Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats. METHODS: Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared. RESULTS: Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, P<0.01; fibrosis, 15 vs. 10%, P<0.001). In contrast, high-dose candesartan and hydralazine prevented these forms of renal damage with lowering blood pressure. Low-dose candesartan also prevented this renal damage without lowering blood pressure. Moreover, there were increased numbers of larger and smaller glomeruli in the juxtamedullary cortex of tempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size. CONCLUSION: These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin-angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.

Azelnidipine attenuates cardiovascular and sympathetic responses to air-jet stress in genetically hypertensive rats.

Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.