(-10) M, respectively, at pH 7.5, 4 degrees C, and 100 mM NaCl). Chloride stabilizes the enzyme-inhibitor complex for each domain primarily by slowing its dissociation rate, as the k-1 values of the N and C domains are markedly decreased (about 30- and 1100-fold, respectively) by 300 mM NaCl. At high chloride concentrations, the chloride effect is much greater for the C domain than for the N domain resulting in a higher affinity of this inhibitor for the C domain. In addition, the inhibitory potency of captopril (C), enalaprilat (E), and lisinopril (L) for each domain was assayed by hydrolysis of Hip-His-Leu. Their Ki values for the two domains are all within the nanomolar range, indicating that they are all highly potent inhibitors for both domains. However, their relative potencies are different for the C domain (L greater than E greater than C) and the N domain (C greater than E greater than L). The different inhibitor binding properties of the two domains observed in the present study provide strong evidence for the presence of structural differences between the two active sites of ACE.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1320019&dopt=Abstract
Br J Pharmacol. 1990 May;100(1):83-9.
Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin-converting enzyme.
Carr RD, Higgs L, Killingback PG, Nicol AK, O'Connor SE, Robson A, Wells E, Simpson WT.
Fisons plc, Pharmaceutical Division, Research and Development Laboratories, Loughborough.
1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 micrograms kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 X 10(-7)-10(-5) mol kg-1 p.o. (congruent to 0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10(-6), 10(-6) and 3 X 10(-5) mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2164863&dopt=Abstract
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