Systemic and Regional Hemodynamic Responses to Tempol in Angiotensin II-Infused Hypertensive Rats.
-Recent studies have indicated that angiotensin II (Ang II) can stimulate oxidative stress. The present study was conducted to assess the contribution of oxygen radicals to hypertension and regional circulation during Ang II-induced hypertension. With radioactive microspheres, the responses of systemic and regional hemodynamics to the membrane-permeable, metal-independent superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol) were assessed in conscious Ang II-infused hypertensive rats. Ang II-infused rats (80 ng/min SC for 12 days: n=25) showed higher mean arterial pressure (MAP: 161+/-4 mm Hg) and total peripheral resistance (TPR: 1.59+/-0.08 mm Hg. min(-1). mL(-1)) than vehicle-infused normotensive rats (116+/-3 mm Hg and 0.95+/-0.04 mm Hg. min(-1). mL(-1), respectively; n=23). The blood flow rates in the brain, spleen, large intestine, and skin were significantly reduced in Ang II-infused rats compared with vehicle-infused rats, whereas rates in the lung, heart, liver, kidney, stomach, small intestine, mesenterium, skeletal muscle, and testis were similar. Vascular resistance was significantly increased in every organ studied except the lung, in which the resistance was similar. Tempol (216 µmol/kg IV) significantly reduced MAP by 30+/-4% from 158+/-7 to 114+/-5 mm Hg and TPR by 35+/-6% from 1.57+/-0.17 to 0.95+/-0.04 mm Hg. min(-1). g(-1) in Ang II-infused rats (n=9) but had no effect on these parameters in vehicle-infused rats (n=8). In Ang II-infused rats, tempol did not affect regional blood flow but significantly decreased vascular resistance in the brain (29+/-6%), heart (31+/-6%), liver (37+/-7%), kidney (30+/-7%), small intestine (38+/-6%), and large intestine (47+/-7%). Ang II-infused hypertensive rats showed doubled vascular superoxide production (assessed with lucigenin chemiluminescence), which was normalized by treatment with tempol (3 mmol/L, n=7). Further studies showed that the NO synthase inhibitor, N:(omega)-nitro-L-arginine methyl ester (11 µmol. kg(-1). min(-1) IV, n=11) markedly attenuated the systemic and regional hemodynamic responses of tempol in Ang II-infused rats. These results suggest that in this model of hypertension, oxidative stress may have contributed to the alterations in systemic blood pressure and regional vascular resistance through inactivation of NO.
Nishiyama
Akira
A
Department of Pharmacology (A.N., T.F., M.R., R.-X.T., S.K., Y.A.) and Research Equipment Center (Y.F.), Kagawa Medical University, Kagawa, Japan.
Fukui
Toshiki
T
Fujisawa
Yoshihide
Y
Rahman
Matlubur
M
Tian
Run-Xia
RX
Kimura
Shoji
S
Abe
Youichi
Y