Metabolism of angiotensin I in isolated rat hearts: Effect of angiotensin converting enzyme inhibitors

In this study, the formation of biologically active angiotensins from angiotensin I (Ang I) in isolated rat hearts was evaluated. The role of angiotensin converting enzyme (ACE) in Ang I metabolism was also investigated. HPLC analysis of heart perfusate showed that ¹²⁵I-Ang I was metabolized extensively (single passage) in the rat coronary circulation in vitro leading to the formation of the biologically active angiotensins: angiotensin II (Ang II), Ang-(2–8), Ang-(3–8) and Ang-(l–7). Ang II was the major product identified in HPLC fractions, corresponding to 7.8 ± 0.89% of the total radioactivity recovered. A similar profile was observed when single-passage metabolism of non-isotopic Ang I was evaluated by HPLC, followed by radioimmunoassay of the eluate fractions. When ¹²⁵I-Ang I was perfused in the presence of ACE inhibitors (enalaprilat, ramiprilat) in concentrations up to 130 μM, the formation of Ang II was only partially inhibited (approximately 50%). A similar tendency was observed for Ang-(2–8), Ang-(3–8) and Ang-(2–7). The formation of Ang-(1–7) and its related fragments Ang-(3–7) and Ang-(4–7) was not changed significantly by ACE inhibitors, although a slight increase in formation of these fragments was observed. No significant changes were observed for the carboxyl-terminal fragments of Ang I: Ang-(2–10), Ang-(3–10), and Ang-(4–10). The fractional metabolism of Ang I was not modified by ACE inhibition. These findings suggest that biologically active angiotensins can be formed from Ang I in the rat coronary circulation. These locally generated peptides may contribute to the actions of the renin-angiotensin system in the heart.     

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.     

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.     

Comparison of angiotensin converting enzyme inhibitors captopril and MK421-diacid in guinea pig atria

Angiotensin I (AI) and angiotensin II (AII) caused concentration-dependent increases in atrial rate in guinea pig isolated right atria. Converting enzyme inhibitors captopril and MK421-diacid did not alter the responses to AII but displaced the curves to AI to the right. The atrial response to generated AII from AI was used as a bioassay to estimate the dissociation constants of converting enzyme inhibitors (Kb) and test for kinetics of simple competition. MK421-diacid was 12-40 times more potent than captopril. However, estimations of Kb for captopril and MK421-diacid were unsatisfactory because at high concentrations of inhibitors the curves to AI were not displaced according to simple competition. We conclude that AI in high concentration can stimulate AII receptors accounting for the stationary displacement of curves to AI in the presence of converting enzyme inhibitors. MK421-diacid also potentiates responses to bradykinin in this assay.     

Synthesis and antienzymic activity of two new angiotensin converting enzyme inhibitors.

Two new analogs of captopril were synthesized. Inhibition of angiotensin converting enzyme (ACE) by these compounds in vitro and in vivo was determined using fluorimetric method. The obtained compounds were much weaker ACE inhibitors than captopril.     

Differential effects of captopril and enalapril, two angiotensin converting enzyme inhibitors, on immune reactivity in experimental lupus disease

We have previously demonstrated that Captopril, an inhibitor of angiotensin converting enzyme (ACE), ameliorates experimental systemic lupus erythematosus in inbred MRL lpr/lpr (MRL/l) mice. In contrast, Enalapril, another ACE inhibitor with antihypertensive properties but lacking a thiol group, did not show similar beneficial effects. To better understand the mode of action of captopril in the autoimmune disease we have evaluated its immunomodulatory properties with special emphasis on antigen-specific and polyclonal B- and T-cell activation. The results obtained strongly suggest that Captopril exerts its immunomodulatory effects through stimulation of T-lymphocytes.     

Effect of time and dose on angiotensin converting enzyme during captopril treatment in the rat

The effect of treatment time and dose of captopril with regard to angiotensin converting enzyme (ACE) in serum, lungs and kidneys of the rat were studied. Normotensive Wistar rats were treated with a constant dose of captopril (0.2 mg/ml) during various time periods. In a second study rats were treated with different captopril doses (6.25 micrograms, 12.5 micrograms, 25 micrograms, 50 micrograms, and 200 micrograms/ml water) during three weeks. Serum ACE activity and pulmonary and kidney plasma membrane ACE concentrations were measured in both studies. Captopril treatment resulted in a rapid decrease of ACE in pulmonary and kidney plasma membranes and a simultaneously increase of serum ACE activity during the first day of treatment. This was followed by increased membrane concentrations of ACE in the lungs and return to normal ACE concentrations in membranes of kidneys, presumably due to increased ACE biosynthesis. Serum ACE activity continued to increase during the whole study. Serum ACE activity increased in a dose dependent manner during treatment with different captopril doses. Increased plasma membrane ACE concentrations were not observed in the rats treated with captopril at doses below 200 micrograms/ml water.     

Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of captopril, enalapril, and HOE 498

The effects of the angiotensin converting enzyme (ACE) inhibitors captopril, enalapril, HOE 498, and its prodrug on reperfusion arrhythmias after 15 min of coronary ligation were investigated in the isolated rat heart. Drug concentrations were equipotent in their effect on angiotensin I pressor response. Furthermore, the effect of indomethacin on ACE inhibition with captopril was studied. Upon reperfusion, ventricular fibrillation occurred in all untreated hearts, in all prodrug HOE 498-treated hearts (15 micrograms/ml), and in 4 of 6 of the enalapril-treated (8 micrograms/ml) hearts. In contrast, in only 2 of 6 (p less than 0.002) of the HOE 498-treated hearts (15 micrograms/ml) and in none (p less than 0.001) of the captopril-treated hearts (80 micrograms/ml) did ventricular fibrillation occur. A massive purine overflow was observed in untreated hearts upon reperfusion. This overflow was significantly reduced by captopril and HOE 498, whereas enalapril and prodrug HOE 498 had no significant effect. Concomitantly, the pressure-rate index was severely impaired after 30 min of reperfusion in the untreated, enalapril, and prodrug HOE 498 groups (33 +/- 9, 52 +/- 11, and 48 +/- 12% of initial values, respectively), but captopril and HOE 498 significantly reduced the impairment of mechanical function (124 +/- 9% and 98 +/- 9%, respectively). In contrast to enalapril and prodrug HOE 498, captopril and HOE 498 markedly reduced noradrenaline overflow during the first minutes of reperfusion. No angiotensin II was detectable in the coronary effluent of untreated hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

Aims

Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined.

Methods

We conducted a nested case–control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor.

Results

Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings.

Conclusions

Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.     

Enhanced contractility of the rat stomach during suppression of angiotensin converting enzyme by captopril in vitro.

1. Intragastric pressure (IGP) was used as an index, of the effect of serosal application of captopril (SQ 14,225; D-3-mercapto-2-methylpropanoyl-L-proline) on the contractility of rat stomach in vitro. 2. Captopril, at concentrations greater than 0.3 microM, enhanced the spontaneous gastric motility (GM) in a concentration-dependent manner whereas concentrations less than 0.3 microM selectively potentiated 4 nM bradykinin (BK)-evoked gastric contractions without significantly affecting the spontaneous GM. 3. The kallikrein inhibitor, aprotinin (100 u ml-1), markedly antagonized the enhanced GM to 1.4 microM captopril and BK (4 nM)-evoked contractions, without affecting the contractions evoked by angiotensin 1 (10 nM) and acetylcholine (0.4 microM). The angiotensin II antagonist, saralasin (50 microM) failed to mimic aprotinin. 4. The enhanced GM to captopril was markedly inhibited by tetrodotoxin (1 microM), and partially inhibited by atropine (1 microM). 5. These results indicate that in vitro, captopril (greater than 0.3 microM) enhances gastric contractility through kininase/ACE inhibitory action, presumably by increasing the concentration of undegraded tissue kinins and substance P. This motor response seems to be predominantly due to activation of the cholinergic neurones but non-cholinergic excitatory neurones are also involved.     

The effects of a converting enzyme inhibitor (captopril) and angiotensin II on fetal renal function.

1. Renal function was studied in chronically catheterized fetal sheep (119-128 days gestation), before and during treatment of the ewe with the angiotensin converting enzyme (ACE) inhibitor, captopril, which crosses the placenta and blocks the fetal renin angiotensin system. 2. An i.v. dose of 15 mg (about 319 micrograms kg-1) of captopril to salt-replete ewes followed by an infusion to the ewe of 6 mg h-1 (about 128 micrograms kg-1 h-1) caused a fall in fetal arterial pressure (P < 0.01), and a rise in fetal renal blood flow (RBF) from 67.9 +/- 5.6 to 84.9 +/- 8.3 ml min-1 (mean +/- s.e. mean) (P < 0.05). Renal vascular resistance and glomerular filtration rate (GFR) fell (P < 0.01); fetal urine flow (P < 0.01); fetal urine flow (P < 0.01) and sodium excretion declined (P < 0.05). 3. Ewes were treated for the next 2 days with 15 mg captopril twice daily. On the 4th day, 15 mg was given to the ewe and fetal renal function studied for 2 h during the infusion of captopril (6 mg h-1) to the ewe. Of the 9 surviving fetuses, 3 were anuric and 3 had low urine flow rates. When 6 micrograms kg-1 h-1 of angiotensin II was infused directly into the fetus RBF fell from 69 +/- 10.1 ml min-1 to 31 +/- 13.9 ml min-1, GFR rose (P < 0.05) and urine flow (P < 0.01) and sodium excretion increased in all fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)     

A study of ozone-induced edema in the isolated rat lung in relation to arachidonic acid metabolism,mixed-function oxidases and angiotensin converting enzyme activities

In order to elucidate the role of arachidonic acid in the pathogenesis of ozone-induced pulmonary edema, isolated rat lungs were exposed to ¹⁴C-arachidonic acid in the presence or absence of ozone and the incorporation of radiolabelled arachidonate into pulmonary cell lipids was studied. The perfusates from these studies were also subjected to differential extraction and thin layer chromatography (t.l.c.) to determine synthesis of both cyclo-oxygenase and lipoxygenase products. In the presence of an edemagenic concentration of ozone, isolated lungs incorporated significantly less exogenous arachidonic acid into phosphatidyl choline and phosphatidyl ethanolamine, whereas incorporation into phosphatidyl inositol or serine was not affected. The edemagenic concentration of ozone also increased production of a variety of arachidonic acid metabolites via cyclo-oxygenase and lipoxygenase pathways. In separate studies, a similar ozone exposure did not affect ¹⁴CO₂ production, resulting from the metabolism of ¹⁴C-antipyrine by mixed function oxidases (MFO). Similarly, an edemagenic concentration of ozone did not affect pulmonary angiotensin converting enzyme activity (ACE) as determined by the rate of formation of ¹⁴C-hippuric acid from ¹⁴C-hippuryl-histidyl-leucine (¹⁴C-HHL). Thus, acute ozone exposure is specifically associated with a reduced incorporation of arachidonate into phospholipids and with an increased conversion of arachidonate into bio-active metabolites.     

Effects of Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, on acetylcholine metabolism in rat brain

Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, caused a fall in the content of acetylcholine (ACh) in different brain areas of the rat following i.p. administration in the range 0.03-30 mg/kg. This effect occurred 0.5 h after a single injection and lasted for at least 6 h. Simultaneous administration of the choline uptake inhibitor hemicholinium-3 (HC-3) with Hoe 065 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 065 acutely enhanced the activity of the enzyme choline acetyltransferase as well as the capacity of the high-affinity choline uptake system which is considered as the rate-limiting step in the synthesis of ACh. Cholinesterase activity in vivo was not altered by the compound. Hoe 065 produced a concurrent elevation of brain cyclic GMP content. Taken together, these results suggest that Hoe 065 acutely increases cholinergic activity within its physiological range, probably by means of an enhanced release of ACh.     

Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22-30 years and nine sex matched elderly subjects aged 65-73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration-time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/- 0.16) and elderly subjects (0.61 +/- 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.     

Age and the pharmacodynamics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

The effect of age on the pharmacodynamic responses to converting enzyme inhibitors, enalapril and enalaprilat was investigated in nine young (22-30 years) and nine sex-matched elderly (65-73 years), healthy volunteers. The groups differed in baseline blood pressure, young 121/64 mmHg, elderly 142/75 mmHg (P less than 0.01), but not in sodium intake or body weight. Both enalapril and enalprilat produced significant falls in blood pressure in both groups but no increase in heart rate in the supine or erect posture. The blood pressure fall was significantly greater in the elderly on both treatments and in both erect and supine posture. The greater fall in blood pressure in the elderly was associated with a more prolonged inhibition of plasma angiotensin converting enzyme activity. The apparent age-related difference in response appears to be due to the difference in baseline blood pressures between the groups. Further study of the usefulness of chronic dosing with angiotensin converting enzyme inhibitors in hypertension in the elderly is indicated.     

Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.     

1H nuclear magnetic resonance study of metronidazole metabolism by perfused rat liver

High-resolution 1H nuclear magnetic resonance (NMR) spectroscopy at 300 MHz has been used to monitor the metabolism of metronidazole by the perfused rat liver. Samples of perfusate removed at various times during the perfusion show resonances from metronidazole and its major metabolites, as well as those from organic metabolites released from the liver. The major metabolite of metronidazole is shown to be its glucuronide conjugate. Metronidazole metabolism and glucuronide production are both stimulated in livers from rats pretreated with phenobarbitone.     

A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy

Objective:Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB.Results:The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril).Conclusions:Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection.KEY WORDS: Angiotensin receptor blockers and angiotensin converting enzyme inhibitors, diabetes, diabetic nephropathy     

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.