Inhibited Serum Angiotensin Converting Enzyme Research Articles

Modulation of acute transient exercise-induced hypertension after oral administration of four angiotensin-converting enzyme inhibitors in normotensive horses

Changes in blood pressure (BP) during acute hypertension in response to angiotensin-converting enzyme inhibitors (ACEIs) have not been investigated in normotensive horses. In this study, six healthy horses were subjected to five trials, consisting in a treadmill exercise workload of 8 m/s for 1 min, 2 h after oral administration (PO) of placebo (0 mg/kg), enalapril (2.0 mg/kg), quinapril (1.0 mg/kg), ramipril (0.2 mg/kg) or benazepril (0.5 mg/kg). Serum angiotensin converting enzyme (ACE) activity was measured and systolic (SBP) and diastolic (DBP) blood pressures were recorded at rest (R), 2 h after placebo or ACEI administration (pre-E) and within the first 20 s after exercise (post-E).Mean maximum serum ACE inhibition 2 h after PO administration was 4.8% (placebo), 39.4% (enalapril), 46.4% (quinapril), 55.0% (ramipril) and 71.68% (benazepril). There were no significant differences in serum ACE inhibition between enalapril and quinapril. SBP and DBP at times R and pre-E were not different in any of the five trials. In response to exercise, SBP increased by 67.6% (placebo), 52.7% (enalapril), 43.1% (quinapril), 26.6% (ramipril) and 4.2% (benazepril). In response to exercise, DBP increased by 20.6, 13.2, 11.7, 16.6 and 3.7% after placebo, enalapril, quinapril, ramipril and benazepril administration, respectively. Serum ACE activity changed during exercise, but statistical significance was not achieved. In conclusion, administration of PO benazepril at a dose of 0.5 mg/kg modulated physiological hypertension induced by exercise in horses that were otherwise normotensive.

Acute Cadmium Exposure Reduces the Local Angiotensin I Converting Enzyme Activity and Increases the Tissue Metal Content.

Cadmium exposure causes health problems that may result from increased oxidative stress and from changes in enzyme metalloproteases activities as angiotensin-converting enzyme (ACE). In fact, cadmium produces inhibition of serum ACE but is not known how cadmium acts on tissue ACE activity and whether following acute exposure tissue cadmium content is increased. In order to elucidate these issues, a cadmium bolus was injected intravenously in Wistar rats, and the cadmium content and the ACE activity were measured in the serum, lungs, aorta and kidneys. Moreover, in order to clarify if the cadmium affects directly tissue ACE activity, acute metal exposure in vitro was performed. Our results demonstrated that 120min following cadmium administration, blood and organ cadmium content were both increased. Serum and lung ACE activity were reduced following acute cadmium exposure, but aortic and kidney ACE activities were not affected. The inhibitory effects induced by cadmium on ACE activity were also observed in the serum, as well as the lungs and the aorta, but not in the kidneys following in vitro exposure. Moreover, the inhibitory effects induced by cadmium on ACE activity were partially restored in vitro by zinc supplementation, suggesting a possible interaction or competition between cadmium and zinc by at the active site of ACE. Summarising, our results suggest that acute cadmium exposure promotes an increase in the tissue metal content that was accompanied by direct inhibition of serum, aorta and lung ACE activity, an effect that is cadmium concentration-dependent and is partially reversed by zinc.

Pharmacodynamic Evaluation of 4 Angiotensin‐Converting Enzyme Inhibitors in Healthy Adult Horses

Angiotensin-converting enzyme (ACE) inhibitors are used in horses with cardiovascular disorders despite the paucity of available data regarding their efficacy. The degree of serum ACE inhibition varies considerably between drugs. Eight healthy adult horses. Randomized prospective study. Horses were fasted overnight prior to receiving one of 4 ACE inhibitors intragastrically, administered at one of 2 dosages, using a randomized Latin square design (benazepril: 0.5 and 0.25 mg/kg; ramipril: 0.3 and 0.1 mg/kg; quinapril: 0.25 and 0.125 mg/kg; perindopril: 0.1 and 0.05 mg/kg). Serum ACE activity was measured using a kinetic spectrophotometric method. There was a significant effect of drug and dosage on maximum ACE inhibition (I(max)), ACE inhibition 24 hours after administration (I(24h)), and area under the curve (AUC(0-48h)). Benazepril at 0.5 mg/kg resulted in significantly higher I(max) (86.9 ± 7.0%) and I(24h) (60.3 ± 7.9%) compared to the other drugs. There was a significant decrease in indirect blood pressure (BP) over time after administration of each drug, but differences in BP were not significantly different between drugs. Pharmacodynamic variables measured after administration of benazepril to horses with free access to hay were not significantly different from those obtained after fasting. Administration of benazepril orally once daily for 7 days did not result in a cumulative effect on ACE inhibition. Of the ACE inhibitors tested, oral benazepril (0.5 mg/kg) is the most effective at inhibiting serum ACE activity in healthy horses.

Inhibition of serum angiotensin-converting enzyme in rabbits after intravenous administration of enalaprilat-loaded intact erythrocytes.

Encapsulation of drugs in intact erythrocytes, because of the profound characteristics of these natural microspheres, has gained considerable attention in recent years. In this study, the inhibition time courses of serum angiotensin-converting enzyme (ACE) activity after intravenous administration of enalaprilat encapsulated in intact erythrocytes was evaluated and compared with free drug, in a rabbit model. Three groups of animals each received free drug, drug-loaded erythrocytes or sham-encapsulated erythrocytes. Serum ACE activity was determined in each case using the synthetic substrate hippuryl-histidyl-leucine and quantitation of the hippuric acid released by a developed and validated HPLC method. The serum ACE inhibition profiles in the three groups showed that the encapsulated drug inhibited the serum ACE more slowly, more efficiently, over a considerably longer time and in a more reproducible manner, than the free drug or sham-encapsulated erythrocytes. We conclude that the erythrocytes can serve as efficacious slow-release drug carriers for enalaprilat in circulation.

Long-Term Treatment With Imidapril but Not With Nifedipine Enhances Plasma NOx Concentration in Patients With Essential Hypertension

We investigated whether long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor imidapril or the calcium channel antagonist nifedipine increases systemic nitric oxide (NO) production in patients with essential hypertension. Twenty-nine patients with essential hypertension were randomly divided into two groups, and they were treated with either imidapril or nifedipine once daily p.o. for 4 weeks. Long-term treatment with imidapril significantly decreased blood pressure and increased plasma NOx concentration. Long-term treatment with nifedipine also caused a comparable extent of significant decrease in blood pressure, but failed to alter plasma NOx levels. The imidapril treatment significantly inhibited serum ACE activity and increased plasma bradykinin concentration. Furthermore, the extent of inhibition of serum ACE activity and the extent of increase in plasma bradykinin concentration in response to the imidapril treatment were both significantly correlated with the extent of increase in plasma NOx concentration. In contrast, no such changes were noted after the nifedipine treatment. These results provide the first evidence that long-term treatment with imidapril enhances plasma NOx concentration in patients with essential hypertension. This effect does not seem to be due to the decrease in blood pressure. The increase in bradykinin concentration may be involved in the enhancing effect of the ACE inhibitor on NOx production in vivo.

Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor β1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat

Combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is used to improve renal outcome achieved by monotherapy in diabetic patients. In addition, interference with the renin-angiotensin system (RAS) reduced expression and excretion of transforming growth factor beta 1 (TGF-beta 1) in diabetic nephropathy. The aim of this study was to investigate the effects of interrupting the RAS by ACE inhibitor (ACE-I) or ARB monotherapy or by combination therapy on proteinuria, kidney hypertrophy and plasma TGF-beta 1 in diabetic rats. Forty-one male Wistar rats were allocated to five groups: 1 = control rats, 2 = diabetic rats (streptozotocin [STZ] 55 mg/kg), 3 = diabetic rats as above receiving enalapril (20 mg/kg/day), 4 = diabetic rats receiving losartan (80 mg/kg/day), 5 = diabetic rats receiving both losartan and enalapril. The study lasted 60 days. Urinary protein excretion, kidney weight, serum ACE activity and plasma TGF-beta1 increased significantly in untreated diabetic rats compared with controls. Administration of losartan, enalapril, or both for 60 days prevented these changes. Furthermore, combined therapy for 30 days normalised urinary protein excretion, while monotherapy did not. Losartan inhibited serum ACE activity both in vivo and in vitro. Plasma TGF-beta 1 levels were positively correlated with blood glucose levels (r=0.4059) and with urinary protein excretion (r=0.3558). Combination therapy with losartan and enalapril was more effective than monotherapy with either drug in achieving an early antiproteinuric response. Long-term treatment with losartan was as effective as the combined treatment, possibly due to a dual inhibitory effect on the RAS. The antiproteinuric effect may be related, in part, to reduced TGF-beta 1.

Comparison of Acute Cardiovascular Effects of Cadmium and Captopril in Relation to Oxidant and Angiotensin Converting Enzyme Activity in Rats

Cadmium (0.1, 0.32, 1.0 mg/kg i.v.) produced dose dependent hypertensive response in pentobarbitone anesthetized Sprague-Dawley (S-D) rats. The peak hypertensive effect was observed within 15 min of cadmium administration. This response gradually decreased over 1-h observation period. Heart rate did not change significantly. Serum malondialdehyde (MDA) levels increased with cadmium administration. The lower dose of cadmium (0.1 mg/kg i.v.) increased serum MDA to 0.14 ± 0.02 nmol/mL as compared to 0.12 ± 0.01 nmol/mL in the control group and was not statistically significant. However, mid (0.32 mg/kg i.v.) and high doses (1.0 mg/kg i.v.) raised serum MDA levels significantly (P<0.01). Cadmium inhibited serum angiotensin converting enzyme (ACE) levels at all the three tested doses and was statistically significant (P<0.01). Captopril (1.0, 3.2 mg/kg i.v.) produced a dose dependent mild hypotensive response. The peak effect was observed within 5 min. Cadmium produced inhibition of serum ACE levels, however, a dose response effect was not observed. Captopril (3.2 mg/kg i.v.) decreased serum ACE levels to 5.4 ± 1.1 U/mL (control levels 10.7 ± 1.4 U/mL). Serum MDA levels were decreased by captopril treatment. A correlation between serum ACE and MDA following higher dose of cadmium was found. These results indicate that acute administration of cadmium, an inorganic blocker of ACE and calcium channels cadmium produced hypertensive response while captopril produced mild hypotensive response in rats.

Nitric oxide donors and angiotensin-converting enzyme inhibitors act in concert to inhibit human angiotensin-converting enzyme activity and platelet aggregation in vitro

This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme activity and platelet aggregation. The NO donor S-nitroso- N-acetylpenicillamine (10 −8–10 −6 M) significantly and dose-dependently inhibited serum angiotensin-converting enzyme activity. The concomitant addition of S-nitroso- N-acetylpenicillamine to angiotensin-converting enzyme inhibitor-treated (captopril or enalaprilat) serum, further reduced angiotensin-converting enzyme activity. In cultured endothelial cells from human umbilical veins (HUVECs), both S-nitroso- N-acetylpenicillamine and 3-morpholinosydnonimine (SIN-1) significantly reduced angiotensin-converting enzyme activity. An additative effect was seen with a combined treatment of captopril and S-nitroso- N-acetylpenicillamine. Treatment with the NO synthase inhibitor N G-monomethyl- l-arginine ( l-NMMA) did not affect angiotensin-converting enzyme activity. Thrombin inhibited endothelial angiotensin-converting enzyme activity, an effect that was abolished when cells were pretreated with l-NMMA. Adenosine 5′-diphosphate (ADP)-induced platelet aggregation was inhibited with S-nitroso- N-acetylpenicillamine, SIN-1 and nitroglycerine. Captopril did not affect aggregation, while a high concentration of enalaprilat (10 −4 M) reduced it. The concomitant addition of 10 −5 M angiotensin-converting enzyme inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-1 and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human angiotensin-converting enzyme activity. NO donors and angiotensin-converting enzyme inhibitors act in concert to inhibit angiotensin-converting enzyme and platelet aggregation.

Abnormal taurocholate ileal transepithelial transport in atherosclerotic mini-pigs and effects of ace inhibitors

In atherosclerotic mini-pigs, we attempted to determine (i) whether high-fat atherogenic diet disturbs the taurocholate transepithelial transport and incorporation in the ileal epithelium mounted in Ussing chambers, and (ii) whether these processes are sensitive to angiotensin converting enzyme (ACE) inhibitors which slow the development of vascular atherosclerosis. In atherosclerotic mini-pigs, the mucosal to serosal transepithelial fluxes were markedly lower (72% inhibition) and free diffusion was more altered than active processes. Taurocholate incorporation into enterocyte (75% inhibition) paralleled the flux reduction. The transport disturbance observed here might be explained by changes in bile salt permeability in relation to alterations of the membrane properties. Taurocholate absorption was lowered by atherogenic diet, whereas bile salts were not trapped in the enterocyte, therefore atherosclerosis-induced alterations preferentially affected the passage through the brush-border. In the ACE inhibitor treated atherosclerotic mini-pigs, perindopril and enalapril similarly inhibited serum ACE activities. Perindopril further corrected taurocholate fluxes by 50% and fully restored taurocholate incorporation. Since enalapril did not restore the atherosclerosis-induced alterations, the involvement of intestinal ACE in bile acid recycling and of an ACE inhibitor class effect on these mechanisms both remain to be ascertained.

First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patient with heart failure: A double-blind, randomized, multicenter study

Significant decreases in blood pressure (BP) may occur when administration of angiotensin-converting enzyme (ACE) inhibitors is initiated for the treatment of heart failure. The purpose of this study was to compare the safety and tolerability of recommended initial doses of the longer-acting ACE inhibitor enalapril (ENAL) with those of the shorter-acting captopril (CAP) in patients with heart failure who were treated concomitantly with digitalis and diuretic agents. We evaluated BP, serum ACE activity, and clinical status when a low, first dose of ENAL (2.5 mg, n = 59) or CAP (6.25 mg, n = 58) was administered in a double-blind, randomized, and parallel fashion to 117 patients with mild to moderate heart failure. BP and serum ACE activity were measured at 30 min and hourly for 8 hours after drug administration. BP decreases were similar for both groups (mean supine BP -6.2/-4.8 mm Hg for ENAL vs -8.3/-6.4 mm Hgfor CAP; mean standing BP -9.2/-5.6 mm Hg for ENAL vs -10.0/-4.7 mm Hg for CAP). Although the maximum mean decrease in BP occurred at hours 4 and 5 in the ENAL group and hours 1 and 2 in the CAP group, considerable between-group overlap was observed for individual patients. Decreases in mean serum ACE activity occurred earlier and were of shorter duration in the CAP group. ENAL significantly inhibited serum ACE activity to a greater extent than did CAP at all time points except the 1st hour. Administration of a first dose of ENAL, 2.5 mg or CAP, 6.25 mg to patients with heart failure was well tolerated.

Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation.

Angiotensin II (Ang II) induces vascular smooth muscle cell migration and growth in vitro and induces DNA synthesis in vascular smooth muscle in vivo. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists inhibit neointimal hyperplasia in many experimental models of restenosis. However, recent clinical trials (MERCATOR and MARCATOR) reported that treatment with low (antihypertensive) doses of an ACE inhibitor (cilazapril) failed to prevent restenosis. Because ACE activity is induced in the neointima after injury, we hypothesize that the inhibition of neointimal development may be dependent on the suppression of tissue ACE activity, which in turn is dependent on the dose of the ACE inhibitor. To test this hypothesis, we treated rats with increasing doses of an ACE inhibitor, quinapril, before injury of the carotid artery. Blood pressure, serum and tissue ACE activity, and neointimal area were measured. The results demonstrated a dose-dependent inhibition by quinapril of serum and tissue ACE activities and neointima formation. However, the IC50s for blood pressure reduction and serum ACE inhibition were significantly lower than that observed for the suppression of neointima formation. The degree of neointimal formation showed a better correlation with residual tissue ACE than with serum ACE or blood pressure. These results demonstrate a dissociation of the ability of an ACE inhibitor to decrease blood pressure and inhibit circulating ACE activity from its ability to inhibit tissue ACE activity. These results suggest that the need for a higher dose of an ACE inhibitor for the inhibition of neointima formation may be due to the relative difficulty in inhibiting tissue ACE activity.

Trandolapril Dose-Response in Spontaneously Hypertensive Rats

The dose-related effects of trandolapril on serum angiotensin-converting enzyme (ACE) activity, blood pressure and cardiac hypertrophy were studied after 2-week oral treatment in adult spontaneously hypertensive rats. Trandolapril caused a dose-dependent decrease in mean blood pressure at doses of 0.03-3 mg/kg. Inhibition of serum ACE was demonstrated by even the lowest dose (-9% at 0.003 mg/kg), was about 40% at 0.03 mg/kg, and rose to 84% at 3 mg/kg. Regression of cardiac hypertrophy (heart:body weight) was seen at doses of trandolapril as low as 0.03 mg/kg (-5.1%), which was also the minimal effective antihypertensive dose. Clear dose-response curves were observed for trandolapril from 0.03 mg/kg upwards with respect to hypotensive effect and regression of cardiac hypertrophy, which were not seen with enalapril. Enalapril had no significant effect on plasma ACE activity except at the highest dose (10 mg/kg), despite demonstrating hypotensive effects with smaller doses. These results indicate that trandolapril is a more potent (by a factor of about 30) inhibitor of ACE than enalapril (only 34% inhibition at 10 mg/kg) and causes a greater degree of regression of cardiac hypertrophy.

The role of enzyme and substrate concentration in the evaluation of serum angiotensin converting enzyme (ACE) inhibition by enalaprilat in vitro

The relationship between serum angiotensin converting enzyme (ACE) activity and concentration of the ACE inhibitor enalaprilat was determined in vitro in the presence of different concentrations ( S = 4–200 mM) of the substrate Hip-Gly-Gly. From Henderson plots, a competitive tight-binding relationship between enalaprilat and serum ACE was found yielding a value of ≈5 nM for serum ACE concentration ( E t ) and an inhibition constant ( K t ) for enalaprilat of ≈0.1 nM. A plot of reaction velocity ( V i ) versus total inhibitor concentration ( I t ) exhibited a non-parallel shift of the inhibition curve to the right with increasing S. This was reflected by apparent Hill coefficients > 1 when the commonly used inhibitory sigmoid concentration-effect model ( E max model) was applied to the data. Slopes > 1 were obviously due to discrepancies between the free inhibitor concentration ( I f ) present in the assay and I t plotted on the abscissa and could, therefore, be indicators of tight-binding conditions. Thus, the sigmoid E max model leads to an overestimation of K i . Therefore, a modification of the inhibitory sigmoid E max model (called “ E max tight model”) was applied, which accounts for the depletion of I f by binding, refers to I t and allows estimation of the parameters E t and IC 50f (free concentration of inhibitor when 50% inhibition occurs) using non-linear regression analysis. This model could describe the non symmetrical shape of the inhibition curves and the results for K i and E i , correlated very well with those derived from the Henderson plots. The latter findings confirm that the degree of ACE inhibition measured in vitro is, in fact, dependent on the concentration of substrate and enzyme present in the assay. This is of importance not only for the correct evaluation of K i but also for the interpretation of the time course of serum ACE inhibition measured ex vivo. The non-linear model has some advantages over the linear Henderson equation: it is directly applicable without conversion of the data and avoids the stochastic dependency of the variables, allowing non-linear regression of all data points contributing with the same weight.

Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects.

Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (tmax) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), whereas other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0-24] and the peak serum concentration (Cmax) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.

Hemodynamic and Humoral Interactions Between Perindopril and Indomethacin in Essential Hypertensive Subjects

To evaluate whether perindopril, a carboxyl-containing new angiotensin-converting enzyme (ACE) inhibitor, exerts its antihypertensive action through the stimulation of prostaglandin synthesis, 10 uncomplicated essential hypertensive patients randomly received indomethacin (50 mg b.i.d.) or the corresponding placebo for 1 week and the reverse treatment after 2 weeks. Perindopril alone tended to reduce serum and urinary thromboxane B2 (TxB2) and to raise urinary 6-ketoPGF1 alpha and PGE2 and inhibited serum ACE activity 24 h post dosing by about 85%. Indomethacin, which significantly inhibited serum TxB2 and urinary TxB2, 6-ketoPGF1 alpha, and PGE2 without interfering with the inhibitory effect of perindopril on ACE, significantly reduced the antihypertensive action of perindopril alone by about 30%, but decreased though not significantly that of perindopril plus placebo. Although the size of the study limits the interpretation, these findings suggest that the stimulation of prostaglandin synthesis plays only a minor role in the antihypertensive action of perindopril.

Effects of the angiotensin converting enzyme inhibitor, lisinopril, on normal and diabetic rats.

The comparative effects of lisinopril, a third generation angiotensin converting enzyme (ACE) inhibitor, on components of the renin-angiotensin system were assessed in normal and in an animal model of diabetes-related hypertension, the streptozotocin-diabetic rat. Two weeks after injection of streptozotocin the mean systolic blood pressure of diabetic rats was elevated 11% above that of normal rats. This effect was prevented by daily injection of insulin. The mean serum ACE activity was elevated 71% above that of normal rats. Lisinopril reduced systolic blood pressure and inhibited serum ACE activity in both normal and diabetic rats in a dose-response fashion. In normal rats maximum inhibition of blood pressure occurred at a mean dose of 1.0 mg/kg and in the diabetic rat at a mean dose of 5.0 mg/kg. At a mean dose of 5 mg/kg, ACE was inhibited by 100 and 92% in normal and diabetic rats, respectively. Plasma renin activity (PRA) increased sharply in both groups of rats treated with the lower doses of lisinopril, only to decrease at the 5 mg/kg level. At 20 mg/kg, PRA continued to decline in normal animals, but not in diabetic rats. Formation of angiotensin II (Ang II) in both normal and diabetic rats was maximally inhibited at doses of 1.0 and 0.1 mg/kg of lisinopril, respectively without a significantly greater effect at the higher doses of the drug. In separate experiments the effects of chronic treatment with lisinopril at two dosage levels on various physiological parameters of streptozotocin-diabetic rats were compared with the effects of another hypotensive agent, hydralazine, an arteriolar vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril and Lisinopril in Renovascular Hypertension Antihypertensne and Hormonal Effects of Two New Angio-Tensin-Converting-Enzyme (ACE) Inhibitors.

We assessed the antihypertensive and hormonal effects of two new angiotensin converting enzyme (ACE) inhibitors. enalapril (MK-421) and lisinopril (MK-521) in 22 patients with renovascular hypertension. All patients had angiographically verified renal artery lesions, 3 had bilateral renal artery stenosis and one a stenosis in a single kidney, and the rest had unilateral renal artery stenosis. After placebo treatment for 3 days in hospital, increasing doses from 5 to 40 mg daily, of both ACE-inhibitors were given. Both drugs induced a significant fall in blood pressure (BP). Significant BP reductions were seen after 2 h with a maximum fall for the enalapril group at a dose of 40 mg 4 h after drug intake (mean supine BP decrease-31/24 mm Hg, standing-29/16 mmHg). The corresponding maximal BP reductions were for the lisinopril group at a dose of 40 mg o.d. at 6 h: mean supine BP fall-25/28 mmHg and standing-33/31 mm Hg. Both drugs significantly inhibited serum ACE to about 5 to 10% of initial values and with a duration for more than 24 h. Both drugs also caused a decrease in plasma All levels and also in plasma aldosterone concentrations. There were no toxic effects and no serious side effects. Careful monitoring of biochemical variables showed no significant changes. We conclude that both enalapril and lisinopril are effective and very Safe agents for the treatment of renovascular hypertension and with a long duration of action and with very good tolerance.

Studies on the Mechanism of the Enhancement of the Antihypertensive Activity of Captopril by A Diuretic in Spontaneously Hypertensive Rats

Captopril (30 mg/kg/day orally for two days) in spontaneously hypertensive rats (SHR) inhibited serum angiotensin converting enzyme (ACE) activity 92.3%; increased plasma renin activity (PRA) 18-fold and reduced mean arterial blood pressure (MABP) 19 mm Hg. Hydrochlorothiazide (HCTZ) (100 mg/kg-day 1; 10 mg/kg-day 2, orally) increased PRA 3-fold but did not affect serum ACE or MABP. HCTZ plus captopril inhibited serum ACE 95.2%; increased PRA 38-fold and reduced MABP 47.5 mm Hg. Captopril or HCTZ plus captopril did not alter the responses of isolated aortic strips to norepinephrine (NE), serotonin, angiotensin II (AII) or isoproterenol. Pressor responses of conscious SHR to AII and NE were unaltered by captopril or HCTZ plus captopril although the bradykinin-induced depressor responses were significantly but equally potentiated. These results suggest that the potentiating effect of HCTZ is due to some mechanism that shifts the animal's blood pressure maintenance system to a renin-dependent state and is not due to changes in vascular reactivity.