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1 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
2 Department of Medicine, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: raouf_khalil{at}hms.harvard.edu.
The incidence of hypertension increases during the late stages of aging; however, the vascular mechanisms involved are unclear. We investigated whether the late stages of aging are associated with impaired nitric oxide (NO)-mediated vascular relaxation and enhanced vascular contraction, and whether oxidative stress plays a role in the age-related vascular changes. Aging (16 months) male spontaneously hypertensive rat s (SHR) non-treated or treated for 8 months with the antioxidant tempol (1 mM in drinking water) or vitamin E (5000 IU/kg chow) and vitamin C (100 mg/kg/d in drinking water), and adult (12 weeks) male SHR were used. After measuring the arterial pressure, aortic strips were isolated from the rats for measurement of isometric contraction. The arterial pressure and phenylephrine (Phe)-induced vascular contraction were enhanced, and the acetylcholine (ACh)-induced vascular relaxation and nitrite/nitrate production were reduced in aging compared with adult rats. In aging rats, the arterial pressure was: non-treated (188±4), tempol-treated (161±6) and E+C-treated (187± mmHg). Phe (10-5 M) caused an increase in active stress in non-treated aging rats (14.3±1.0) that was significantly (P<0.05) reduced in tempol- (9.0±0.7) and E+C-treated rats (9.8±0.6x104N/m2). ACh produced a small relaxation of Phe contraction in non-treated aging rats that was enhanced (P<0.05)in tempol- and E+C-treated rats. L-NAME (10-4 M), inhibitor of NO synthase, or ODQ (10-5 M), inhibitor of cGMP production in smooth muscle, inhibited ACh relaxation and enhanced Phe contraction in tempol- and E+C-treated, but not the non-treated aging rats. ACh-induced vascular nitrite/nitrate production was not different in non-treated, tempol- and E+C-treated aging rats. Relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was smaller in aging than adult rats, but was not different between non-treated, tempol- and E+C-treated aging rats. Thus, during the late stages of aging in SHR rats, an age-related inhibition of a vascular relaxation pathway involving not only NO production by endothelial cells, but also the bioavailability of NO and the smooth muscle response to NO is partially reversed during chronic treatment with the antioxidants tempol and vitamins E and C. The data suggest a role for oxidative stress in the reduction of vascular relaxation and thereby the promotion of vascular contraction and hypertension during the late stages of aging.
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