Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation.

Abstract

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/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 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 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.

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

“…Furthermore, less sensitive indices (scores of area and thickness of fatty streaks) were doubled in the thoracic aorta, if the analysis was restricted to rabbits with hypercholesterolaemia. It is important to note that molsidomine elevated neither extent, nor incidence of the hypercholesterolaemia, unlike NO synthase inhibitors (Cayatte et al, 1994;Naruse et al, 1994). Hence, augmented plasma cholesterol levels can be ruled out as an explanation for the accelerated atherosclerosis with the NO donor.…”

“…The latter findings are hard to reconcile with the proposal that hypercholesterolaemia as such, suppresses endothelial NO release (Minor et al, 1990). However, one cannot exclude that progressive reduction of NO release aggravates fatty streak development (Cayatte et al, 1994;Naruse et al, 1994), and it has been proposed that treatment with L-arginine restores cholinergic-mediated relaxation ' Author for correspondence. (Cooke et al, 1991) and suppresses intimal thickening (Cooke et al, 1992) in this model.…”

The Role of Viruses in Cardiac Allograft Vasculopathy

“…This view is supported by the fact that pharmacological inhibition or genetic deficiency of eNOS accelerates atherogenesis in animal models (54). Furthermore, endothelium-dependent vasodilatation mediated by NO is impaired in animal models of atherosclerosis, and in patients.…”

The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

“…The chronic inhibition of nitric oxide synthase (NOS) 1 accelerates atherosclerosis in cholesterol-fed rabbits (1,2). Supplementation of L-arginine, the substrate for NOS, has been shown to decrease fatty streak formation in rabbits and correct endothelial dysfunction in hypercholesterolemic humans (3)(4)(5).…”