LONG-TERM INHIBITION OF NO SYNTHESIS PROMOTES ATHEROSCLEROSIS IN THE HYPERCHOLESTEROLEMIC RABBIT THORACIC AORTA - PGH(2) DOES NOT CONTRIBUTE TO IMPAIRED ENDOTHELIUM-DEPENDENT RELAXATION

We examined whether prostaglandin (PG) H-2, as an endothelium-dependen t contracting factor, or the disturbed production of endothelium-deriv ed relaxing factor, impairs endothelium-dependent relaxation and wheth er longterm inhibition of nitric oxide (NO) synthesis aggravates ather osclerosis in hypercholesterolemic rabbits. Male New Zealand White rab bits were fed one of the following diets: (1) standard chow; (2) 2% ch olesterol-supplemented chow; (3) standard chow with 80 mu g/mL N omega -nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 mu g/mL L-NAME in their drinking water. The rabbits were fed t hese diets for 8 or 12 weeks. Then aortic rings were obtained, and cha nges in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-depen dent aortic relaxation to acetylcholine. Pretreatment with the thrombo xane A(2)/PGH(2) receptor antagonist ONO-3708 did not reverse this imp aired response. Vessels from both normocholesterolemic and hypercholes terolemic rabbits given L-NAME showed more impaired endothelium-depend ent relaxation than those from their dietary counterparts not given L- NAME. Morphometric analysis revealed marked enlargement of intimal ath erosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbit s. These findings suggest that PGH(2) does not contribute to impaired endothelium-dependent relaxation and that long-term. administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.