THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.     

Differential systemic and regional hemodynamic profiles of four angiotensin-I converting-enzyme inhibitors in the rat

Summary Angiotensin-converting enzyme (ACE) inhibitors decrease blood pressure by reducing systemic vascular resistance. That the peripheral vasodilating properties of ACE inhibitors might not be homogeneously distributed in all vascular beds and might differ from one drug to another has been investigated in the normotensive rat by the pulsed Doppler technique using the active components of four different ACE inhibitors: captopril, enalapril, perindopril, and ramipril.Systemic (cardiac output and blood pressure) and regional (kidney, mesentery, hindquarter) hemodynamic responses to saline or to cumulative bolus injections (0.01–1 mg/kg) of captopril, enalaprilat, perindoprilat, or ramiprilat were continuously monitored. The effects of successive bolus injections (0.3–300 ng/kg) of angiotensinII were also investigated. The four ACE inhibitors produced an almost complete blockade of plasma angiotensin-II converting-enzyme activity (83%, 100%, 100%, and 100%, respectively), induced dose-dependent decreases in mean blood pressure, did not significantly affect cardiac output, and reduced total peripheral and mesenteric vascular resistances to the same extent. Hindlimb vascular resistance was identically decreased, but to a lower extent than total peripheral resistance by enalaprilat, perindoprilat, and ramiprilat, whereas it was increased by captopril at low doses only. Renal resistance was markedly decreased by the four drugs, and éspecially by captopril. The decreasing rank order for ACE-inhibitor-induced vasodilation is exactly the same (renal>total peripheral=mesenteric >hindlimb vascular resistances) as that of angiotensin-II-induced regional vasoconstriction, indicating that the vasodilator properties of ACE inhibitors are mainly due to angiotensin-II vasomotor tone suppression. None of the investigated compounds significantly affected mesenteric and hindlimb blood flows, except captopril, which lowered the latter significantly. Finally, the four drugs increased renal blood flow markedly.Thus, the four drugs exhibited different regional vasodilating patterns, those of enalaprilat, perindoprilat, and ramiprilat being almost similar, while that of captopril was different.     

Effects of digoxin, furosemide, enalaprilat and metoprolol on endothelial function in young normotensive subjects

1. Endothelial dysfunction is seen in patients with essential hypertension or congestive heart failure (CHF). The present study aimed to evaluate the direct effect on endothelium- dependent vasodilation (EDV) of different pharmacological drugs commonly used in the treatment of these conditions. 2. Forearm blood flow (FBF) was measured in 37 young healthy normotensive subjects with venous occlusion plethysmography during local intra-arterial infusions of methacholine (MCh; 2-4 microg/min), evaluating EDV, and sodium nitroprusside (SNP; 5-10 microg/min), evaluating endothelium-independent vasodilation (EIDV). The measurements of EDV and EIDV were undertaken under baseline conditions and were repeated after 1 h intra-arterial infusion of digoxin (0.1 mg/h), furosemide (5.0 mg/h), enalaprilat (2,4 mg/h), metoprolol (1.2 mg/h) or saline (controls). 3. Enalaprilat and digoxin improved the FBF response to MCh at 4 microg/min (from 22.7+/-2.3 to 25.5+/-2.1 mL/min per 100 mL tissue (P < 0.01) and from 18.2+/-2.4 to 22.2+/-2.0 mL/min per 100 mL tissue (P < 0.05), respectively). No significant changes where induced by furosemide or metoprolol in response to MCh at 4 microg/min (from 19.4+/-2.0 to 22.9+/-2.8 and from 15.3+/-2.4 to 14.7+/-1.1 mL/min per 100 mL tissue, respectively). No significant changes in basal FBF or EIDV were induced by the different drugs. When the endothelial function index was calculated as the MCh: SNP FBF ratio, a significant improvement was seen only with enalaprilat (1.1+/-0.1 to 1.2+/-0.1; P < 0.01) and furosemide (1.0+/-0.1 to 1.3+/-0.4; P < 0.05). 4. In conlusion, the results of the present study show that enalaprilat and furosemide improve endothelial vasodilatory function, while no major effect was induced by digoxin or metoprolol. Thus, different direct effects on the endothelium in young normotensive subjects were induced by drugs commonly used in the treatment of hypertension or CHF.     

静脉注射依那普利拉治疗重症高血压的疗效及安全性

目的验证国产依那普利拉（Ｅ）治疗重症高血压的降压疗效及安全性，以提供高血压急症的新药。方法对上海、镇江、扬州等４家医院收治的１７２例高血压病重症患者，男１１８例，女５４例，平均年龄（５３±９）岁，静脉注射Ｅ。分组：（１）对三组高血压病（各１０例）分别静脉注射Ｅ１．２５ｍｇ、２．５ｍｇ、５ｍｇ；（２）Ｅ与甲磺酸酚妥拉明（Ｐ）各５４例单次静脉注射开放平行比较试验；（３）３４例为２４小时内多次静脉注射Ｅ（ｑ６ｈ），观察２４小时内血压、心率及不良反应。结果结果显示：（１）不同剂量Ｅ静脉注射以２５ｍｇ降压效果最好；（２）两组比较：用药后２、４、６小时Ｅ组降压幅度优于Ｐ组（Ｐ＜０．０５），总有效率为９６．３％，Ｐ组总有效率９０７％；（３）２４小时多次给Ｅ，总有效率达１００％。Ｅ主要不良反应：轻度头昏（６／１１８）、头痛（２／１１８）、肢体麻木（４／１１８）及咳嗽（５／１１８）。结论国产Ｅ是一种安全有效的治疗高血压急症用药，我们推荐静脉首选剂量２．５ｍｇ为宜。     

Passive and Carrier-Mediated Intestinal Absorption Components of Two Angiotensin Converting Enzyme (ACE) Inhibitor Prodrugs in Rats: Enalapril and Fosinopril

The intestinal absorption mechanism of two ACE inhibitor prodrugs, enalapril and fosinopril, was investigated in rats using a single-pass perfusion method. A modified boundary layer solution was applied to determine the apparent intestinal wall permeability. The prodrug enalapril is well absorbed from rat jejunum, whereas the parent drug, enalaprilat, is poorly absorbed. The permeability of enalapril is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine but not by the amino acids L-leucine or L-phenylalanine, indicating a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast, fosinopril is readily absorbed by a concentration-independent mechanism without the involvement of the peptide carrier.     

Formed and preformed metabolite excretion clearances in liver,a metabolite formation organ: Studies on enalapril and enalaprilat in the single-pass and recirculating perfused rat liver

Single-pass and recirculating rat liver perfusion studies were conducted with [¹⁴C]enalapril and [³H] enalaprilat, a precursor-product pair, and the data were modeled according to a physiological model to compare the different biliary clearances for the solely formed metabolite, [¹⁴C]enalaprilat, with that of preformed [³H]enalaprilat. With single-pass perfusion, the apparent extraction ratio (or biliary clearance) of formed [¹⁴C]enalaprilat was 15-fold the extraction ratio of preformed [³H] enalaprilat, an observation attributed to the presence of a barrier for cellular entry of the metabolite. Upon recirculation of bolus doses of [¹⁴C]enalapril and [³H]enalaprilat, the biliary clearance, estimated conventionally as metabolite excretion rate/midtime metabolite concentration, for formed [¹⁴C]enalaprilat was again 10-to 15-fold higher than the biliary clearance for preformed [³H]enalaprilat, but this decayed with perfusion time and gradually approached values for preformed [³H]enalaprilat. The decreasing biliary clearance of formed enalaprilat with recirculation was explained by the dual contribution of the circulating and intrahepatic metabolite (formed from circulating drug) to excretion. Physiological modeling predicted (i) an influx barrier (from blood to cell) at the sinusoidal membrane as the rate-limiting process in the overall removal of enalaprilat, (ii) a 15-fold greater extraction ratio or biliary clearance for formed [¹⁴C]enalaprilat over [³H]enalaprilat during single-pass perfusion, and (iii) the time-dependent and declining behaviour of the biliary clearance for formed [¹⁴C]enalaprilat during recirculation of the medium. In the absence of a direct knowledge of eliminating organs in vivo, this variable pattern for excretory clearance of the formed metabolite within the organ is indicative of a metabolite formation organ.Glossary C _R denotes the reservoir concentration - C _In andC _Out,L respectively, denote the input and output concentrations. - Q _L is the total hepatic plasma flow rate. - Q _Bile is the bile flow rate - f _p and f_L denote the unbound fractions in plasma and liver tissue, respectively - C_p is the concentration in renal plasma; C_L is the concentration in liver; - C _Bile is the concentration in bile. - v _R,V _p,V _L, andV _Bile denote the reservoir plasma, hepatic plasma, tissue, and bile volumes, respectively - CL _d ⁱⁿ andCL _d ^ef denote the influx and efflux clearances, respectively - CL _int,L ^m ,L represents the hepatic metabolic intrinsic clearance of the drug - CL _int,L ^b L denotes the biliary intrinsic clearance This work was supported by the Medical Research Council of Canada. I. A. M. de Lannoy was a recipient of the Ontario Graduate Fellowship from the Ontario Ministry of Health; K. S. Pang was a recipient of the Faculty Development Award, Medical Research Council, Canada.     

Inhibition of pulmonary endothelial angiotensin converting enzyme activity by trandolaprilat in vivo

The purpose of the present study was to contrast a commonly used ACE inhibitor (enalaprilat) with a novel ACE inhibitor (trandolaprilat) in their ability to inhibit 1) pulmonary capillary endothelial-bound ACE activity in vivo, 2) arterial pressure responses to i.v. angiotensin I and bradykinin, and 3) selected tissue ACE activity ex vivo, in rabbits. Pulmonary capillary endothelium-bound ACE activity in vivo was estimated via the single pass transpulmonary hydrolysis of the substrate ³H-Benzoyl-Phenylalanyl-Alanyl-Proline (BPAP). Doses of acutely administered trandolaprilat (8 μg/kg) or enalaprilat (10 μg/kg) were equieffective in reducing the pressor response to angiotensin I. At these doses, trandolaprilat produced a greater inhibition of pulmonary capillary endothelial-bound ACE activity (66.5 ± 4.7% reduction of baseline BPAP metabolism vs. 52.7 ± 4.2% by enalaprilat, P < 0.05). Chronically administered trandolaprilat (8 μkg/day for 8 days) was more effective than enalaprilat (either 8 μg/kg/day or 10 μg/kg/day for 8 days) in reducing the angiotensin-1 induced increase in mean arterial pressure (increases of 9.7 ± 1.4 mmHg vs. 20.3 ± 2.3 mmHg and 19.1 ± 5.7 mmHg respectively; P < 0.01), as well as in reducing BPAP metabolism. In agreement with in vivo data, trandolaprilat was 5.5-, 3.6-, and 2.5-times more effective than enalaprilat in reducing ACE activities in the aorta, left ventricle, and lung, respectively. We conclude that trandolaprilat is a more potent, longer acting, and more tissue-selective ACE inhibitor than enalaprilat, and that the method outlined here can be used to aid in the development of tissue-specific ACE inhibitors. Drug Dev. Res. 41:22–30, 1997. © 1997 Wiley-Liss, Inc.     

Intravenous enalaprilat and autonomic reflexes

Thirty healthy patients, who were to undergo surgery which required tracheal intubation, were given an intravenous injection of enalaprilat (either 0.5 mg, 1 mg, 2 mg or 4 mg; six patients for each dose) or normal saline 17 minutes before induction of anaesthesia with thiopentone 3-5 mg/kg, and suxamethonium 1.5 mg/kg. Postural manoeuvres were performed 5 minutes before and 6, 11 and 16 minutes after enalaprilat or saline. Complete inhibition of angiotensin converting enzyme occurred with all doses of enalaprilat, which allowed the four different treatment groups to be considered as one large treated group. The mean arterial pressure was almost unchanged during the postural manoeuvres; the heart rate increased, mostly similarly (by approximately 10%) in both groups. Mean arterial pressure in the recumbent position decreased over the 17 minutes before induction in the enalaprilat group, and increased slightly in the control group (treated mean, -5.0%; controls mean, 1.8%; difference, -6.8%; 95% confidence intervals of difference, -2.3 to -11.3%, p less than 0.01). This difference was again seen after induction (treated, -8.0%; controls, 7.7%; confidence intervals of difference, -0.6 to -31%) and for a 5-minute period shortly after tracheal intubation. The increases in mean arterial pressure produced by intubation itself were similar in both groups (treated, + 36%; controls, + 35%; 95% confidence intervals of difference, -16% to + 18%). Changes in heart rate after induction were also similar in both groups. It is concluded that intravenous enalaprilat acted as a hypotensive agent with a sparing effect on autonomic reflexes, both before and after induction of anaesthesia.