Disease relevance of CI 928

• Hemodynamic and hormonal effects of quinaprilat in patients with congestive heart failure [1].
• Two patients treated with quinaprilat withdrew due to hypotension; one patient required a dosage reduction [2].
• Ultrastructural grading of mitochondrial damage revealed best preservation with quinaprilat during ischemia (100% [no damage], P =.001 vs control) [3].
• We conclude that quinaprilat can be used during CABG to reduce the incidence of postoperative hypertension [4].
• The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end-stage renal disease (ESRD) on chronic hemodialysis [5].

High impact information on CI 928

• Quinaprilat induces arterial vasodilation mediated by nitric oxide in humans [6].
• RESULTS: Compared with placebo, single and multiple doses of quinaprilat increased cardiac index and reduced pulmonary capillary wedge pressure, mean arterial pressure, systemic vascular resistance, and right atrial pressure in a dose-related manner [1].
• Quinapril is a new non-sulphydryl ACE inhibitor whose active metabolite, quinaprilat, has a relatively short accumulation half-life compared with enalapril and lisinopril but has an enhanced affinity for the converting enzyme, allowing rapid excretion of the drug while retaining a 24-hour antihypertensive effect with once-daily dosing [7].
• Cell culture studies showed antioxidative effects of quinaprilat, revealed concentration-dependent down-regulation of endothelial ET-1 release, and indicated formation of nitrosoglutathione by quinaprilat [8].
• Beneficial effects of quinaprilat on coronary vasomotor function, endothelial oxidative stress, and endothelin activation after human heart transplantation [8].

Chemical compound and disease context of CI 928

• The pharmacokinetics of quinapril and quinaprilat in patients with congestive heart failure [9].
• When administered during ischemia, quinaprilat significantly improved recovery of coronary flow (70% +/- 8%, P =.028 vs quinaprilat during reperfusion [49% +/- 5%] and P =.023 vs control [48% +/- 6%]). l-Arginine (55% +/- 7%) showed no significant effect [3].
• High-energy phosphates, which were consistently elevated in all treatment groups, showed a significant increase in adenosine triphosphate with quinaprilat during ischemia (2.24 +/- 0.14 micromol/g vs 1.81 +/- 0.12 micromol/g in control group, P =.040) [3].
• In patients with coronary disease, short-term administration of quinaprilat was able to improve the impaired response to bradykinin [10].
• To test whether quinaprilat, a new angiotensin converting enzyme inhibitor, has any venous effect, its immediate effects were measured on mean circulatory filling pressure (MCFP), intravascular volume and total body vascular (i.e., venous) compliance in conscious rats with mild congestive heart failure induced by coronary artery ligation [11].

Biological context of CI 928

• Quinaprilat pharmacokinetics were studied using a specific assay [12].
• The IC50 values of ramiprilat and quinaprilat were about the same with both active sites [13].
• Dosing on a mg/kg basis resulted in quinaprilat AUC and Cmax values that were generally comparable across the age range of patients in this study [14].
• Blood pressure reduction was observed in four of six patients, with onset reliably two to four hours after dosing and duration up to 48 hours, associated with quinaprilat concentrations in plasma above 90 ng/mL for at least 33 hours postdose [15].
• RESULTS: All treatments substantially improved postischemic recovery of external heart work (62% +/- 6%, 69% +/- 3%, and 64% +/- 5% in quinaprilat during cardioplegia, quinaprilat during reperfusion, and l-arginine groups, respectively, vs 35% +/- 5% in control group, P <.001) with similarly increased external stroke work and cardiac output [3].

Anatomical context of CI 928

• In cytokine-treated human lung microvascular endothelial cells, B1 receptor activation by ACE inhibitors (enalaprilat, quinaprilat) or peptide ligands (des-Arg10-Lys1-bradykinin, des-Arg9-bradykinin) inhibited PKC epsilon with an IC50 = 7 x 10(-9) M [16].
• Quinapril and its metabolite quinaprilat in human milk [17].
• In the present study, we electrophysiologically investigated PAC function in intact endothelium of aorta (EA) and mesenteric artery (EMA) from stroke-prone spontaneously hypertensive rats (SHRSP), SHRSP after 4 weeks of treatment with quinaprilat (10 mg/kg/day), and normotensive Wistar-Kyoto (WKY) rats [18].
• The effects of quinaprilat, captopril, enalaprilat and lisinopril on the NAD(P)H oxidase activity of the mononuclear leukocytes were measured photometrically [19].
• To test whether quinaprilat, a new angiotensin-converting enzyme (ACE) inhibitor, has any venous effect, we measured its immediate effects on mean circulatory filling pressure (MCFP), intravascular volume, and total body vascular (i.e., venous) compliance in conscious rats with healed myocardial infarction induced by coronary artery ligation [20].

Associations of CI 928 with other chemical compounds

• METHODS: Coronary vasomotor responses and transcardiac metabolism of glutathione, oxidized glutathione, and ET-1 were determined before and after quinaprilat infusion in 32 heart transplant recipients [8].
• 5. Adding quinaprilat to the bath following repeated exposure (with or without L-NAME), at the time BK and HT-BK no longer induced relaxation, fully restored vasorelaxation, while quinaprilat alone had no effect [21].
• Sera from the same patients were also tested with the addition to the incubation media of quinaprilat, an inhibitor of the metalloproteinase angiotensin-converting enzyme [22].
• Multiple-dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite (CI-928) [23].
• The effects of quinaprilat, captopril, enalaprilat and lisinopril on phorbol myristate acetate-induced reactive oxygen species generation were investigated in vitro [19].

Gene context of CI 928

• PURPOSE: Experiments were designed to determine whether angiotensin converting enzyme inhibition with quinaprilat can prevent endothelin-mediated decreases in renal blood flow and the glomerular filtration rate in the anesthetized dog [24].
• The A(1-7)-induced relaxation was not affected by AT1 or AT2 receptor blockade or cyclo-oxygenase inhibition, but was attenuated by the B2 receptor antagonist, Hoe 140, and augmented by the angiotensin-converting enzyme (ACE) inhibitor, quinaprilat [25].
• The mean P(alb) of the sera combined with quinaprilat was reduced to 0.34+/-0.35 [22].
• Quinapril and quinaprilat were extracted from human plasma and urine by using a Bond-Elut C18 cartridge [26].
• Quinaprilat did not influence the formation of Ang 1-9, but it inhibited formation of Ang II [27].

Analytical, diagnostic and therapeutic context of CI 928

• Two groups received quinaprilat (1 microg/mL), initiated either with cardioplegia (n = 7) or during reperfusion (n = 7) [3].
• The pharmacokinetic profile of quinaprilat in these CAPD patients was similar to that previously observed in patients with RDND [15].
• Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment [5].
• The dose-response and duration-of-effect after single intravenous doses of quinaprilat and placebo (part A) and after administration of oral quinapril solution and intravenous quinaprilat (part B) were assessed in a randomized, crossover study of two groups of 12 healthy volunteers [28].
• Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography [5].

References