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Several recent studies have suggested that angiotensin-converting enzyme (ACE) inhibitors ameliorate chronic cyclosporin A (CyA) tubulo-interstitial disease by mechanisms independent of their antihypertensive effects. The aim of the present study was to determine whether ACE inhibition exerts a direct beneficial effect on the tubulo-interstitium in an in vitro model of chronic CyA nephropathy.
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CyA promoted CF collagen synthesis, PTC cytotoxicity (suppressed viability, growth and sodium transport), and tubulo-interstitial fibrogenic cytokine release (CF secretion of insulin-like growth factor I and PTC secretion of TGFbeta1 and platelet-derived growth factor). Enalaprilat completely reversed the stimulatory effects of CyA on CF collagen synthesis (CyA + enalaprilat 6.40 +/- 0.50% vs. CyA alone 8.33 +/- 0.56% vs. control 6.57 +/- 0.62% vs. enalaprilat alone 5.55 +/- 0.93%, p < 0.05) and PTC secretion of TGFbeta1 (0.71 +/- 0.11, 1.13 +/- 0.09, 0.89 +/- 0.07, and 0.67 +/- 0.09 ng/mg protein/day, respectively, p < 0.05). However, the other manifestations of CyA toxicity were not significantly reversed by concomitant enalaprilat administration.
The hypotensive and hormonal responses of an AT1-subtype angiotensin II receptor antagonist, SR 47436, were investigated and compared with those of DuP 753 (losartan), the leading AT1-receptor antagonist, and captopril and enalapril, two major angiotensin converting enzyme (ACE) inhibitors, in conscious, sodium-replete and sodium-depleted non-human primates.
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A dual pathway for Ang II generation exists in human resistance arteries, mediated by ACE and a chymostatin-sensitive enzyme, probably chymase. We confirm that a marked species difference exists in the mechanism of Ang II generation between the human and the rabbit. More efficacious suppression of the renin-angiotensin system may require development of novel enzyme inhibitors or combinations of currently available drugs.
The purpose of this study was to determine if the changes in renal function acutely produced by an inhibitor of angiotensin converting enzyme (ACE) in the sodium-depleted conscious marmoset can be explained primarily by blockade of the renin-angiotensin system. Intravenous injection of a dose of the ACEI, enalaprilate (2 mg/kg), that produced a maximal lowering of blood pressure (BP), also decreased renal vascular resistance and increased renal blood flow. Glomerular filtration rate was unchanged by enalaprilat, leading to a fall in the filtration fraction. In comparison, a dose of the renin inhibitory monoclonal antibody, R-3-36-16 (0.1 mg/kg), that also produced a maximal fall in BP, produced similar changes in renal hemodynamics to those observed after administration of the ACEI. Combined administration of 2 mg/kg enalaprilat and 0.1 mg/kg R-3-36-16 produced changes in BP and renal hemodynamics similar to those produced by the same doses of either agent administered alone. Enalaprilat (2 mg/kg) significantly increased urine volume (UV) and urinary sodium excretion (UNaV). In contrast, these parameters were not significantly altered by 0.1 mg/kg R-3-36-16. However, when given at a 10-fold higher dose, the monoclonal antibody produced an increase in UNaV and UV identical to that produced by the ACEI alone. Enalaprilat did not increase UV and UNaV excretion to a greater extent than the high dose of the renin inhibitory antibody. These results demonstrate that acute administration of an ACEI affects BP and renal function in the sodium-depleted conscious primate primarily by inhibition of the renin-angiotensin system.
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In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.
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Eighty SD rats were used to prepare burn serum. Hearts of another 24 SD rats were isolated to reproduce Langendorff perfusion model. The rat hearts were divided into different groups with different perfusion fluids as K-H buffer group, K-H buffer containing 20% burn serum group (burn serum group), K-H buffer containing 20% burn serum and 2 microg/mL enalaprilat group (enalaprilat group), and K-H buffer containing 20% burn serum and 1 nmol/mL Ang (1-7) group [Ang(1-7) group]. The rat hearts were perfused for 30 mins with each of above-mentioned fluids in different groups. Then left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), +/- dp/dt max, coronary flow(CF), level of creatine kinase (CK) and lactate dehydrogenase (LDH) in respective coronary effluent were determined.
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The effects of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalaprilat and enalapril, and the bioactive peptides angiotensin II (Ang II), [Sar1,Ile8]angiotensin II ([Sar1,Ile8]Ang II), bradykinin and D-Arg[Hyp3,D-Phe7]bradykinin) on mitogen-induced proliferation of T-lymphocytes were evaluated in C57 mouse spleen cells. Captopril (CP) dose-dependently enhanced concanavalin A (Con A)-induced proliferation of T-lymphocytes, with the effective stimulatory concentration range between 0.02-10 mM. The mitogen-induced proliferative response was inhibited at high concentrations (> 10 mM) of CP which affected the number of viable cells. Enalapril dose-dependently inhibited Con A-induced T-lymphocyte proliferation at 0.44-20 mM. This was comparable to the ACE inhibitory peptide, which had a similar range. Enalaprilat, the active parent diacid of enalapril, also showed a weaker inhibitory effect on the Con A-induced proliferative response (4-20 mM). The bioactive peptides had little effect, except at a relatively high concentration. Angiotensin II (Ang II) at 0.05 mM inhibited the Con A-induced proliferative response while [Sar1,Ile8]Ang II, a specific antagonist of Ang II, had no effect. Both bradykinin and its specific antagonist, D-Arg[Hyp3,D-Phe7]bradykinin, had no effect on Con A-induced T-lymphocyte proliferation. The ACE inhibitors and bioactive peptides had little or no cytotoxic effects, except when present at or more than 5 mM. In conclusion, the effects of ACE inhibitors such as captopril and enalapril on Con A-induced T-lymphocyte proliferation were confirmed after a pilot study recently reported. These effects, especially with the stimulatory effect of CP, are unrelated to their ability to inhibit angiotensin-converting enzyme and perturbation of the bioactive peptides such as angiotensin II and bradykinin.
The early effects of the diabetic milieu on retinal tissue and their relation to the Renin-Angiotensin system (RAS) activation are poorly known. Here we investigated RAS signaling in retinas explanted from adult rats exposed for 48 h to high glucose (HG), with or without the Angiotensin Converting Enzyme inhibitor enalaprilat, which blocks RAS. HG was observed to i) initiate a phosphotyrosine-dependent signaling cascade; ii) up-regulate Angiotensin(1) Receptor (AT(1)R); iii) activate src tyrosine kinase and increase phosphorylation of Pyk2, PLCgamma1 and ERK1/2; and iv) activate Akt and the transcription factor CREB. In the presence of enalaprilat, tyrosine phosphorylation signal and AT(1)R upregulation decreased and activation of PLCgamma1 and CREB reverted, showing their relation to RAS signaling. In line with Akt activation, no apoptosis or synapse degeneration was found. Müller glia was activated, but in a RAS-independent manner. Our results suggest that, in early phases of HG exposure, a pro-survival cell program may be induced in the retina.
The present results provide evidence that angiotensin-converting enzyme inhibitors remarkably enhance liver regeneration.
A nonrandomized, nonblinded, prospective clinical trial was performed.
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The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of enalapril maleate, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, are reviewed. Enalapril is rapidly converted by ester hydrolysis to enalaprilat, a potent ACE inhibitor; enalapril itself is only a weak ACE inhibitor. Enalapril lowers peripheral vascular resistance without causing an increase in heart rate. In patients with congestive heart failure, enalapril has beneficial hemodynamic effects based on reduction of both cardiac preload and afterload. Approximately 60% of a dose of enalapril is absorbed after oral administration. Excretion of enalaprilat is primarily renal. Accumulation of enalaprilat occurs in patients with creatinine clearances less than 30 mL/min. Enalapril 10-40 mg per day orally has shown efficacy comparable to that of captopril in treating patients with mild, moderate, and severe hypertension, hypertension caused by renal-artery stenosis, and in congestive heart failure resistant to digitalis and diuretics. When given alone for hypertension, enalapril has efficacy comparable to that of thiazide diuretics and beta blockers. Side effects observed with enalapril have generally been minor. Captopril-associated side effects such as skin rash, loss of taste, and proteinuria have been observed in a small number of patients receiving enalapril to date; neutropenia less than 300/mm3 has been noted with captopril but not enalapril. The incidence of these side effects has been noted to be greatly decreased in patients on low doses of captopril. Enalapril appears to be similar in efficacy to captopril for treating hypertension and congestive heart failure. Whether enalapril is safer than low-dose captopril in patients at high risk for captopril-associated side effects will require further investigation.
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We have studied the effects of various angiotensin-converting enzyme (ACE) inhibitors on intraocular pressure (IOP) of rabbits with experimentally induced ocular hypertension and their mechanism of action. Acute ocular hypertension was induced by infusion of 5% glucose (15 ml/kg) through marginal ear vein, whereas chronic glaucoma was induced by injection of alpha-chymotrypsin into the posterior chamber of the eye. IOP was measured by tonometer. All ACE inhibitors were instilled topically in the eye in a sterile solution. The effect of ACE inhibitors also was studied on serum cholinesterase (true and pseudo) and the enzyme ACE in vitro. Enalaprilat, ramiprilat, and fosinopril produced a time-dependent decrease of IOP in both acute and chronic models of ocular hypertension in rabbits. The decrease in IOP was observed for >4 h, and the extent of decrease was comparable to that with both pilocarpine and betaxolol. Prodrugs enalapril and ramipril failed to produced any change in IOP. Losartan also produced a significant decrease in IOP in the chronic model of ocular hypertension in rabbits. All the three ACE inhibitors were found to inhibit ACE activity in aqueous humor. The enzyme cholinesterase was found to be inhibited by enalaprilat, ramiprilat, and fosinopril. However, atropine did not alter the IOP-lowering effect of enalaprilat in rabbits. Indomethacin pretreatment produced slight but significant inhibition of the IOP-lowering effect of enalaprilat in rabbits. Our data suggest that ACE inhibitors enalaprilat, ramiprilat, and fosinopril produce a significant ocular hypotensive effect in acute and chronic models of ocular hypertension in rabbits. Inhibition of ACE in aqueous humor, and in ocular tissues, resulting in reduced angiotensin II formation, could be one of the major mechanisms responsible for the IOP reduction by ACE inhibitors in rabbits.
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The response of renin release to the administration of renin inhibitors cannot be studied with conventional enzymatic methods used to measure plasma renin. In the present experiments, a novel multirange enzyme-linked immunosorbent assay for human and primate renin was used to investigate the changes in plasma immunoreactive renin after renin inhibition. A potent and long-acting statine-containing renin inhibitor, CGP 29 287, was injected in conscious marmosets after mild or severe sodium depletion. In mildly sodium-depleted marmosets, CGP 29 287 (0.1 mg/kg i.v.) reduced mean arterial blood pressure and completely inhibited plasma renin activity for up to 30 minutes. This response was associated with a transient increase in plasma immunoreactive renin concentration. After a dose of 1.0 mg/kg i.v., the reduction of mean arterial pressure and the complete inhibition of plasma renin activity persisted for up to 120 minutes. These effects were accompanied by a sustained increase in plasma immunoreactive renin concentration. In severely sodium-depleted marmosets, CGP 29 287 (1.0 mg/kg i.v.) induced a marked fall in systolic blood pressure and complete inhibition of plasma renin activity within 30 minutes of injection. Plasma immunoreactive renin levels increased to 257% of pretreatment values. The converting-enzyme inhibitor enalaprilat (2 mg/kg i.v.) induced a fall in systolic blood pressure of similar magnitude, which was accompanied by an increase in plasma renin activity. Levels of plasma immunoreactive renin increased to 210% of pretreatment values. Hydralazine (0.2 mg/kg i.v.) did not increase plasma renin activity or plasma immunoreactive renin levels despite a comparable hypotensive effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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Studies on the effects of peptidase inhibitors on substance P-like immunoreactive material (SPLI) released by K(+)-induced depolarization from slices of the rat spinal cord showed that bacitracin was the most potent agent to protect SPLI from degradation. Captopril and thiorphan which inhibit, respectively, angiotensin I converting enzyme and endopeptidase-24.11 also protected SPLI from degradation. However other inhibitors of these two enzymes, kelatorphan for endopeptidase-24.11 and enalaprilat for angiotensin I converting enzyme were essentially inactive, indicating that both enzymes are probably not involved in the degradation of endogenous substance P. Instead, the non-additive protecting effect of bacitracin, captopril and thiorphan might be due to the blockade of some 'bacitracin-sensitive enzyme' playing a key role in the catabolism of SP within the rat spinal cord.
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The cis and trans isomeric composition of a proline peptide bond can be determined by routine free-solution capillary electrophoresis measurements provided that one isomeric form is preferentially stabilized by a dissociable ionic group. This capability is illustrated using the angiotensin converting enzyme (ACE) inhibitor (S)-1-N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-ala-L-pro, which has the trade name enalapril. Electropherograms indicate that the two isomeric forms of enalapril can be separated with baseline resolution at 15 degrees C using capillary buffers having pH values in the dissociation ranges of the enalapril carboxyl group, pK(cis) and pK(trans) of 2.6 and 3.1, and of the enalapril amine group, pK(cis) and pK(trans) of 5.9 and 5.6. Such baseline resolution indicates that the isomeric composition does not change during analysis, facilitating measurement of the isomer composition of a sample prior to its injection into the capillary. Thus the effect of pH, ionic strength, or an aprotic solvent on the isomeric composition of enalapril can be measured under uniform analytical conditions. The trans isomer composition changes from 68% in the cationic form, pH <2, to 50% in the isoelectric form, pH approximately 4.5, to 60% in the anionic form, pH >7. Addition of salt to the isoelectric form or addition of an aprotic solvent to any form prior to analysis increases the trans isomer composition. Similar analyses can be made using the alternative ACE inhibitors captopril and enalaprilat.
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The present study showed that when NPE occurs, a high lung AngII concentration was associated with an imbalance between ACE mRNA to ACE2 mRNA expression level. Activated local RAS in lung tissue resulted in lung injury. Enalaprilat treatment may attenuate lung injury by interventing local RAS in lung tissue with decreased ratio of ACE mRNA to ACE2 mRNA and lung AngII concentration. The result will be significant for the angiotensin converting enzyme inhibitor used in the theatment of NPE.
The angiotensin-converting enzyme inhibitor (ACE-I) enalapril has been shown to lower elevated levels of circulating adhesion molecules (cAM) in critically ill patients. To delineate the mechanisms of this possibly beneficial effect of enalapril, we studied the acute effects of enalapril in a well-defined model of endotoxin-triggered, cytokine-mediated cAM up-regulation. In a randomized, controlled trial, 30 healthy male volunteers received 2 ng/kg lipopolysaccharide (LPS) after pretreatment with placebo or 20 mg/day enalapril for 5 days or with a single dose of 20 mg of enalapril 2 h before LPS infusion. LPS infusion increased TNF levels 300-fold above normal, circulating (c) E-selectin levels by 425% (CI, 359%-492%), and P-selectin, VCAM-1, ICAM-1, and von Willebrand factor levels by 47%-74%. LPS infusion also enhanced ICAM-1 and CD11b expression 2- to 3-fold on monocytes. However, no differences were seen between treatment groups (P > 0.05), despite 95% inhibition of ACE activity by enalapril. Inhibition of ACE activity by enalapril does not influence plasma indices of endothelial activation after endotoxin infusion in healthy individuals. Our results do not support the concept of a beneficial clinical effect of enalaprilat in septicemia.
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Neither the infusion of angiotensin II nor the acute administration of enalaprilat significantly alters the activity of the sympathetic nervous system as reflected by plasma norepinephrine or systemic venous norepinephrine spillover in patients with chronic congestive heart failure. These data weaken the hypothesis that angiotensin II is an important regulator of sympathetic activity in congestive heart failure.
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Influence of enalaprilat, angiotensin converting enzyme inhibitor, on a functional proteinuria associated with increase in diuresis unduced by furosemide, 1-deamino-arginine vasotocin (1d-AVT) injection or water loading was investigated in experiments with Wistar rats. Intraperitoneal injection of 0.1 mg/100 g b.w. of enalaprilat resulted in reduction of glomerular filtration rate, solute-free water reabsorption and solutes excretion, particularly potassium excretion, after 1d-AVT administration and decrease in diuresis and solute-free water excretion after oral water loading. Enalaprilat injection did not influence on the level of proteinuria induced by the various types ofdiuresis and albuminuria during water diuresis and 1d-AVT-dependent saluresis. The data obtained have shown that decrease in angiotensin II production in the renal structures does not affect protein excretion rate during examined forms of proteinuria and suggest existence of a multicomponent system of the pressure stabilization in the glomerular apparatus.
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Angiotensin-converting enzyme (ACE) inhibitors are well established as long-term antihypertensives and have also been proved useful in hypertensive emergencies. Therefore, we investigated whether intraoperative i.v. enalaprilat may reduce the incidence of perioperative hypertensive reactions in coronary artery bypass grafting (CABG).
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The angiotensin-converting enzyme inhibitor enalaprilat is formed in vivo in liver and kidney by esterolysis of the antihypertensive drug enalapril. To gain insight into the renal elimination of enalaprilat, we carried out multiple-indicator dilution experiments in the isolated perfused rat kidney. Kidneys were perfused single pass with an amino acid-supplemented Krebs-Henseleit buffer containing 20% bovine red blood cells and 4% bovine serum albumin, at a flow rate of 0.11 +/- 0.02 (SD) ml.s-1 x g-1. A bolus of 51Cr-labeled red blood cells (vascular red blood cell indicator), 125I-labeled albumin (vascular plasma indicator), L-[14C]glucose (interstitial space indicator), and [3H]-enalaprilat was injected into the renal artery, and timed samples of venous blood (up to 1 min) and urine (up to 10 min) were collected. The data were analyzed using a variable-transit-time, space-distributed model with modifications accounting for glomerular filtration and the observed 14% protein binding of enalaprilat; the glomerular filtration rate (GFR) estimated from L-glucose clearance was 9.0 +/- 2.9% of total plasma flow. The ratio of renal clearance of unbound enalaprilat to GFR was 1.56 +/- 0.29, indicating both glomerular filtration and net tubular secretion of enalaprilat. Unidirectional influx from plasma to tubular cells exceeded tubular secretion by a factor of 2.2 +/- 0.5. Thus only about one-half of the enalaprilat taken up by the tubular cells was excreted into urine, with the remainder refluxing into the capillary blood stream, indicating bidirectional permeation of enalaprilat across the basolateral tubular membrane.
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We investigated the degradation of angiotensin I (Ang I) by guinea pig aqueous humor at physiological pH (pH 7.4) and assessed the activity of responsible enzymes using various enzyme inhibitors. The aqueous humor was incubated with Ang I in the presence or absence of an enzyme inhibitor at 37 degrees C for the appropriate time period. The resulting peptides were analyzed by a Beckman HPLC system with a Waters microBondapak C18 analytical column using a 30-min increasing linear gradient of 10 to 40% acetonitrile containing 0.05% trifluoroacetic acid (TFA) and H2O containing 0.05% TFA at a flow rate of 1 mL/min. Detection was done by absorbance at 214 nm. Angiotensin II (Ang II) was a major product (39.3+/-4.10 nmol x h(-1) mL(-1), n = 5) of Ang I hydrolysis. Traces of angiotensin 1-9, angiotensin IV, and angiotensin 1-7 were also produced. Chymostatin (0.05 mmol/L), EDTA (1 mmol/L), enalaprilat (0.1 mmol/L), and ebelacton B (0.01 mmol/L) inhibited generation of Ang II from Ang I by guinea pig aqueous humor by 89+/-4.6, 56+/-7.6, 33+/-5.1, 20+/-6.5%, respectively. Our findings indicate that guinea pig aqueous humor contains several enzymes that can form Ang II. The chymostatin-sensitive type of enzyme was the most active one found in guinea pig aqueous humor. Angiotensin I converting enzyme, carboxypeptidase A, and deamidase may also contribute to angiotensin II formation in guinea pig ocular fluid.
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Acyanotic infants requiring cardiac surgery may have high perioperative concentrations of A-II. Hypothermic CPB is associated with a decrease in A-II concentration. Reductions in gut mucosal perfusion seen in some infants during hypothermic CPB are not related to increases in A-II concentrations.
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Early antihypertensive treatment with beta1 blockers and diuretics has proved to delay progression in diabetic nephropathy. Application of angiotensin converting enzyme inhibitors (ACE-I) may also be relevant. To elucidate possible differences in acute renal response to ACE-I and beta-blockers, kidney function was investigated before and after enalaprilat (10 mg) and metoprolol (10 mg) i.v. in 8 microalbuminuric insulin-dependent diabetic patients on no antihypertensive therapy (Study A). Glomerular filtration rate (clearance of 125I-iothalamate) was unchanged with both agents. ACE-I gave rise to efferent renal vasodilation: renal resistance and filtration fraction fell, renal plasma flow (RPF; 131I-hippuran) tended to rise (2p = 0.07) and blood pressure and urinary albumin excretion rate (UAE; radioimmunoassay) were reduced. In contrast, metoprolol caused a decline in RPF, an increase in renal resistance and filtration fraction, and no change in blood pressure or UAE. In 10 diabetic, nephropathic patients undergoing treatment with metoprolol and thiazide (Study B), the acute response to enalaprilat corresponded closely to that observed in Study A, including a decrease in UAE and blood pressure. Over 6 months the addition of enalapril (20 mg/d) to metoprolol and thiazide produced a more pronounced UAE-reduction, although no significant decrease in blood pressure was observed. The present findings support that ACE-I may process specific renoprotective effects. A combination therapy with beta1 blockers, ACE-I, and diuretics is suggested.
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Brief ischemia followed by reperfusion induces arteriolar microvascular endothelial dysfunction, while venular endothelial function is preserved in this porcine model. ACE inhibition enhances coronary blood flow at the time of reperfusion and can prevent impairment of endothelium-dependent arteriolar responses. However, ACE inhibition does not enhance ventricular segmental shortening acutely despite improved microvascular endothelial function and augmented postischemic coronary blood flow in this model of ischemia-reperfusion.
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The affinity of three substrates for the intestinal peptide carrier is explained based on their three-dimensional (3D) structural data. The kinetic transport parameters of three ACE-inhibitors, enalapril, enalaprilat, and lisinopril, have been determined in an in vivo system using rat intestine. The observed kinetic transport parameters (+/- asymptotic standard error) of enalapril are: 0.81 (+/- 0.23) mM, 0.58 (+/- 0.37) mumol/h per cm2, and 0.56 (+/- 0.04) cm/h for the half-maximal transport concentration (KT), the maximal transport flux (Jmax) and the passive permeability constant (Pm). Enalaprilat was transported by passive diffusional with a Pm of 0.51 (+/- 0.04) cm/h. For lisinopril the kinetic transport parameters were 0.38 (+/- 0.19) mM, 0.12 (+/- 0.07) mumol/h per cm2, and 0.18 (+/- 0.02) cm/h for KT, Jmax, and Pm, respectively. The affinity of the ACE-inhibitors for the intestinal peptide carrier has been evaluated based on their ability to inhibit the transport rate of cephalexin. The inhibition constants (Ki) of enalapril, enalaprilat and lisinopril were 0.15, 0.28 and 0.39 mM, respectively. 3D structural analysis of lisinopril using molecular modelling techniques reveals that intramolecular hydrogen bond formation is responsible for decreased carrier affinity.
Since angiotensin converting enzyme (ACE) metabolizes bradykinin, the hypotensive effect of ACE inhibitors could be partly due to an increased bradykinin activity. We therefore investigated the influence of HOE K86-4321 [D-Arg-(Hyp2-Thi5,8-DPhe7)-bradykinin], a selective bradykinin-2 receptor antagonist, on the effects of enalaprilat (0.3 and 3.0 mg/kg) and zofenoprilat (0.1 and 1.0 mg/kg) on the heart rate, mean arterial blood pressure, cardiac output and total peripheral resistance in rats. Both enalaprilat and zofenoprilat reduced mean arterial pressure (from 110 +/- 7 to 85 +/- 6 and from 108 +/- 9 to 72 +/- 9 mmHg, respectively; P less than 0.05) and total peripheral resistance (from 515 +/- 35 to 413 +/- 29 and from 495 +/- 45 to 310 +/- 25 x 10(-3) mmHg/litre per min per kg, respectively; P less than 0.05); the heart rate and cardiac output changed little. In the presence of HOE K86-4321, which by itself did not affect the haemodynamic variables measured, the effects of the two ACE inhibitors were significantly reduced. These results suggest that bradykinin-2 receptor-mediated vasodilation, although not involved in blood pressure regulation, influences the reduction in blood pressure induced by enalaprilat and zofenoprilat in normotensive rats. Furthermore, at comparable ACE-inhibiting doses, zofenoprilat was more effective in reducing mean arterial pressure, which might be related to the presence of a sulphydryl group.
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Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as angiotensins, atrial natriuretic factor (ANF), bradykinin and endothelin. The effects of a highly selective NEP inhibitor (NEPI), retrothiorphan, of a converting enzyme inhibitor (CEI), enalaprilat, and of the combination, CEI + NEPI, were assessed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs) and renovascular hypertensive rats. NEPI increased diuresis, natriuresis and urinary cyclic GMP (cGMP), ANF and bradykinin in the three models. NEPI decreased blood pressure in DOCA-salt hypertensive rats only, whereas CEI decreased blood pressure in SHRs and renovascular hypertensive rats only and increased plasma renin. CEI had no effect on urinary aldosterone or bradykinin in any of the three models. CEI + NEPI increased diuresis and natriuresis in DOCA-salt hypertensive rats and SHRs, and increased urinary cGMP, ANF and bradykinin and plasma renin levels. CEI and NEPI interacted significantly to decrease blood pressure and to increase urinary cGMP in SHRs only. Hence, NEPI increases diuresis, natriuresis and urinary cGMP, ANF and bradykinin in experimental hypertension, whereas CEI acts on blood pressure and increases in plasma renin in SHRs and renovascular hypertensive rats. The significant interaction between CEI and NEPI to decrease blood pressure in SHRs indicates that simultaneous blockade of the two metallopeptidases results in potentiation of the hypotensive effect and that the SHRs appear to be a good model for studying NEP and ACE coinhibition. Finally, NEP rather than ACE appears to be involved in bradykinin renal catabolism in experimental hypertension.