Role of oxidative stress in age-related reduction of NO-cGMP-mediated vascular relaxation in SHR.
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 mo) male spontaneously hypertensive rats (SHR) nontreated or treated for 8 mo with the antioxidant tempol (1 mM in drinking water) or vitamin E (E; 5,000 IU/kg chow) and vitamin C (C; 100 mg. kg-1. day-1 in drinking water) and adult (12 wk) male SHR were used. After the arterial pressure was measured, 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 ACh-induced vascular relaxation and nitrite/nitrate production were reduced in aging compared with adult rats. In aging rats, the arterial pressure was nontreated (188 +/- 4), tempol-treated (161 +/- 6), and E + C-treated (187 +/- 1 mmHg). Phe (10-5 M) caused an increase in active stress in nontreated aging rats (14.3 +/- 1.0) that was significantly (P < 0.05) reduced in tempol-treated (9.0 +/- 0.7) and E + C-treated rats (9.8 +/- 0.6 x 104 N/m2). ACh produced a small relaxation of Phe contraction in nontreated 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 nontreated aging rats. ACh-induced vascular nitrite/nitrate production was not different in nontreated, 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 nontreated, 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.
Payne
Jason A
JA
Harvard Medical School, VA Boston Healthcare-Research, 1400 VFW Parkway, 3/2B123, W. Roxbury, MA 02132, USA. raouf_khalil@hms.harvard.edu
Reckelhoff
Jane F
JF
Khalil
Raouf A
RA
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D009569:Nitric Oxide; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester