omapatrilat and Kidney-Diseases

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiovascular Diseases; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kidney Diseases; Kinins; Neprilysin; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pyridines; Randomized Controlled Trials as Topic; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Serpins; Thiazepines

Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensin-converting enzyme.. Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to three groups of eight subjects with varying degrees of renal function (CLCR values, normal > or = 80; mild to moderate impairment < 80 to > or = 30; severe impairment < 30 mL/min/1.73 mL2) and to six subjects undergoing maintenance hemodialysis. Omapatrilat and its metabolites (phenylmercaptopropionic acid, S-methylomapatrilat, S-methylphenylmercaptopropionic acid, and cyclic S-oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, Cmax or AUC(0-T) = intercept + slope x CLCR, was tested for a possible linear correlation between Cmax (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR.. For omapatrilat and its inactive metabolites, phenylmercaptopropionic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (tmax) were 1.5 to 2, 2 to 3, 2.5 to 3.5, and 7 to 10 hours, respectively, and were independent of renal function. After Cmax attainment, plasma concentrations declined rapidly to about 10% of Cmax values. Cyclic S-oxide-omapatrilat, a potentially active metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accumulation of omapatrilat and phenylmercaptopropionic acid and moderate accumulation of the S-methylated metabolites. For omapatrilat and S-methylphenylmercaptopropionic acid, neither Cmax nor AUC(0-T) was CLCR dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the Cmax and AUC(0-T) for S-methylomapatrilat were CLCR dependent.. The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CLCR. For patients with reduced renal function, adjusting initial omapatrilat dose is not suggested. Hemodialysis did not significantly contribute to the clearance of omapatrilat. The long-term pharmacodynamic response to omapatrilat will dictate dose-adjustment needs.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Chromatography, High Pressure Liquid; Female; Humans; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged; Pyridines; Renal Dialysis; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Cell Adhesion Molecules; Desoxycorticosterone; Drug Therapy, Combination; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; Organophosphonates; Pyridines; Rats; Thiazepines

The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied.. The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1).. Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats.. Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Collagen; Desoxycorticosterone; Drug Therapy, Combination; Enalapril; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; NF-kappa B; Organophosphonates; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Apolipoproteins E; Atherosclerosis; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus; Glycated Hemoglobin; Kidney; Kidney Diseases; Male; Mice; Mice, Knockout; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Protease Inhibitors; Pyridines; Quinapril; Tetrahydroisoquinolines; Thiazepines

The renoprotective efficacy of the vasopeptidase inhibitor omapatrilat (OMA) was compared with that of enalapril (ENA) in male Munich-Wistar rats subjected to 5/6 nephrectomy. ENA and OMA administered beginning on day 2 after surgery were equally effective in normalizing systolic BP (SBP) and preventing glomerulosclerosis (GS) for 12 wk. Micropuncture studies of rats performed using a similar treatment protocol demonstrated greater reduction of glomerular capillary hydraulic pressure with OMA than with ENA, at similar mean arterial pressures. To investigate whether these glomerular hemodynamic differences might be associated with differences in chronic renoprotective efficacy, additional rats were included in a protocol in which treatment was delayed until 4 wk after surgery (after the onset of hypertension and proteinuria) and continued for a longer period. Both treatments normalized SBP, but OMA resulted in more sustained reduction of proteinuria than did ENA. At week 20, OMA- and ENA-treated rats exhibited less GS than did untreated (control) rats at week 12, but only the difference in control versus OMA values was statistically significant [GS scores: control (12 wk), 36 +/- 4%; ENA (20 wk), 22 +/- 6%; OMA (20 wk), 14 +/- 2%]. The remaining ENA-treated rats were euthanized at 32 wk because of rapidly increasing proteinuria, whereas the remaining OMA-treated rats demonstrated a substantially slower increase in proteinuria until euthanasia at 50 wk. At this extremely late time point, OMA-treated rats exhibited GS scores similar to those of ENA-treated rats at 32 wk and control rats at 12 wk [GS scores: ENA (32 wk), 34 +/- 5%; OMA (50 wk), 38 +/- 8%]. It is concluded that, in this model, OMA affords greater long-term renoprotection than ENA when doses are adjusted to yield equivalent control of SBP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Disease Progression; Hemodynamics; Kidney; Kidney Diseases; Male; Neprilysin; Protease Inhibitors; Punctures; Pyridines; Rats; Rats, Wistar; Renal Circulation; Thiazepines; Time Factors