omapatrilat and Inflammation

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

Previous results have shown that inhibition of the renin-angiotensin system (RAS) either with an angiotensin II (Ang II), type 1 receptor blocker (losartan) or with an angiotensin converting enzyme inhibitor (ACEI, enalapril) has a protective effect on cardiovascular, renal, hepatic and cerebral structure and function during aging. The present study has analyzed the effect of chronic administration of a newly developed compound, omapatrilat, on clinical, histological and biochemical changes due to aging. Omapatrilat combines the action of an ACEI and of an inhibitor of a neutral endopeptidase involved in the metabolism of the atrial natriuretic peptide. The final effect is a decrease of a vasoconstrictor and proinflammatory mechanism like the RAS and the potentiation of two vasodilating compounds like bradykinin and the atrial natriuretic peptide. Based on these actions, its protective effect might be greater than formerly used pharmacological agents. Determinations have been performed on young adults (6 months old), adults (12 months old) or senile (18 months old) rats. Omapatrilat (35 mg/kg/day during 6 months and 20 mg/kg/day thereafter) was administered in the drinking water since weaning until sacrifice. Cardiovascular, renal, and cerebral structure as well as cognitive behavior, cardiovascular and renal function has been analyzed. The biochemical analysis has also established whether the beneficial action of Ang II inhibition is related to an increased activity of the nitric oxide synthase as observed in previous studies. Moreover, this study has tried to determine the relationship between the protective effect of these drugs and the levels of antioxidant defenses present in the blood and/or in the tissues. Hence, enzymatic and non-enzymatic antioxidants have been evaluated.

Topics: Aging; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Atrial Natriuretic Factor; Cardiovascular System; Cognition; Inflammation; Kidney; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Rats; Renin-Angiotensin System; Thiazepines; Vasoconstriction; Vasodilation

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 +/- 2 g, n = 114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Fibrosis; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Male; Membrane Potentials; Metalloendopeptidases; Myocardial Contraction; Papillary Muscles; Pyridines; Rats; Rats, Wistar; Sodium Chloride, Dietary; Thiazepines; Ventricular Remodeling

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