enalaprilat-anhydrous and omapatrilat

Nephrotic syndrome (NS) is a clinical state characterized by massive proteinuria, hypoalbuminemia, and eventual edema formation. Although the mechanisms underlying this phenomenon are not yet fully clarified, it is well accepted that nephrin and podocin are involved in the development of proteinuria. The effects of early treatment with various antiproteinuric therapies on proteinuria and glomerular staining of nephrin and podocin in rats with experimental NS have not been previously studied. Proteinuria and glomerular nephrin and podocin immunofluorescence were examined in rat kidneys with adriamycin-induced NS and the effects of antiproteinuric drug therapies during 5 wk with enalapril, losartan, alone or in combination, omapatrilat, and mycophenolate mofetil on these parameters were assessed. Injection of adriamycin caused a significant increase in daily (from 21.8 +/- 1.4 to 983.1 +/- 45.8 mg/day, P < 0.01) and cumulative protein excretion (from negligible values to 22,490 +/- 931 mg, P < 0.001) during 5 wk. Early treatment with enalapril significantly decreased the daily (641.7 +/- 82.4 mg/day, P < 0.0023) and cumulative proteinuria (15,727 +/- 2,204 mg, P < 0.001). A similar effect, although to a lesser extent, was obtained after omapatrilat treatment: cumulative proteinuria was reduced to 18,706 +/- 1,042 mg, P < 0.001. In contrast, losartan treatment did not significantly influence the cumulative proteinuria that remained comparable (20,351 +/- 1,360 mg, P > 0.05) to that observed in untreated NS rats. Unexpectedly, when losartan was given in combination with enalapril, it abolished the beneficial effects of the latter. Pretreatment with mycophenolate mofetil exerted a moderate antiproteinuric effect, which appeared only during the last week of the experimental treatment. Nephrotic rats exhibited severe disruption of slit diaphragm structure as seen by rapid and profound loss of nephrin and podocin. Beneficial effects of enalapril, omapatrilat, and mycophenolate mofetil paralleled the preservation of nephrin, as determined immunohistochemically, and enabled prediction of significant antiproteinuric responses. Enalapril alone or in combination with losartan resulted in significant preservation of podocin. Pretreatment with enalapril, and to a lesser extent omapatrilat, is superior to losartan in reducing proteinuria in NS rats. A combination of ACE inhibitors with ANG II receptor blockers does not provide any advantageous antiproteinuric therapy in

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Doxorubicin; Enalaprilat; Enzyme Inhibitors; Fluorescent Antibody Technique; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Losartan; Male; Membrane Proteins; Mycophenolic Acid; Nephrotic Syndrome; Protein Synthesis Inhibitors; Proteinuria; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone; Drinking; Eating; Enalaprilat; Endothelin Receptor Antagonists; Endothelins; Hypertension; Kidney; Male; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium; Thiazepines

The respective role of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) in the degradation of bradykinin (BK) has been studied in the infarcted and hypertrophied rat heart. Myocardial infarction (MI) was induced in rats by left descendant coronary artery ligature. Animals were killed, and hearts were sampled 1, 4, and 35 days post-MI. BK metabolism was assessed by incubating synthetic BK with heart membranes from sham hearts and infarcted (scar) and noninfarcted regions of infarcted hearts. The half-life (t1/2) of BK showed significant differences among the three types of tissue at 4 days [sham heart (114 +/- 7 s) > noninfarcted region (85 +/- 4 s) > infarcted region (28 +/- 2 s)] and 35 days post-MI [sham heart (143 +/- 6 s) = noninfarcted region (137 +/- 9 s) > infarcted region (55 +/- 4 s)]. No difference was observed at 1 day post-MI. The participation of ACE and NEP in the metabolism of BK was defined by preincubation of the membrane preparations with enalaprilat, an ACE inhibitor, and omapatrilat, a vasopeptidase inhibitor that acts by combined inhibition of NEP and ACE. Enalaprilat significantly prevented the rapid degradation of BK in every tissue type and at every sampling time. Moreover, omapatrilat significantly increased the t1/2 of BK compared with enalaprilat in every tissue type and at every sampling time. These results demonstrate that experimental MI followed by left ventricular dysfunction significantly modifies the metabolism of exogenous BK by heart membranes. ACE and NEP participate in the degradation of BK since both enalaprilat and omapatrilat have potentiating effects on the t1/2 of BK.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cell Membrane; Chromatography, High Pressure Liquid; Enalaprilat; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Myocardial Infarction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Wistar; Thiazepines; Ventricular Function, Left