dihydropyridines and Nephrosis

The renoprotective effect of cilnidipine ((+/-)-2-methoxyethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate, CAS 132203-70-4), a L/N-type calcium channel antagonist, on puromycin aminonucleoside (PAN)-induced nephrosis was investigated in rats. In the Experiment I, rats were given an intravenous injection of PAN (70 mg/kg). Cilnidipine (3 mg/kg/day) and enalapril (CAS 75847-73-3, 5 mg/kg/day) were administered orally from 6 days after treatment with PAN (day 6) to day 26, and urinary analysis was performed on days 9, 15, 20 and 27. In the Experiment II, nephrosis was also induced by intravenous injection of PAN (70 or 100 mg/kg) in rats which were treated with cilnidipine and enalapril from days 6 to 10. Systolic blood pressure was measured on day 7 and urinary analysis was performed on day 10. On day 11, serum was collected and the kidneys were removed for immunofluorescence staining for nephrin and podocin proteins. In PAN-treated rats, the daily urinary protein excretion was dramatically elevated on day 5, reached a peak on day 9 and gradually returned to a normal level from days 15 to 27. Cilnidipine (3 mg/kg/ day) significantly suppressed the increase in proteinuria on day 9 and also improved the decrease in creatinine clearance without evident effect on the blood pressure. Furthermore, the elevations in serum total cholesterol and triglyceride tended to be suppressed by cilnidipine. The expression of nephrin and podocin proteins in PAN-treated rats showed the granular pattern in the glomeruli, while the intensity of staining seemed to be dependent on the urinary protein excretion level in the cilnidipine-treated rats. The results obtained in this study suggest a renoprotective effect of cilnidipine in PAN-induced nephrosis in rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antimetabolites, Antineoplastic; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Enalapril; Fluorescent Antibody Technique; Male; Membrane Proteins; Nephrosis; Protective Agents; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley

An animal model having both hypertension and reduced renal function was produced by intraperitoneal injection of puromycin aminonucleoside (PAN) in spontaneously hypertensive rat (SHR). Using this model, two different dihydropyridine Ca blockers, CS-905 and nicardipine, were compared with regard to the relationship between hypotensive effects and changes in renal function in a conscious state. A single oral administration of CS-905 or nicardipine at doses of 3 or 10 mg/kg produced a dose-dependent decrease in blood pressure and an increase in heart rate. Glomerular filtration rate (GFR) was decreased only at 10 mg/kg. However, there was a substantial difference between the two drugs with respect to the relationship between blood pressure and GFR. The decrease of GFR by nicardipine was observed when blood pressure was at the lowest level, while GFR decreased by CS-905 returned to the initial level when blood pressure reached a nadir. Percent decrease of GFR by CS-905 was significantly less than that by nicardipine although both agents produced almost the same degree of peak hypotension. These results suggest the decrease in GFR by Ca blockers depends not only on the degree of hypotension but other factors as well, such as the rate of blood pressure lowering. Despite the hypotension, both agents produced a marked natriuresis. Since the natriuresis was not accompanied by an increase in GFR, it was assumed that the natriuretic effect of Ca blockers stemmed from their tubular effects rather than glomerular ones.

Topics: Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Heart Rate; Hypertension; Kidney Function Tests; Male; Nephrosis; Nicardipine; Puromycin Aminonucleoside; Rats; Rats, Inbred SHR; Sodium