Beneficial Effect of Nifedipine and Moxonidine on Glomerulosclerosis in Spontaneously Hypertensive Rats

Abstract

The effect of calcium channel blockers on the development of glomerulosclerosis and progression of renal failure in different models of renal injury is still controversial. We compared the effects of blood pressure lowering with high doses of nifedipine (27 mg/kg body weight/day) and with the sympatholytic agent moxonidine (8 mg/kg body weight/day) in 6-month-old male spontaneously hypertensive rats (SHRsp). As controls we studied untreated hypertensive SHRsp and normotensive Wisfar-Kyoto rats (WKY). After 3 months of treatment, left ventricular (LV) weight and systolic blood pressure (tail plethysmography) were lower in both treated groups (144 +/- 21.4 mm Hg and 144 +/- 13.5 mm Hg v 193 +/- 38.6 mm Hg in untreated SHRsp), but remained higher than in WKY (116 +/- 16.0 mm Hg). Stereological analysis of perfusion fixed kidneys showed an unchanged total volume of cortex and medulla, but a higher mean glomerular volume in nifedipine treated SHRsp. The glomerulosclerosis index was similarly reduced by both antihypertensive agents (92.8 +/- 68.1 in untreated SHRsp v 27.2 +/- 12.9 and 18.2 +/- 9.8 in the two treatment groups, respectively). This was accompanied by a similar reduction of total cortical arterial wall volume (from 36.3 +/- 16.5 mm3 to 18.9 +/- 2.53 and 15.3 +/- 2.53 mm3, respectively) and by reduction of tubular atrophy or interstitial fibrosis, respectively. In this model nifedipine lowered blood pressure and inhibited development of glomerulosclerosis to the same extent as a sympatholytic agent. This was accompanied by increased glomerular volume and filtration area in nifedipine treated animals.

Effects of the selective I1 imidazoline receptor agonist, moxonidine, on gastric secretion and gastric mucosal injury in rats

“…Moxonidine, an 1,-imidazoline receptor agonist, has been found to exhibit a 70 to 600 fold greater selectivity for the I,-imidazoline receptor relative to the M2-adrenoceptor, depending on the tissue studied and the assay conditions . In the present study, moxonidine beneficially altered gastric function at doses which were less than those previously shown to be required to decrease blood pressure in spontaneously hypertensive rats (Chrisp & Faulds, 1992;Irzyniec et al, 1992). Gastric acid secretion in conscious rats was inhibited with an ED50 of 0.04 mg kg-', i.p.…”

Renoprotective Effect of Azelnidipine in Rats

“…14,15) SHRsp, bred to develop hypertension soon after birth, rapidly present with hypertensive disorders of various organs. [16][17][18] Regarding the kidney, elevation of plasma renin level begins at age 18 weeks 19) and disturbance of renal function from 22-24 weeks. 20) Although many attempts have been made at treating SHRsp with ARBs or CCBs, treatment was often performed before the appearance of hypertensive disorders, and it remains unknown whether these drugs exert renoprotective effects when they administered after the onset of kidney disease.…”

Sympathetic Hyperactivity in Chronic Renal Failure

“…Nonetheless, attenuation of progression of renal failure by inhibition of sympathetic action, by either renal denervation or pharmacologic agents, has been found in diverse rat models of CRF, such as subtotal nephrectomy by surgical excision (52, 80), or by infarction (81)(82)(83)(84), NOS inhibition (85-88), streptozotocininduced diabetes (89), and type 2 diabetes in corpulent SHR (90,91) and in salt-loaded stroke-prone SHR (92,93). When studied, the efficacy was comparable to that of interference with the RAS (52, 82, 90) or with a calcium antagonist (94). Both ␣-adrenergic blockade (51, 85,87,88,90,91) and ␤-adrenergic blockade (51, 80,83,84,92,93) have protective action, and summation of their effects occurs (51).…”