enalaprilat-anhydrous and Proteinuria

Several observations question the role of blood pressure and renal hemodynamic changes in the long-term antiproteinuric effect of ACE inhibition. To differentiate blood pressure and renal effects in the initial antiproteinuric response, the placebo-controlled acute effects of the ACE inhibitor enalaprilat (10 mg i.v.) on blood pressure, renal hemodynamics, and proteinuria were compared with those of nitroprusside in nine patient with non-diabetic proteinuria. In addition, we studied whether an exogenous angiotensin II infusion reverse the initial enalaprilat-induced antiproteinuric response. Enalaprilat and nitroprusside reduced MAP by -11.3 +/- 2.4% and -14.1 +/- 2.3%, respectively, whereas only enalaprilat showed renal hemodynamic effects, reflected by an increase in ERPF of 18.4 +/- 5.4% and a decrease in FF of -17.1 +/- 2.6%. Despite the contrasting renal hemodynamic profiles, enalaprilat (-10.6 +/- 4.8%) and nitroprusside (-12.8 +/- 5.1% equally decreased proteinuria. Exogenous infusion of angiotensin II completely reversed the blood pressure reduction and renal efferent vasodilatation induced by enalaprilat. proteinuria also increased by 13.1 +/- 7.8% to placebo level, albeit statistically non-significant. We conclude that the initial antiproteinuric effect of ACE inhibition appears to be mediated by blood pressure reduction and does not require its specific renal hemodynamic effect. Further studies should clarify whether the renal efferent vasodilatation during ACE inhibition is required to gradually induce renal structural changes that prevent the abundant passage of proteins.

Topics: Adult; Angiotensin II; Blood Pressure; Cross-Over Studies; Drug Therapy, Combination; Enalaprilat; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nitroprusside; Proteinuria; Single-Blind Method; Vasoconstrictor Agents; Vasodilator Agents

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.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Diuresis; Diuretics; Dose-Response Relationship, Drug; Enalaprilat; Female; Furosemide; Glomerular Filtration Rate; Kidney; Peptidyl-Dipeptidase A; Potassium; Proteinuria; Rats; Rats, Wistar; Vasotocin; Water

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