ACE抑制剂卡托普利对实验性围手术期心肌缺血的影响

目的:图手术期心肌缺血主要是因为应激引起冠状动脉内皮功能障碍所致,所以观察卡托普利对其影响。方法:杂种犬20只均分为4组:Ⅰ组(对照组),Ⅱ组(心肌梗塞模型组),Ⅲ组(心梗 胃大部切除术)和Ⅳ组(心梗 卡托普利 胃大部切除术)。心梗2周后行胃大部分切除术,测定Ⅲ、Ⅳ两组的基础状态、术前和术后的血流动力学指标、血浆内皮素(ET)及一氧化氮(NO)。用组织原位杂交方法观察4组非梗塞区冠脉内皮-氧化氮合酶(NOS)mRNA表达水平。结果:在Ⅲ组,手术使LV dP/dt_(max)、心脏指数(CI)及NO下降,引起LVEDP、PCWP、总外周阻力(TPR)、左室舒张压力下降时间常数(T值)和ET升高。在Ⅳ组,用卡托普利后40min,TPR下降,T值升高;手术使血流动力学指标回降,不影响其它指标。组织原位杂交示,NOS mRNA在Ⅰ组高度表达,Ⅱ组和Ⅳ组次之,Ⅲ组最低。结论:卡托普利能预防胃大部切除术引起的左室舒缩障碍和冠脉内皮功能障碍。     

Control of essential hypertension with captopril, an angiotensin converting enzyme inhibitor.

1 Captopril, an orally active angiotensin converting enzyme inhibitor, was compared with hydrochlorothiazide (HCT) in the treatment of mild and moderate essential hypertension. 2 Twenty outpatients received no antihypertensive therapy for 2 weeks, after which they were given placebo for 8 weeks. Since their diastolic blood pressure remained above 100 mm Hg, they were then randomized to receive either captopril (twelve patients) or HCT (eight patients) for a 4-week titration period. If the supine diastolic blood pressure (SDBP) was normalized, (less than or equal to 90 mm Hg) by the end of titration period, the established regimen was continued for an 8-week maintenance period; if not, the alternate drug was added in increasing doses for up to 4 weeks and the combined therapy was maintained for the remaining 4 weeks. 3 After the first 4 weeks of therapy, both groups showed a statistically significant decrease in both systolic and diastolic blood pressure. Normalization of SDBP occurred in 75% of patients treated with captopril alone, and the addition of HCT produced normalization in the remainder. HCT alone resulted in normalization of SDBP in 50% of patients and the blood pressure of the remaining patients was normalized after the addition of captopril. 4 Captopril given orally, either alone or in conjunction with HCT, is an effective agent for the control of mild and moderate essential hypertension. 5 In our series the main side effects encountered were vertigo and dizziness, transient eosinophilia, a rise of BUN and or/a rise of SGPT or SGOT.     

Different effects of captopril and other angiotensin converting enzyme inhibitors on cardiovascular preparations.

The effects of captopril and of other angiotensin-converting enzyme inhibitors (zofenopril, fosenopril and enalaprilic acid) were tested on the isolated rabbit heart and aorta. Captopril elicited an erratic negative inotropic effect and a reduction in basal coronary perfusion pressure (10(-5)-10(-4) M). The increase of coronary perfusion pressure induced by vasopressin, methoxamine, angiotensin II and Bay K 8644 was partially antagonized by captopril (10(-7)-10(-4) M) in a non-specific manner. These actions were not modified by saralasin or indomethacin and by ex vivo pretreatment with captopril itself. On the aortic strips, the contraction plateau induced by KCl and angiotensin II was partially inhibited (10(-6)-10(-4) M), while no effect was observed on those induced by noradrenaline, serotonin and PGF2 alpha. The Ca2+ concentration-response curve appeared shifted to the right in a non-competitive manner. The other angiotensin-converting enzyme inhibitors showed no effect up to 10(-4) M on isolated heart or aorta. Results obtained with captopril were consistent with vasorelaxant activity independent of the tissue renin-angiotensin system. Modulatory activity on the intracellular calcium movement may be involved.     

Anti-atherosclerotic effects of an angiotensin converting enzyme inhibitor and an angiotensin II antagonist in Cynomolgus monkeys fed a high-cholesterol diet.

1. We investigated the relationship between angiotensin II formation and the development of atherosclerotic lesions in the aorta of monkeys (Macaca fascicularis) fed a high-cholesterol (4% cholesterol and 6% corn oil) diet for 6 months, and studied the effects of an angiotensin converting enzyme (ACE) inhibitor, trandolapril (10 mg kg-1 per day, p.o.), and an angiotensin II type 1 receptor antagonist, 2-butyl-4-(methylthio)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl] (1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR 720; 20 mg kg-1 per day, p.o.). 2. The level of low-density lipoprotein was significantly increased by the cholesterol diet, whereas that of high-density lipoprotein was significantly decreased. The relative areas of the atherosclerotic lesions in the thoracic aorta in the normal and cholesterol-diet groups were 1.3+/-0.3 and 64+/-10%, respectively. 3. Plasma renin and ACE activities showed no differences between the normal and cholesterol-diet groups. ACE activity and the concentration of angiotensin II were significantly increased in the aorta of the cholesterol-fed monkeys. 4. Trandolapril and HR 720 decreased significantly the area of the atherosclerotic lesions in the thoracic aorta of cholesterol-fed monkeys, but not the mean blood pressure and the levels of low-density and high-density lipoproteins. 5. In plasma and aorta, trandolapril, but not HR 720, decreased significantly the ACE activities in the cholesterol-fed monkeys, while both of these drugs decreased significantly the angiotensin II levels. 6. In conclusion, blockade of angiotensin II function in vascular tissues by trandolapril or HR 720 may play an important role in preventing the development of atherosclerotic lesions.     

Effects of the angiotensin converting enzyme inhibitor, captopril, in essential hypertension

1 Plasma and biliary concentrations of amoxycillin and ceftriaxone were measured after bolus intravenous administration (500 mg) in four subjects with normal hepato-biliary and renal function. 2 The mean plasma elimination half-life for ceftriaxone (t 1/2 = 330 +/- 30 min) was considerably longer than that for amoxycillin (t 1/2 = 60 +/- 9 min). 3 The biliary concentration of ceftriaxone was above plasma concentration of the drug throughout the study period, whereas amoxycillin concentration in the bile was lower than that in plasma. 4 Both plasma and biliary concentrations of ceftriaxone were substantially higher than previously determined minimum inhibitory concentration (MIC) values for E. coli (and several other common biliary tract pathogens) for over 6 h following drug administration. Amoxycillin concentration in plasma fell below MIC by 2 h, and did not reach inhibitory concentrations in bile.     

Effect of angiotensin II and captopril on renal tubular function in man.

The effects of nonpressor doses of intravenous angiotensin II and of the converting enzyme inhibitor captopril on renal excretory function were investigated in eight healthy volunteers during sustained water diuresis on a constant intake of 150 mmol sodium per day. The angiotensin II-analogue val5-angiotensin II-asp1-beta-amide was infused i.v. at an average dose of 2.6 ng kg-1 min-1 which was the highest dose without a significant effect on arterial blood pressure. This subpressor dose of angiotensin II significantly decreased urine volume, urinary excretion of sodium, chloride and phosphate and distal delivery [(CH2O + CCl)/GFR X 100] in the absence of changes in GFR or distal fractional chloride absorption [CH2O/(CH2O + CCl)]. In a second series of experiments, an oral dose of 50 mg of the angiotensin I-converting enzyme inhibitor captopril was given to the sodium replete volunteers. In this study, captopril did not affect arterial blood pressure, GFR or any of the determined parameters of renal tubular function. Our results strongly suggest that the nonpressor dose of angiotensin II induced renal retention of sodium chloride via increased absorption in the proximal tubule. Thus, they further support the concept that angiotensin II participates in the regulation of renal sodium chloride excretion by affecting proximal tubular absorptive capacity. However, in the sodium replete stage, angiotensin II is of no major importance in regulating sodium chloride excretion.     

Enalapril: a new angiotensin converting enzyme inhibitor

Enalapril maleate is a new angiotensin converting enzyme inhibitor marketed in the U.S. by Merck Sharp and Dohme. It has been demonstrated to actively interfere with the renin-angiotensin-aldosterone system. This is reflected by both hemodynamic (decreased blood pressure) and humoral (increased plasma renin, angiotensin I, and decreased angiotensin II) responses to enalapril therapy. Activity in the kallikrein-bradykinin system is still controversial. Enalapril maleate is a prodrug which is quickly absorbed, hydrolyzed by the liver to the active metabolite enalaprilic acid, and excreted 33 percent in the bile and 61 percent in the urine. The therapeutic dosage range is 10-40 mg/d, maximum of 40 mg, given once or twice daily. The onset and duration of action are dose related. Vertigo and headache have been the most commonly reported side effects. Clinical comparison of enalapril to hydrochlorothiazide, beta-adrenergic blockers, and captopril find it efficacious in the treatment of essential hypertension. Efficacy in treating congestive heart failure and hypertension secondary to renal artery stenosis has also been demonstrated for both angiotensin converting enzyme inhibitors. The overall efficacy and safety of enalapril and captopril appear equivalent when used at low doses in patients with uncomplicated hypertension.     

Specific direct radioimmunoassay of angiotensin II (AT II) in human plasma and the effect of angiotensin converting enzyme (ACE) inhibitor

Specific direct radioimmunoassay of angiotensin II (AT II) in human plasma was developed to evaluate the dynamics of endogenous AT II in various types of hypertension. Detection limit of this method was less than 2.3 pg/ml, and normal value is less than 25 pg/ml. Cross reactivity of antibody with AT I and III was 0.037% and 21%, respectively. There were good correlation between the value measured by direct method, and that of extraction method (r = 0.96, P < 0.01) and plasma renin activity (r = 0.80, P < 0.01). By oral administration of ACE inhibitor (captopril 50 mg), AT II levels were suppressed to 10 pg/ml or less in most patients with essential hypertension, renal parenchymal hypertension and renovascular hypertension up to 2 h. However, AT II levels in patients treated with ACE inhibitors chronically were not different from the AT II levels in patients without ACE inhibitor. In primary aldosteronism AT II was extremely low levels. AT II markedly increased by the stimulation test using furosemide (1 mg/kg i.v.). These results suggest that this method may be useful to clarify the pathophysiology of hypertension and the escape of the inhibition by ACE inhibitor.     

The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor

It is well-known that angiotensin converting enzyme (ACE) inhibitor not only decreases blood pressure (BP) but also improves insulin sensitivity. To elucidate the mechanisms of these actions of ACE inhibitor, we evaluated its effect on both BP and insulin sensitivity (M-value) as estimated by the glucose clamp technique in essential hypertensives in comparison with the effect of angiotensin receptor (AT) antagonist. We also evaluated the effect of ACE inhibitor on BP, M-value and muscle fiber composition in fructose-fed rats (FFR) as an insulin-resistant hypertensive model with or without treatment with Hoe 140 (kinin receptor antagonist). In essential hypertensives, both ACE inhibitor and AT antagonist decreased BP and improved insulin sensitivity to the same extent. In FFR, ACE inhibitor also decreased BP and improved insulin sensitivity. Moreover, Hoe 140 showed no effect on these actions of ACE inhibitor. The composite ratio of type I fiber of soleus muscle was decreased significantly in FFR compared to control and ACE inhibitor produced a recovery of the composite ratio of type I fiber to the same as control. These results suggested that muscle fiber composition of skeletal muscle is linked to insulin resistance, and that ACE inhibitor may modulate muscle fiber composition through its vasodilative effect in hypertension. These results also suggest that for vasodilation, it is more important to inhibit angiotensin II than to block degradation of kinins or to improve insulin sensitivity by ACE inhibitor.     

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.
2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h^-1 (means ± s.d.) in patients with creatinine clearances (CL_cr) of > 100, 41-100, 21-40, and 8-20 ml min^-1, respectively.
3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CL_cr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CL_cr < 40ml min^-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.
4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.     

Angiotensin converting enzyme inhibitor captopril suppresses a genetic polydipsic behavior

The STR/N inbred mouse is a behavioral mutant that drinks up to four times its body weight in water or normal saline per day when given free access, despite the lack of physiological need. Since angiotensin II (AII) is a powerful elicitor of drinking behavior, we investigated the influence of the angiotensin converting enzyme inhibitor, captopril, on the amount of water consumed by the STR/N mouse. Oral administration of captopril, which inhibits formation of AII (active octapeptide) from AI (precursor decapeptide), resulted in a reduction of 46 to 79% in water consumption of 53 polydipsic STR/N mice, and a 20-42% increase in water consumption of 12 of 13 Swiss/Webster (S/W) normodipsic control mice. These results suggest that the polydipsic behavior of the STR/N mutant may involve mediation by AII and/or another molecule which is also suppressed by captopril, such as another peptide, which, for activation, requires cleavage by a peptidase which is inhibited by captopril.     

Effects of angiotensin II and an angiotensin converting enzyme inhibitor on alcohol intake in P and NP rats.

While it is known that randomly bred normotensive Wistar stock and hypertensive rats alter their alcohol consumption when activity in the renin-angiotensin (R-A) system is modified, the effect of manipulations to the R-A system on alcohol intake in genetically selected alcohol-preferring P and -nonpreferring NP rats has not been assessed. In Experiment 1, nine P rats and 8 NP rats were injected with the saline vehicle and offered limited access to 10% (v/v) alcohol for 40 min each day for 7 days. When intake stabilized both groups were given daily intraperitoneal injections of the angiotensin converting enzyme inhibitor, ceranapril (20 mg/kg) 45 min prior to alcohol access for 11 days. Ceranapril (SQ 29,852) reduced alcohol intake in both the P and NP animals, while saline had no effect. In Experiment 2, these same two groups of P and NP rats were injected with three doses of angiotensin II (ANG II) (100, 200, 400 micrograms/kg) immediately prior to alcohol access. Each dose was tested for 10 consecutive days, with a 14-day period of no drug preceding and following the ANG II treatments. ANG II reduced alcohol intake in the NP rats and produced a dose-dependent reduction in the alcohol consumption of the P rats. These findings indicate that the renin-angiotensin system can modify alcohol consumption in rats selectively bred for high and low alcohol intake.     

Platelet function during antihypertensive treatment with quinapril, a novel angiotensin converting enzyme inhibitor.

The effect of various antihypertensive medications on platelet function is of increasing interest. Conflicting effects of captopril on platelet function are reported and the impact of angiotensin converting enzyme (ACE) inhibitors not containing a sulfhydryl group such as enalapril, lisinopril, and quinapril on platelet function remains unstudied. Therefore, the aim of the present study was to examine the effect of antihypertensive treatment with quinapril, a novel ACE inhibitor not containing a sulfhydryl group, on platelet function. Ten white men (age range of 32-61 years) with untreated mild-to-moderate essential hypertension (supine diastolic blood pressure greater than 95 mm Hg) were treated with 4 weeks each of placebo and quinapril in a double-blind, randomized, crossover design. Quinapril (20 mg twice a day) significantly lowered systolic (p less than 0.01) and diastolic blood pressure (p less than 0.01) without any significant effect on heart rate or plasma catecholamines. No significant change was noted for in vitro platelet aggregation induced by epinephrine, ADP, or collagen. Plasma concentrations of the platelet release factors beta-thromboglobulin and platelet factor 4 did not change, nor did the platelet content of norepinephrine, platelet weight (mg/10 ml of blood), circulating platelet count, or platelet size. Thus, as assessed by a broad spectrum of platelet parameters, we found that antihypertensive treatment with quinapril has no significant effect on platelet function in patients with mild-to-moderate essential hypertension. These "platelet-neutral" properties of quinapril suggest that quinapril, both from a thromboembolic and a hemostatic point of view, may be a rather safe agent for treatment of hypertension.     

Effects of angiotensin I-converting enzyme inhibitor (SA-446) on renal function in dogs

The effects of an orally active inhibitor of angiotensin-converting enzyme (SA-446) on systemic arterial pressure, renal function and renin release were examined in anesthetized dogs. Intrarenal infusion of the larger dose of SA-446 (0.1 mg/min) caused an increase in RBF, urine flow and renin release and caused a fall in blood pressure. The smaller dose of SA-446 (0.02 mg/min) did not affect the blood pressure, but it increased the urine flow. However, the same dose of SA-446 in combination with probenecid caused a significant fall in blood pressure. The potentiation of SA-446 with probenecid may be explained by the elevation in plasma SA-446 concentration via the inhibition of its tubular secretion by probenecid.     

Hypotensive effects of angiotensin II analogues and angiotensin converting enzyme inhibitors in water-deprived Brattleboro rats.

The hypotensive effects of three different angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril, and lisinopril) and two angiotensin II (AII) analogues ([Sar1Ile5Ala8]AII and [Sar1Ile5Thr8]AII) were compared in conscious, freely-moving Brattleboro rats after 14 h of water deprivation. There was no difference between the hypotensive effects of the three ACE inhibitors. Neither was there any difference between the hypotensive effects of the two AII antagonists, although when administered following ACE inhibition, [Sar1Ile5Thr8]AII caused a transient pressor effect that was significantly less than that caused by [Sar1Ile5Ala8]AII. ACE inhibition caused a greater fall in blood pressure (BP) than AII antagonism and caused an additional fall in BP during AII antagonism. These results indicate an additional hypotensive effect of ACE inhibitors, over that of AII antagonists, that is not readily accounted for in terms of nonspecific effects of the former or agonistic properties of the latter.     

Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update.

The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of an angiotensin converting enzyme (ACE) inhibitor on plasma endorphin level

1. In addition to their antihypertensive effect, ACE inhibitors have been reported to increase general well-being, general health and vitality and work performance. The cause of these effects is not known. A possible mechanism may be release of beta-endorphins. 2. In the present study changes in plasma concentration of beta-endorphins on days with ACE inhibitor treatment (n = 12) and on non-treatment control days (n = 12) were compared in 6 patients. 3. Both on control and treatment days the beta-endorphin level fell, by 7.1 and 10.0%, respectively, from 8.00 a.m. to 8.00 p.m., reflecting the known diurnal rhythm of this opioid. This difference between the control and treatment days is not statistically significant. 4. The study should be extended to determine endorphin concentration in the cerebrospinal fluid, and other opioids should be looked for.