Disease relevance of Trandolaprilat

• Trandolaprilat inhibits the angiotensin converting enzyme (ACE) and displays similar pharmacodynamic properties to other ACE inhibitors, improving haemodynamic and cardiac parameters in patients with essential hypertension [1].
• Treatment with 30 microM trandolaprilat suppressed ischemia/reperfusion-induced changes in myocardial ion content [2].

High impact information on Trandolaprilat

• Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metabolism [3].
• When expressed in COS-7 cells, the AnCE protein is a secreted enzyme, which converts angiotensin I to angiotensin II and is inhibited by captopril (IC50 = 5.6 x 10(-9) M) and trandolaprilat (IC50 = 2 x 10(-8) M) [4].
• 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 [5].
• In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine [6].
• Trandolapril is a non-sulfhydryl prodrug which, after oral administration, is hydrolysed in the liver to its active diacid, trandolaprilat [1].

Biological context of Trandolaprilat

• CONCLUSIONS: The ACE inhibitor trandolaprilat reduces VSMC proliferation by lengthening the G2-M phase of the cell cycle, and produces a decrease in cellular protein content [7].
• OBJECTIVE: To investigate the effect of the angiotensin converting enzyme (ACE) inhibitor trandolaprilat on vascular smooth muscle cell growth, and to analyse its mechanism of action [7].
• After single or repeated administration the active metabolite, trandolaprilat, showed an inverse correlation between maximal plasma concentrations (Cmax) and CLCR (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CLCR (r = -0.635 day 1 and r = -0.794 day 10) [8].
• However, the Cmax and AUC values for trandolaprilat were directly proportional to the highest doses, 2 and 4 mg, suggesting linear kinetics for the trandolaprilat, which is not bound to ACE [9].
• The effect of CRF on the pharmacokinetics and pharmacodynamics of trandolaprilat is of significance only when CLCR is < 30 ml/min/1.73 m2 [8].

Anatomical context of Trandolaprilat

• The effect of trandolaprilat on translational protein synthesis was also examined using the cell-free protein synthesis system of reticulocyte lysate and messenger RNA from VSMC [7].
• Previous exposure to bradykinin unmasks an endothelium-dependent relaxation to the converting enzyme inhibitor trandolaprilat in isolated canine coronary arteries [10].
• Trandolaprilat caused relaxations [IC50(-log M)8.59] in rings with endothelium previously exposed to bradykinin [10].
• Experiments were designed to study the effects of trandolaprilat on endothelium-dependent responses in isolated blood vessels [11].
• In inhibitory activity (IC50) on the Ang I induced contraction of the rat thoracic aorta, trandolaprilat was about 2.4 times as potent as enalaprilat [12].

Associations of Trandolaprilat with other chemical compounds

• Treatment with 10-100 microM of trandolaprilat for the last 10 min of pre-ischemia recovered approximately 50-90% of pre-ischemic LVDP during reperfusion, whereas that with 30-100 microM of enalaprilat restored approximately 55-65% of the pre-ischemic LVDP [2].
• Quantification of trandolapril and its metabolite trandolaprilat in human plasma by liquid chromatography/tandem mass spectrometry using solid-phase extraction [13].

Gene context of Trandolaprilat

• Following 6 weeks of double-blind treatment with placebo or 0.25 to 16 mg/day trandolapril, an analysis of drug effect on trough blood pressure (BP) stratified by age, gender, weight, pre-treatment plasma renin activity, and trandolaprilat concentration was performed [14].
• Since a number of interactions between ET-1 and the renin-angiotensin system have been reported previously, experiments were repeated during angiotensin converting enzyme (ACE) inhibition by trandolaprilat (2 mg/kg iv) [15].
• 1. Trandolaprilat was found to inhibit angiotensin I (Ang I)-induced contraction of the rat thoracic aorta, and to augment bradykinin(BK)-induced contraction of the guinea pig ileum [12].

Analytical, diagnostic and therapeutic context of Trandolaprilat

• These results suggest that trandolaprilat is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts and altered BK metabolism is, at least in part, involved in this effect [2].

References