Angiotensin-converting Enzyme Inhibitor Quinapril Research Articles

Identification of a Gut Commensal That Compromises the Blood Pressure-Lowering Effect of Ester Angiotensin-Converting Enzyme Inhibitors.

Background:Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects.Methods and Results:To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus. C. comes, an anaerobic species of Coprococcus, harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril.Conclusions:Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats

Background/Aims: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (pro)renin receptor ((P)RR) blockade and angiotensin converting enzyme (ACE) inhibition on the progression of diabetic nephropathy in rats. Methods: Diabetes (DM) was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (P)RR blocker „handle region” decoy peptide (HRP, 0,1 mg/kg/day) or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day) and grouped as follows: 1. Control (n=10); 2. DM (n=8); 3. DM+HRP (n=6); 4. DM+Q (n=10); 5. DM+Q+HRP (n=10). Renal functional parameters, histology and gene expressions were evaluated. Results: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2) phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-ß1 expression and ERK(1/2) phosphorylation to the same extent. Conclusion: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2) phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy.

Correction of hemorheology blood and proteolysis of hemostasis in patients with peptic ulcers of the stomach and duodenum, diabetes mellitus II type

In the research the hemostasis and proteolysis systems have been studied. The hypercoagulation syndrome in the patients with peptic ulcer, combined with diabetes mellitus has been established. The reaction of fibrinolysis and proteolysis systems has been inadequate to the degree of hemostasis coagulation activity, which may be the evidence of body's compensatory mechanisms reduction. Application of the angiotensin-converting enzyme inhibitor quinapril on the background of the Helicobacter therapy is pathogenically reasonable and helps to eliminate violations.

In Vivo Kinetics of Indoxyl Sulfate in Humans and Its Renal Interaction with Angiotensin-Converting Enzyme Inhibitor Quinapril in Rats

Indoxyl sulfate (IS) is an organic anion uremic toxin that accumulates in patients with chronic kidney disease (CKD). The aims of this study were to examine the kinetic profiles of IS in humans at a steady state after multiple doses of L-Trp, a precursor of IS, and the in vivo interaction of IS with the angiotensin-converting enzyme inhibitor quinapril, whose active metabolite is a substrate of organic anion transporter 3 (OAT3) in rats. First, 12-h kinetics after single doses of Trp (2, 4, and 8 g) were examined in two healthy volunteers. Second, 24-h kinetics after a single dose of 2 g of Trp was studied in six volunteers. Third, 35-h kinetics after single and multiple doses of 2 g of Trp were examined in five volunteers. In anesthetized rats, quinapril or probenecid, an inhibitor of OATs, was given intravenously before IS, and blood and urine samples were taken until 90 min. Trp and IS concentrations were determined by high-performance liquid chromatography. Ultrafiltration was used to measure serum unbound IS concentrations. Renal tubular secretion of IS accounted for more than 90% of its renal clearance in the steady state of serum IS levels after multiple doses in humans. In animals, the serum area under the curve of IS increased in conjunction with a decrease in renal clearances after coadministration of IS with quinapril or probenecid. It is concluded that quinapril may inhibit the urine excretion of IS via OAT3-mediated renal tubular transport in patients with CKD.

Heart Rate Variability in Conscious and Anesthetized Rats under the Action of Angiotensin Converting Enzyme Inhibitors

We studied the effects of three various angiotensin converting enzyme inhibitors (enalapril, lisinopril and quinapril) on heart rhythm variability in anesthetized and immobilized rats. In all cases (except for quinapril in experiments on anesthetized animals), the preparations reduced the total rhythm variability and, according to spectrum analysis, increased activity of the parasympathetic autonomic nervous system to different degrees and decreased sympathetic tone. Quinapril and lisinopril produced the most pronounced influence on heart rhythm in anesthetized rats; enalapril was less potent in this respect. In immobilized animals, quinapril and enalapril showed the greatest activity and lisinopril the lowest. The more pronounced effect of quinapril both under anesthesia and during immobilization appears to be linked to the highest affinity of quinaprilat to circulatory and tissue compartments of the renin-angiotensin-aldosterone system.

Analysis of the angiotensin-converting enzyme inhibitors perindopril, lisinopril, and quinapril by HPLC

A unified HPLC method for analyzing the angiotensin-converting enzyme (ACE) inhibitors perindopril, lisinopril, and quinapril using a single column with a nonpolar phase based on octadecylsilica gel and a universal eluant (a mixture of acetonitrile and aqueous heptanesulfonic acid and triethylamine) is described; this method significantly decreases workload and the cost of analysis. The method can be used for the analysis of substances and different therapeutic formulations containing ACE inhibitors.

Cardiovascular effects of inhibition of renin-angiotensin-aldosterone system components in hypertensive rats given salt excess

This study examined the role of the renin-angiotensin-aldosterone system (RAAS) in mediating cardiovascular and renal damage in spontaneously hypertensive rats (SHR) given salt excess. Since the circulating RAAS is inhibited in this model, it permits examination of the role of local tissue RAASs in mediating this injury. To this end, male 8-wk SHR were divided into 7 groups. The control group (C) received normal NaCl (0.6%) diet. All other groups were given 8% NaCl chow. In addition, group 2 was given placebo, group 3 the mineralocorticoid receptor blocker eplerenone (100 mg.kg(-1).day(-1)), group 4 the angiotensin converting enzyme inhibitor quinapril (3 mg.kg(-1).day(-1)), group 5 the angiotensin II type 1 receptor blocker candesartan (10 mg.kg(-1).day(-1)), and groups 6 and 7 eplerenone and either quinapril or candesartan. The treatments lasted 8 wk. Compared with controls, mean arterial pressure (MAP), renal blood flow, coronary flow reserve, minimal coronary vascular resistance, diastolic time constant, and maximal rate of ventricular pressure fall were all adversely affected by salt loading. Left ventricular mass and fibrosis as well as proteinuria were also markedly increased by salt overload. Eplerenone induced only slight changes, whereas quinapril and candesartan normalized all indexes except MAP. Combination therapy also normalized all indexes, including MAP. These data suggest that 1) cardiovascular and renal damage induced by salt excess in the SHR were not pressure dependent; 2) mineralocorticoids were only marginally involved in this model; and 3) local tissue generation of angiotensin II may be, at least in part, responsible for the other adverse effects.

Effect of Quinapril on In-Stent Restenosis and Relation to Plasma Apoptosis Signaling Molecules

Angiotensin-converting enzyme inhibitors have been reported to inhibit in-stent restenosis. To assess the effect of angiotensin-converting enzyme inhibition on in-stent restenosis and its relation to apoptosis, 86 patients with chronic coronary artery disease who required stent implantation in the left anterior descending coronary artery or a major diagonal branch were studied. Patients were randomized to receive quinapril 40 mg/day orally (n = 43) or a placebo (n = 43). Drug therapy was initiated 1 week before initial stenting and continued for 6 months. Plasma levels of the apoptotic signaling molecules soluble Fas and soluble Fas ligand obtained from blood drawn from the left anterior descending coronary artery were measured just before initial stenting and 6 months later, at the time of repeat coronary angiography. In-stent restenosis was present in 9.3% of patients in the quinapril group and 25.6% of patients in the placebo group (p = 0.047). Mean late luminal loss was 0.56 +/- 0.51 mm in the quinapril group and 0.95 +/- 0.95 mm in the placebo group (p = 0.003). There were no significant differences in plasma soluble Fas or soluble Fas ligand levels at baseline. At 6 months, the change in plasma soluble Fas level was significantly higher in the quinapril group (0.72 +/- 1.24 ng/ml) than in the placebo group (0.28 +/- 0.72 ng/ml) (p = 0.024). The change in plasma soluble Fas ligand levels at 6 months was significantly higher in the quinapril group (7.43 +/- 12.2 pg/ml) than in the placebo group (0.06 +/- 6.8 pg/ml) (p = 0.002). In conclusion, the angiotensin-converting enzyme inhibitor quinapril inhibits in-stent restenosis by stimulating apoptosis after percutaneous intervention.

ACE inhibitors in the treatment of heart failure

The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathogenesis of congestive heart failure (CHF). Abnormal activation of the RAAS adversely affects cardiac performance and impairs functional status, increasing both afterload and preload through direct and indirect mechanisms. Conventional first-line therapy for CHF consists of diuretics and/or digitalis. Diuretics offer rapid relief of symptoms, effective volume control, and ease of administration, but are associated with a number of disadvantages, including further activation of neurohormonal systems resulting in augmented vasoconstriction. Angiotensin-converting enzyme (ACE) inhibitors, which block the RAAS by inhibiting production of angiotensin II from angiotensin I, are emerging as the vasodilators of choice in combination with diuretics with or without concomitant digitalis. Direct comparative studies have shown that ACE inhibitors provide acute and long-term symptomatic, hemodynamic, and exercise-related benefits as well as improved functional class and, possibly, slowed progression of disease with enhanced survival in specific subgroups. Captopril was the first orally effective ACE inhibitor associated with improved exercise tolerance and functional class in large multicenter trials of patients with severe heart failure and mild to moderate heart failure. Enalapril reduced the probability of death in patients with severe heart failure in the CONSENSUS trial. The new ACE inhibitor quinapril has been shown to improve hemodynamic status both acutely and chronically and to produce dose-related improvements in exercise tolerance. ACE inhibitors have a favorable safety profile, although hypotension can occur with initial doses, particularly in volume-depleted patients or at times when excessive initial doses are administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

In humans and rats, a synergistic blood pressure reduction was observed when the fibrate gemcabene (CI-1027) was coadministered with the angiotensin-converting enzyme inhibitor quinapril. In a quinapril (3 mg/kg) pharmacokinetic rat study, there was a 40% decrease in urinary excretion and a 53% increase in plasma area under the curve from 0 to 24 h of the active metabolite quinaprilat when coadministered with gemcabene (30 mg/kg). This observation revealed a possible transporter-mediated drug-drug interaction (DDI) between gemcabene and quinapril. This led to a series of studies investigating the underlying clearance mechanisms associated with these compounds intended to elucidate renal transporter interactions between quinapril and gemcabene. In vitro transporter studies using human embryonic kidney 293 cells transfected with human or rat organic anion transporter 3 (hOAT3, rOat3) revealed that quinaprilat is a substrate in both species, with a K(m) value of 13.4 microM for hOAT3. Subsequent studies discovered that gemcabene inhibited quinaprilat uptake by hOAT3 and rOat3 at IC(50) values of 35 and 48 microM, respectively. Moreover, gemcabene acylglucuronide, the major metabolite of gemcabene glucuronidation, also inhibited hOAT3- and rOat3-mediated uptake of quinaprilat at IC(50) values of 197 and 133 microM, respectively. High plasma concentrations of gemcabene (>100 microM) achieved in humans and rats upon oral dosing corroborate with gemcabene inhibition of renal OAT3-mediated secretion of quinaprilat in vitro. This investigation established that a DDI between gemcabene and quinapril involving inhibition of renal transporters and subsequent elevation in plasma concentrations of quinaprilat is responsible for the apparent synergistic blood pressure reduction observed with these compounds.

Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats

The incidence of diabetes mellitus is increasing. Cardiac dysfunction often develops, resulting in diverse arrhythmias. These arise from ion channel remodeling or from altered speed and pattern of impulse propagation. Few studies have investigated impulse propagation in the diabetic heart. We previously showed a reduced conduction reserve in the diabetic heart, with associated changes in intercellular gap junctions. The present study investigated whether these effects are sex specific. Hearts from control and streptozotocin-diabetic male and female rats were used. Optical mapping was performed with the voltage-sensitive dye di-4-ANEPPS, using Langendorff-perfused hearts. Isolated ventricular cells and tissue sections were used for immunofluorescent labeling of the gap junction protein connexin43 (Cx43). The gap junction uncoupler heptanol (0.75 mM) or elevated K(+) (9 mM, to reduce cell excitability) produced significantly greater slowing of propagation in diabetic males than females. In ovariectomized diabetic females, 9 mM K(+) slowed conduction significantly more than in nonovariectomized females. The subcellular redistribution (lateralization) of the gap junction protein Cx43 was smaller in diabetic females. Pretreatment of diabetic males with the angiotensin-converting enzyme inhibitor quinapril reduced Cx43 lateralization and the effects of 9 mM K(+) on propagation. In conclusion, the slowing of cardiac impulse propagation in type 1 diabetes is smaller in female rats, partly due to the presence of female sex hormones. This difference is (partly) mediated by sex differences in activation of the cardiac renin-angiotensin system.

ADMA Impairs Nitric Oxide–Mediated Arteriolar Function Due to Increased Superoxide Production by Angiotensin II–NAD(P)H Oxidase Pathway

Asymmetrical dimethylarginine (ADMA) is thought to be an endogenous regulator of arteriolar tone by inhibiting NO synthase. However, our previous studies showed that, in isolated arterioles, ADMA induced superoxide production as well. Thus, the mechanisms by which ADMA affects arteriolar tone remain obscure. We hypothesized that ADMA, by activating NAD(P)H oxidase, increases superoxide production, interfering with NO mediation of flow-induced dilation. In the presence of indomethacin, isolated arterioles from rat gracilis muscle ( approximately 160 microm at 80 mm Hg) were incubated with ADMA (10(-4) mol/L), which elicited significant constriction (from 162+/-4 to 143+/-4 microm) and eliminated the dilations to increases in intraluminal flow (from a maximum 31+/-2% to 3+/-1%; P<0.05). In the presence of ADMA, superoxide dismutase plus catalase restored dilations to flow (from a maximum 3+/-1% to 28+/-2%). Endothelial denudation or incubation of arterioles with the NAD(P)H oxidase inhibitor apocynin or the angiotensin-converting enzyme inhibitor quinapril inhibited ADMA-induced constriction. In addition, apocynin, quinapril, or the angiotensin type 1 receptor blocker losartan restored flow-induced dilations reduced by ADMA. Furthermore, inhibition of NO synthase abolished the "superoxide dismutase/catalase-restored" flow-induced dilation in the presence of ADMA. ADMA-induced increased production of superoxide, assessed by dihydroethidium fluorescence, was inhibited by apocynin, quinapril, or losartan. We suggest that ADMA activates the local renin-angiotensin system, and the angiotensin II released activates NAD(P)H oxidase; superoxide produced interferes with the bioavailability of NO, resulting in diminished flow-induced dilation, a mechanism that may contribute to the development of arteriolar dysfunction and increased tone associated with elevated ADMA levels.

Lack of efficacy of quinapril on vascular damage in limited cutaneous systemic sclerosis

Gliddon et al. conducted a randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy of the angiotensin-converting enzyme inhibitor quinapril for the management of vascular damage in systemic sclerosis (SSc). The trial comprised 213 patients with limited cutaneous SSc or Raynaud's phenomenon (mean age 54 years, 182 females) who were randomly assigned to receive 80 mg/day, or the maximum tolerated dose, of quinapril (n = 105) or placebo (n = 108) for 2-3 years. Patients were assessed every 3 months. The number of new ischemic digital ulcers was recorded as the primary end point, while the frequency of Raynaud's phenomenon episodes, skin score, health status, pulmonary artery pressure and treatments for ischemia were also monitored as secondary end points. There were no detectable differences between patients treated with quinapril and those receiving placebo; however, although no severe adverse effects were observed, patients taking quinapril experienced significantly more adverse effects.

Does prior PCI increase the risk of subsequent CABG?

Chocron and colleagues have reported that prior percutaneous coronary intervention (PCI) leads to a worse outcome in patients subsequently undergoing coronary artery bypass graft (CABG).1 In view of the fact that around one-third of patients with multivessel disease treated with bare metal stents will require re-intervention within a few years,2 this conclusion is potentially worrying and raises several questions. (i) Is the conclusion justifiable? (ii) Are the findings consistent with other studies in the literature? (iii) If real, what are the likely pathophysiological mechanisms? (iv) Will the findings be different drug-eluting stents? (v) What are the clinical implications for patients and the economic implications for health services? The obvious weakness of the study of Chocron et al. 1 is that it is a re-analysis of the primary end-point of the IMAGINE trial according to whether the patients had undergone PCI prior to CABG, a question which the IMAGINE trial was not designed to answer. Rather, IMAGINE was a randomized trial of the angiotensin-converting enzyme (ACE) inhibitor quinapril in 2553 subjects with preserved left ventricular function after CABG, which concluded that there was no difference in time to occurrence of the primary end-point (a composite of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, coronary revascularization, unstable angina requiring hospitalization, documented angina not requiring hospitalization, stroke, or congestive heart failure requiring hospitalization) in the active or placebo group.3 Re-emphasizing that IMAGINE was not actually designed to … *Corresponding author. Tel: +44 1865 221121, Fax: +44 1865 220244, Email: David.taggart{at}orh.nhs.uk

The Role of Quinapril in the Presence of a Weight Loss Regimen: Endothelial Function and Markers of Obesity in Patients With the Metabolic Syndrome

Forty-four patients with the metabolic syndrome were placed on a reduced-calorie and reduced-fat regimen to lose weight throughout a 56-week period. The patients were treated in a crossover fashion with placebo and the angiotensin-converting enzyme inhibitor quinapril for 24 weeks each. The study measured endothelial-dependent flow-mediated dilation plus serum obesity markers of adiponectin and leptin. Metabolic parameters improved after 56 weeks. Serum adiponectin level increased by 18% (P<.05 vs baseline) and serum leptin level decreased by 16% with placebo (P<.05 vs baseline). These findings were potentiated further in the quinapril group. In comparison with baseline, flow-mediated dilation was increased by 13% in the placebo group (P=.055 vs baseline) and by 43% in the quinapril group (P<.001 vs baseline and placebo). These findings suggest that weight loss therapy improves endothelial function and markers of obesity. These results are potentiated with quinapril and are independent of changes in metabolic parameters.

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice

To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury. The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury. Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls. Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response. These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.

Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition

To elucidate the molecular mechanisms of the cardioprotective effect of angiotensin-converting enzyme (ACE) inhibitors, we evaluated whether the effect of quinapril involved in bradykinin-endothelial nitric oxide synthase (eNOS) and oxidative stress-lectin-like oxidized LDL receptor-1 (LOX-1) pathway. Dahl salt-sensitive hypertensive (DS) rats were fed a diet containing 8% NaCl and treated with one of the following drug combinations for 5 weeks, from 6 weeks of age to left ventricular hypertrophy stage (11 weeks): vehicle; quinapril; quinapril plus the bradykinin B2 receptor antagonist FR172357; the NAD(P)H oxidase inhibitor apocynin; or quinapril plus apocynin. eNOS expression, which was decreased in hypertrophy stage, was significantly increased by quinapril and/or apocynin, but not by quinapril plus FR172357. Upregulated expression of NAD(P)H oxidase p22phox, p47phox, gp91phox and LOX-1 was significantly decreased by quinapril to a similar degree as after treatment with apocynin, but not by quinapril plus FR172357. Quinapril and/or apocynin treatment effectively ameliorated left ventricular weight and vascular changes such as increase in medial thickness and perivascular fibrosis and suppressed expression of transforming growth factor-β1, type I collagen and fibronectin mRNA, but not that of quinapril plus FR172357. These results suggest that the ACE inhibitor quinapril may have cardioprotective effects in this model of hypertension mediated at least in part through effects on the bradykinin-eNOS and oxidative stress-LOX-1 pathway.

Modulation of potassium currents by angiotensin and oxidative stress in cardiac cells from the diabetic rat

Diabetes induces oxidative stress and leads to attenuation of cardiac K+ currents. We investigated the role of superoxide ions and angiotensin II (ANG II) in generating and linking oxidative stress to the modulation of K+ currents under diabetic conditions. K+ currents were measured using patch-clamp methods in ventricular myocytes from streptozotocin (STZ)-induced diabetic rats. Superoxide ion levels, indicating oxidative stress, were measured by fluorescent labelling with dihydroethidium (DHE). ANG II content was measured using enzyme-linked immunosorbent asssay (ELISA). The results showed DHE fluorescence to be significantly higher in cells from diabetic males, compared to controls. Relief of stress by the NADPH oxidase inhibitor apocynin or by superoxide dismutase (SOD) but not by catalase reversed the attenuation of K+ currents and reduced DHE fluorescence. In cells from diabetic females, neither apocynin nor SOD augmented K+ currents, ANG II was not elevated and DHE fluorescence was significantly weaker than in cells from males. Reduced glutathione (GSH) also augmented K+ currents in cells from diabetic males but not females. In ovariectomized diabetic females K+ currents were augmented by GSH and apocynin. Current augmentation and the attenuation of DHE fluorescence by apocynin were significantly blunted by excess ANG II (300 nm). Diabetic male rats pretreated with the angiotensin-converting enzyme (ACE) inhibitor quinapril were hyperglycaemic, but their cellular ANG II levels and DHE fluorescence were significantly decreased. In cells from these rats, K+ currents were insensitive to apocynin. In conclusion, diabetes-related oxidative stress attenuates K+ currents through ANG II-generated increased superoxide ion levels. When ANG II levels are lower, as in diabetic females or following ACE inhibition in males, oxidative stress is reduced, with blunted alterations in K+ currents.

Potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in a model of type 2 diabetes mellitus, obesity, and mild hypertension

Experimental findings suggest that the obese Zucker rat (OZR) is a model of type 2 diabetes-related nephropathy with several metabolic abnormalities. However, the exact mechanisms by which these factors cause early glomerulosclerosis and proteinuria remain unclear. Furthermore, structural abnormalities and regulation of podocytes have recently emerged as prominent underlying factors in proteinuria. The aim of this study was to evaluate the potential role of angiotensin-converting enzyme inhibitors and statins on early podocyte damage in an experimental model of type 2 diabetes mellitus. We used OZR to evaluate some of the pathogenic mechanisms and the effects of two drugs, an angiotensin-converting enzyme (ACE) inhibitor (quinapril) and a statin (atorvastatin), involved in the development of proteinuria and especially podocyte damage. We studied glomerular and tubulointerstitial injury by assessing inflammation mediators (murine monoclonal antibody against CD68 [ED1+], interleukin-8 [IL-8], interferon-gamma-inducible protein 10 [IP-10]) and podocyte damage markers using desmin staining and electron microscopy. Glomerular lesions were correlated with cholesterol (r = 0.676), proteinuria (r = 0.804), triglycerides (r = 0.593), insulin (r = 0.345), creatinine (r = 0.266), and glucose (r = 0.245). In addition, podocytes from OZR showed positive staining for desmin. Use of the ACE inhibitor quinapril normalized proteinuria, cholesterol levels, glomerular lesions, and podocyte morphology. In contrast, atorvastatin ameliorated but did not normalize renal damage, with a partial reduction in desmin staining and podocyte morphology. Treatment with both drugs resulted in only a slight reduction in IL-8 and IP-10 in the tubulointerstitium. In the OZR, cholesterol was an important determinant of renal injury. Most notably, glomerulosclerosis in the OZR Is characterized by early podocyte damage and tubulointerstitial injury. In addition, our findings showed that quinapril primarily normalized podocyte morphology, whereas atorvastatin ameliorated renal lesions through the diminution of lipids and by its lipid-independent pleiotropic effect.

The non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis.

In addition to its vasoactive effects, angiotensin II has proinflammatory properties. Angiotensin-converting enzyme (ACE) inhibitors reduce the production of angiotensin II and could therefore act as anti-inflammatory agents. Here we investigated the capacity of the ACE inhibitor quinapril to modulate inflammatory arthritis. We studied the effect of quinapril on disease activity in mice with collagen-induced arthritis (CIA). Mice received oral quinapril (10 mg/kg/day) at the time of arthritis induction (prophylaxis protocol) or at the onset of mild arthritis (therapy protocol). Concentrations of immunoglobulin G (IgG) subtypes specific for bovine Type II collagen and TNF-alpha were measured by enzyme-linked immunoassay. Quinapril significantly diminished the activity of CIA when given as prophylaxis or therapy (prophylaxis protocol, P<0.001; therapy protocol P=0.002). Antigen-specific IgG2a antibodies were reduced by 52% (P=0.02) in the quinapril prophylaxis protocol. Suppression of arthritis by quinapril was associated with reduced articular expression of TNF-alpha by 68% (P=0.01) in the prophylaxis protocol and 27% (P=0.06) in the therapy protocol. Quinapril therapy also inhibited expression of splenocyte TNF-alpha production following lipopolysaccharide (LPS) in vitro stimulation by 59% (P=0.02). In parallel human in vitro experiments, ACE inhibition suppressed LPS-stimulated production of TNF-alpha by monocytes. In order to confirm that the action of quinapril occurred predominantly through suppression of angiotensin II, parallel experiments with the angiotensin receptor antagonist candesartan cilexetil demonstrated that this agent also inhibited disease activity in CIA. These data suggest that angiotensin II is a mediator of chronic inflammation and that ACE inhibition may have therapeutic effects in human inflammatory arthritis.