Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects

Enalapril is a converting enzyme inhibitor with a prolonged duration of action. We investigated the arterial pressure and hormonal responses to angiotensin I infusion(s) in eight normotensive human volunteers at various intervals after administration of 10 mg enalapril to assess more precisely its duration of action, particularly in relationship to angiotensin II's influence on aldosterone secretion and renal vasoconstriction. In normotensive sodium-restricted subjects, there was significant attenuation (p less than 0.025) of diastolic blood pressure response to angiotensin I infusion even as long as 28 h after administration of enalapril. This was accompanied by a significant (p less than 0.02) accumulation of angiotensin I and reduction of the angiotensin II increment in response to angiotensin I infusion. In contrast to the persistent efficacy of enalapril, as assessed by angiotensin I infusion, basal levels of angiotension II had returned to control levels by 22-24 h postdrug. Yet there was a persistent reduction of diastolic blood pressure even as long as 28 h postdrug. The persistent hypotension could not be explained on the basis of changes in other potential vasoactive factors (epinephrine, norepinephrine, bradykinin, or prostaglandin), as none of these was significantly modified by enalapril administration. In summary, enalapril in a dose of 10 mg p.o. produced a significant reduction in blood pressure in this study for up to 28 h. Unlike captopril, enalapril does not modify circulating prostaglandins and kinins. Although the level of activation of the renin-angiotensin system had returned to control values 24 h after enalapril administration, there was evidence from the angiotensin I infusions of continued blockade of the angiotensin-converting enzyme for as long as 28 h.     

A single dose study of the effects of fenoldopam and enalapril in mild hypertension

Summary To clarify the contribution made by the reninangiotensin system activation to the short lived hypotensive response to fenoldopam, the haemodynamic effects of a combination of fenoldopam (100 mg) and enalapril (5 mg) were compared with fenoldopam alone, enalapril alone and placebo in a balanced, randomised, double blind, single dose study in eight hypertensive patients.Fenoldopam caused an acute fall in blood pressure which lasted approximately 3 h after dosing and was associated with a reflex tachycardia. Enalapril caused a more gradual fall in blood pressure (onset 2 h) without a reflex tachycardia.The combination of drugs produced greater reductions in blood pressure sustained for a longer period than fenoldopam alone and with a more rapid onset than enalapril alone.In combination the hypotensive effects of fenoldopam and enalapril were clearly additive and not synergistic.Activation of the renin-angiotensin system does not antagonise significantly the hypotensive effect of fenoldopam.     

Aldosterone response to metoclopramide is mediated through the autonomic nervous system in man

Summary This study primarily examines the role of the autonomic nervous system in the aldosterone response to metoclopramide since there is conflicting evidence as to the involvement of a dopaminergic mechanism in this response.Six normal male volunteers in metabolic balance at 100 mmol sodium/day and 60 mmol potassium/day constant intake received metoclopramide, 10 mg i.v., on five different occasions. The dosing was either metoclopramide alone or combined with ganglionic, muscarinic, -adrenergic or calcium-channel blockade.Metoclopramide increased serum aldosterone significantly to 163.3% of basal level at 10 min. Atropine blunted this response and the 10 min level was significantly reduced to 116.03% of the basal value. The highest aldosterone levels were attained when metoclopramide was administered during a trimethaphan infusion and a peak of 292.8% of basal level occurred at 90 min. In the presence of atenolol, with or without nifedipine, the metoclopramide-induced aldosterone response was significantly greater at 15 min than with metoclopramide alone.The results of this investigation suggest that the aldosterone response to metoclopramide is mediated by acetylcholine released from post-ganglionic cholinergic nerve terminals, and that an adrenergic mechanism exerts a tonic inhibitory influence on aldosterone secretion in man.     

The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.

The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set-point, (b) did not affect baroreflex sensitivity since the slopes of the RR-interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR-interval responses as well as the overall RR-interval-time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug-induced fall in blood pressure.     

Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats

The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction.     

Influence of enalapril on the endothelial function of DOCA-salt hypertensive rats

In the present study, we investigated whether the correction of endothelial dysfunction can be independent of the normalization of high blood pressure levels by enalapril in deoxycorticosterone (DOCA-salt) hypertensive rats. Aorta morphology and the response of aortas with (E+) and without (E-) endothelium to noradrenaline, acetylcholine, and sodium nitroprusside were studied. DOCA-salt hypertensive and normotensive (control) rats were or were not treated with enalapril (5 mg/day/rat in the drinking fluid) for 1, 7, or 15 days. Blood pressure was measured before and after 1, 3, 7, and 15 days of enalapril treatment. Enalapril normalized the high blood pressure levels in 50% (responders) of the hypertensive rats after 3 to as many as 15 days but not after 1 day of treatment. Initial blood pressure levels were not different between responders and nonresponders. Blood pressure levels of normotensive control rats were not altered by enalapril treatment. The tunica media of aortas of DOCA-salt hypertensive rats treated or not treated with enalapril for 15 days was thicker than aortas from normotensive rats. Enalapril corrected the reduced response to acetylcholine observed in aorta from hypertensive rats from the first day of treatment. This treatment rendered aortas from normotensive control rats more sensitive (lower EC(50)) to acetylcholine without a change in the maximal responses. The responses to sodium nitroprusside, a nitric oxide donor, were unaltered in aorta E+ or E- from control and hypertensive rats before and after enalapril treatment. Enalapril did not correct the increased responses to noradrenaline observed in aorta E+ of hypertensive rats. These results suggest that the high blood pressure in DOCA-salt hypertension is not correlated with the altered response to endothelium-dependent agents (either dilator or constrictors). The endothelium-dependent vasodilation by antihypertensive agents can be corrected independently of normalization of blood pressure levels or the vascular morphology.     

Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet

1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.     

EFFECT OF ENALAPRIL ON BODY SODIUM AND HANDLING OF A SODIUM CHLORIDE LOAD IN HYPERTENSIVE AND NORMOTENSIVE RATS

1. The effect of enalapril on handling of an Na load and on body Na during 96 h of zero Na intake was measured in hypertensive rats (GH and SHR) and their normotensive controls (N and WKY) by a whole body counting method. 2. Enalapril treatment led to a greater fall in body Na in the first 24 h after the Na load (as expected from the known effect of ACE inhibition on aldosterone production) and thus to a slightly faster excretion of an amount equivalent to the load. 3. Enalapril-treated rats were unable to maintain body Na on a zero Na intake. This was also expected from the known effect on aldosterone production, though other mechanisms are not excluded. The effect was more marked in the SHR and WKY than in GH and N but there was no significant difference in this effect between the hypertensives and their respective control strains.     

Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the 5-HT4 receptor

Objective: Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at 5-HT₄ receptors. The 5-HT₃ antagonist tropisetron is thought to act as an antagonist at 5-HT₄ receptors. In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the 5-HT₄ receptor in aldosterone secretion. Methods: Following a single-blind, random design, ten normal male volunteers received one of the following regimens on three occasions, with at least 2-week intervals: metoclopramide 10 mg i.v.; tropisetron 5 mg by slow i.v.i., or; tropisetron by slow i.v.i., followed by 10 mg metoclopramide i.v. Results: In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149% of basal level and remained significantly elevated for the next 20 min. With tropisetron alone, there was a significant 37.8% drop at 60 min and the aldosterone levels remained low for the duration of the experiment. Metoclopramide reversed the decline mediated by tropisetron significantly at 30 and 90 min. Aldosterone levels after the latter regimen also did not differ significantly from baseline at any time period. Conclusion: These results would suggest the existence of a tonic stimulatory influence of 5-HT via 5-HT₄ receptors on aldosterone secretion, which could be augmented by metoclopramide and blocked by tropisetron. However, the effect of tropisetron per se should be interpreted with caution given the lack of a saline group Received: 25 April 1995/Accepted in revised form: 4 December 1995     

The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus.

The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components of the renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses. Six ewes received 1 mg kg-1 enalapril i.v. while 3 were given 2 mg kg-1. Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90 min after administration (P less than 0.001, P less than 0.002 respectively). The maximum tachycardia was seen at 60 min (P less than 0.05). The foetuses of the ewes given 1 mg kg-1 enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P less than 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P less than 0.05) but were almost at basal levels by the end of the experiment. Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of 1 mg kg-1, and 25-30 min after the administration of 2 mg kg-1. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. Enalapril at 1 mg kg-1 thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-1, and there was an unexpected foetal death in this group.     

依那普利对肝纤维化大鼠门静脉血流动力学及基质金属蛋白酶1组织抑制剂表达的影响

目的 探讨血管紧张素转换酶抑制剂（ACEI）依那普利对肝纤维化大鼠门静脉血流动力学和基质金属蛋白酶1组织抑制剂（TIMP-1）表达的影响. 方法 30只大鼠完全随机分为正常对照组、模型组、治疗组,每组10只.模型组和治疗组通过四氯化碳（CCl4）损伤制备肝纤维化门静脉高压模型,治疗组在造模的同时用依那普利灌胃.3组大鼠均测量门静脉压（PVP）、平均动脉压（MAP）、门静脉血流速度（BFR）;进行肝纤维化分级和胶原沉积半定量检测;检测TIMP-1的蛋白及mRNA表达并进行半定量分析. 结果 模型组的PVP高于正常对照组和治疗组,治疗组亦高于正常对照组均（P＜0.05）;模型组和治疗组的MAP均低于正常对照组（均P＜0.05）;模型组的BFR明显低于正常对照组和治疗组（均P＜0.05）.模型组肝纤维化V级的大鼠明显多于治疗组（P＜0.05）,模型组和治疗组肝细胞变性/坏死（＋）及（＋＋）的大鼠明显多于正常对照组（P＜0.01）,模型组和治疗组炎性细胞浸润（＋）及（＋＋）的大鼠明显多于正常对照组（P＜0.01或P＜0.05）.治疗组和模型组的胶原沉积面积[（6.393±2.113）×10-2、（10.030±3.565）×10-2]均明显大于正常对照组[（1.538±0.458）×10-2,均P＜0.01],但治疗组明显小于模型组（P＜0.01）.治疗组与模型组比较TIMP-1的蛋白表达有明显下降,TIMP-1 mRNA的表达亦有明显下降,但模型组和治疗组两指标明显高于正常对照组（均P＜0.05）. 结论 依那普利可以有效地改善肝纤维化大鼠的门静脉血流动力学;亦可有效地下调CCl4引起的肝纤维化大鼠TIMP-1的蛋白和mRNA表达,进而抑制大鼠肝纤维化的发展.     

INCREASE IN SERUM TOTAL ANGIOTENSIN-CONVERTING ENZYME ACTIVITY WITH ENALAPRIL THERAPY IN HUMANS: A CONTROLLED TRIAL

1. In a controlled, randomized double-blind trial, 15 patients with essential hypertension were treated with enalapril 5-20 mg/day, or doxazosin 1-8 mg/day, during a 7 week dose titration phase. This was followed by 7 weeks of combined treatment with doxazosin and enalapril. 2. Blood was taken after a 2 week placebo run-in phase, and at 3 and 7 weeks in the single-agent and combined treatment phases, for measurement of plasma renin activity (PRA), plasma angiotensin II (AII), plasma aldosterone and serum free and total angiotensin-converting enzyme (ACE) activities. 3. Doxazosin had no effect on serum free or total ACE activities. 4. Enalapril reduced serum free ACE activity and increased serum total ACE activity, which at 7 weeks was significantly greater than in patients receiving doxazosin. 5. In those patients who received enalapril, 10 mg/day for 3 weeks and then 20 mg/day for 4 weeks (n = 12), with or without doxazosin, mean serum total ACE activity increased by 51%. PRA was also increased in this group, but there were no changes in plasma AII or aldosterone concentrations.     

The role of the renin-angiotensin system in the control of cell communication in the heart: effects of enalapril and angiotensin II.

The influence of the renin-angiotensin system on the control of cell communication was investigated in isolated ventricular cell pairs of adult rats. It was found that angiotensin II (1 microgram/ml) reduced the junctional conductance (gj) by about 55% within 20 s. This effect of angiotensin II was suppressed by DuP 753--an angiotensin receptor blocking agent. Enalapril (1 microgram/ml)--an angiotensin converting enzyme inhibitor--caused an increase in junctional conductance (106%) within 2 min. The effect of enalapril on gj was not related to activation of beta-adrenergic receptors or cAMP-dependent protein kinase. The effect of angiotensin II on gj was suppressed by staurosporine--a potent inhibitor of protein kinase C. This finding indicates that the peptide is changing gj through activation of protein kinase C. The increase in cell coupling caused by enalapril raises the possibility that the antiarrhythmic action of enalapril as well its effect in congestive heart failure are related to an increase in electrical synchronization of cardiac myocytes.     

Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.     

TIME COURSE OF CHANGES IN BLOOD PRESSURE, ALDOSTERONE AND BODY FLUIDS DURING ENALAPRIL TREATMENT: A DOUBLE-BLIND RANDOMIZED STUDY VS HYDROCHLOROTHIAZIDE PLUS PROPRANOLOL IN ESSENTIAL HYPERTENSION

Aldosterone suppression is said to play a major role in the long term hypotensive efficacy of angiotensin converting enzyme inhibitors. However, in previous reports from other laboratories, plasma volume has been found mostly increased and sodium balance sometimes positive. The effects of the angiotensin converting enzyme inhibitor enalapril (10-40 mg/day, p.o., for 6 weeks) on blood pressure, body fluid volumes, renal function and plasma aldosterone were compared to those of hydrochlorothiazide (50 mg/day, p.o.) alone for 2 weeks and in association with propranolol (80-160 mg/day, p.o.) for 4 more weeks during a randomized double-blind parallel study in 14 essential hypertensives. Hydrochlorothiazide alone and in combination with propranolol induced slight and not significant change in either blood pressure and body fluids. The maximum hypotensive response to enalapril was achieved only after 2 weeks of continuous treatment possibly because after 1 week the hypotensive efficacy was lessened by a significant (P less than 0.05) fluid retention secondary to a transient and not significant fall in renal perfusion. At this time aldosterone was not significantly changed compared to pretreatment values. After 6 weeks on enalapril, blood pressure was significantly reduced, plasma aldosterone further but not significantly decreased and extracellular fluid volume was normal. These findings indicate that aldosterone suppression contributes to the blood pressure lowering effect of enalapril by offsetting the salt and water retention observed on starting treatment and due to direct vasodilation.     

Attenuation of alcohol intake by a serotonin uptake inhibitor: Evidence for mediation through the renin-angiotensin system

Although the serotonin uptake inhibitors have been shown to reduce alcohol intake in both animals and man, the mechanism of this effect is unclear. It is known that enhanced serotonergic activity can stimulate activity in the renin-angiotensin system and that elevated activity in the renin-angiotensin system can reduce voluntary alcohol intake. Therefore, serotonin uptake inhibitors such as fluoxetine might exert their effect on alcohol intake, in part, through the renin-angiotensin system. The present experiment assesses this possibility by examining the effect of the angiotensin converting enzyme inhibitor, enalapril, on the fluoxetine-induced decrease in alcohol intake. Four groups of rats were offered limited access to alcohol for 1 hr each day. When intake stabilized each group was injected with 2.5, 5.0 or 10.0 mg/kg of fluoxetine or the saline vehicle 1 hr prior to the access to alcohol. Fluoxetine produced a dose-dependent decrease in alcohol intake. Following this, all groups received injections of 1 mg/kg of the angiotensin converting enzyme inhibitor, enalapril, 40 min prior to the fluoxetine. Enalapril had no effect on alcohol intake in the saline group, but reversed the suppression in alcohol intake produced by the 2.5 mg/kg and 5.0 mg/kg doses of fluoxetine and partially reversed the effect of the 10.0 mg/kg dose. These findings indicate that the fluoxetine-induced reduction in alcohol intake may, in part, be mediated through the renin-angiotensin system.     

A randomized cross-over study of enalapril in congestive heart failure: Haemodynamic and hormonal effects during rest and exercise

Summary We performed a randomized double-blind placebo controlled cross-over study of enalapril in 16 patients with chronic congestive heart failure, to assess haemodynamic and hormonal effects at rest and on exercise. Acute effects were measured 4 h after enalapril 10 mg, and chronic effects after 6 weeks treatment with enalapril 10–20 mg per day.Exercise tolerance, assessed by the duration of a maximal bicycle ergometer test, was not altered by enalapril. Mean blood pressure was reduced after enalapril, at rest and on exercise, acutely by 7% and 8% respectively, and chronically by 14% and 16%. Systemic vascular resistance was reduced by 16% at rest both acutely (NS) and chronically (p<0.05). The resting pulmonary capillary wedge pressure was reduced by 28% with chronic treatment. In the acute study, total body oxygen consumption on exercise was 26% higher after enalapril. Chronically, resting oxygen consumption was reduced by 13% after enalapril, with mixed venous oxygen saturation increasing by 16%.In the acute study enalapril increased plasma renin activity at rest and on exercise by 181% and by 189%, and reduced aldosterone by 49% (NS) and 39% (p<0.05), and these effects were sustained after 6 weeks. Enalapril increased antidiuretic hormone concentrations at rest acutely by 73% (NS) and chronically by 34% (p<0.05) but not on exercise; the increase in the acute study correlated with plasma enalaprilat levels (r=0.66, p<0.05). Enalapril did not alter plasma catecholamine concentrations.Patients preferred enalapril to placebo, and radiographic heart size was reduced during chronic treatment. There were no serious adverse effects.We conclude that enalapril is an effective angiotensin converting enzyme inhibitor of clinical value in chronic heart failure, but study design and methods of assessment of benefit can have a major influence on the results of pharmacological studies in such patients.     

Enalapril: pharmacokinetic/dynamic inferences for comparative developmental toxicity. A review.

Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the second and third trimester of pregnancy in humans is associated with specific fetal and neonatal injury. The syndrome, termed "ACEI fetopathy" in humans, does not appear to have a similar counterpart in experimental animals. The present paper reviews pharmacokinetic and pharmacodynamic aspects of enalapril that are physiologically important during pregnancy and intrauterine development in humans and in experimental animal species with the aim of better understanding the comparability of the manifestations of enalapril developmental toxicity in animals and humans. The human fetus is at a disadvantage with regard to in utero enalapril exposure in comparison to some of the animal species for which gestational pharmacokinetic data are available. Important reasons for the higher vulnerability of the human fetus are its accessibility by enalapril and the earlier (relative to animal species) intrauterine development of organ systems that are specific targets of ACEI pharmacologic effect (the kidney and the renin-angiotensin system). In humans, these systems develop prior to calcarial ossification at the end of first trimester of pregnancy. The specific pharmacodynamic action of enalapril on these systems during fetal life is the chief determinant of the etiology and pathogenesis of ACEI fetopathy in humans. In contrast, in most of the studied animal species, these target systems are not developed until close to term when the fetus is relatively more mature (and therefore less vulnerable), so that the window of vulnerability is narrower in comparison to the human. Among animal species, the best concordance in fetal pharmacodynamics to the human is seen in the rhesus monkey, but further studies are necessary to determine if similar developmental pathology is induced in this animal model upon repeated administration of the drug during the relevant period of intrauterine development. Animal-human concordance of developmental toxicity is least likely in the rat because of greater disparities in enalapril availability to the fetus and the relative development of the kidney and skeletal ossification compared to that in humans.     

依那普利辅助治疗慢性肺心病

目的：探讨依那普利辅助治疗慢性肺心病的疗效。方法：慢性肺心病９８例，分为２组，依那普利组５８例（男性３１例，女性２７例；年龄６２±ｓ８ａ），给依那普利２．５ｍｇ，ｐｏ，ｔｉｄ，加常规疗法（头孢唑林３ｇ，ｉｖ，ｇｔ，ｂｉｄ；阿米卡星０．４ｇ，ｉｖ，ｇｔ，ｑｄ；氨茶碱０．１ｇ，ｐｏ，ｔｉｄ）。对照组４０例（男性２１例，女性１９例；年龄６３±７ａ）仅给常规疗法（用法同上）。２组疗程均２ｗｋ。结果：依那普利组治疗后ＣＩ，ＥＦ，ＣＯ，ＳＶ，ＦＶＣ，ＦＥＶ１，ＭＭＦ，ＰＥＦ，Ｐａｏ２，Ｐａｃｏ２，ＲＶＤ，ＲＶＯＴ改善较治疗前及对照组有显著差异（Ｐ＜０．０５或＜０．０１）。依那普利组临床总有效率９７％，显著高于对照组（８０％）（Ｐ＜０．０１），且不良反应少。结论：依那普利辅助治疗慢性肺心病疗效佳。     

Effects of enalapril on changes in cardiac output and organ vascular resistances induced by alpha 1- and alpha 2-adrenoceptor agonists in pithed normotensive rats.

1. Cardiac output, its distribution and regional vascular resistances were determined with tracer microspheres in pithed rats in the presence of the angiotensin converting enzyme inhibitor enalapril. The effects of enalapril on the cardiovascular responses elicited by either the alpha 1-adrenoceptor agonist phenylephrine or the alpha 2-adrenoceptor agonist xylazine were determined. 2. Enalapril decreased diastolic and mean blood pressure by decreasing cardiac index and total peripheral resistance. It induced vasodilatation in the kidney, epididimides, epididimidal fat and pancreas/mesentery. Vasoconstriction in the lungs, testes and liver was evident following enalapril administration as well as a decrease in the proportion of cardiac output passing to them, whilst the pancreas and mesentery received a greater proportion of the cardiac output. All the above effects of enalapril were reversed by infusion of angiotensin II at a rate of 75 ng kg-1 min-1. 3. Xylazine increased blood pressure by increasing both cardiac output and total peripheral resistance. Enalapril did not affect the increase in cardiac output caused by xylazine but decreased the effect of the alpha 2-agonist on blood pressure by preventing the increase in total peripheral resistance. Inhibition by enalapril of xylazine-induced vasoconstriction in the kidneys, testes, fat and gastrointestinal tract contributed to the decrease in total peripheral resistance. Enalapril also inhibited xylazine-induced changes in cardiac output distribution to the liver, lungs and heart. All the above effects of enalapril were reversed by infusion of angiotensin II. 4. Enalapril decreased the sustained phase of the pressor response to an infusion of phenylephrine whilst having no effect on the initial peak pressor response to a bolus injection of phenylephrine. Phenylephrine increased both cardiac output and total peripheral resistance and enalapril abolished its effect on total peripheral resistance whilst having no effect on the increase in cardiac output. Enalapril inhibited phenylephrine-induced vasoconstriction in the testes, fat, muscle, spleen and gastrointestinal tract. Enalapril also inhibited phenylephrine-induced changes in cardiac output distribution to the lungs and liver. The infusion of angiotensin II did not fully reverse the inhibitory effect of enalapril either on the phenylephrine-induced increases in diastolic blood pressure or on the vasoconstriction in the fat, spleen and gastrointestinal tract, but did reverse all other effects of enalapril.(ABSTRACT TRUNCATED AT 400 WORDS)