N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and proliferation in an L-NAME/SHR model

Objective To determine the responses of the new dihydropyridine N- and L-type calcium antagonist, cilnidipine, on systemic and renal hemodynamics, glomerular dynamics, renal function, and histopathology in an N-omega-nitro-L-arginine methylester spontaneously hypertensive rat (L-NAME/SHR) model of nephrosclerosis. Methods Five groups of 20-week-old male SHR were studied using renal micropuncture techniques and histo pathological analyses: group 1, control; group 2, cilnidipine (10 mg/kg per day) by gavage, for 3 weeks; group 3, L-NAME (50 mg/l) in drinking water, for 3 weeks; group 4, combination Of L-NAME and cilnidipine, for 3 weeks; group 5, L-NAME for 3 weeks, followed by cilnidipine for a subsequent 3 weeks. Results Cilnidipine significantly reduced mean arterial pressure, total peripheral resistance and renal vascular resistance, while increasing effective renal blood flow and glomerular filtration rate (P < 0.01) in L-NAME/SHR. These hemodynamic changes were associated with significantly increased single nephron glomerular filtration rate (SNGFR) and plasma flow (SNPF) and decreased afferent glomerular arteriolar resistances when cilnidipine was used alone, and with increased SNGFR and SNPF, but decreased glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary protein excretion, serum creatinine and uric acid concentrations (at least P < 0.05) in L-NAME-exacerbated SHR nephrosclerosis. In addition, glomerular and arteriolar injuries were markedly reversed (both P < 0.01), and glomerular apoptosis and cellular proliferation were inhibited and associated with glomerular tuft enlargement and an increase in cell number. Conclusion Cilnidipine not only prevented, but reversed, the severe renal hemodynamic and glomerular dynamic changes, including apoptosis and glomerular cellular proliferation, in L-NAME/SHR-exacerbated nephrosclerosis. This dual-channel calcium antagonist thus exerted renoprotective pathophysiological effects in the L-NAME/SHR. J Hypertens 20:993-1000 (C) 2002 Lippincott Williams Wilkins.