L-NAME Induces Direct Arteriolar Leukocyte Adhesion, Which Is Mainly Mediated by Angiotensin-II

Abstract

Objective: Acute inhibition (1 h) of nitric oxide synthase (NOS) with L‐NAME causes leukocyte recruitment in the rat mesenteric postcapillary venules that is angiotensin‐II (Ang‐II) dependent. Since 4‐h exposure to Ang‐II provokes arteriolar leukocyte adhesion, this study was designed to investigate whether subacute (4‐h) NOS inhibition also causes this effect. Methods: Rats were intraperitoneally injected with saline, L‐NAME, or 1H‐[1,2,4]‐oxidazolol‐[4,3‐a]‐quinoxalin‐1‐one (ODQ). Leukocyte accumulation in the mesenteric microcirculation was examined 4 h later via intravital microscopy. Some groups were pretreated with losartan, an AT₁ Ang‐II receptor antagonist. Results: At 4‐h, L‐NAME caused a significant increase in arteriolar leukocyte adhesion and leukocyte–endothelial cell interactions in postcapillary venules. Mononuclear cells were the predominant leukocytes attached to the arteriolar endothelium. Administration of losartan inhibited L‐NAME‐induced arteriolar leukocyte adhesion by 90%. L‐NAME provoked increased expression of P‐selectin, E‐selectin, ICAM‐1, and VCAM‐1 in arterial endothelium, which was attenuated by losartan pretreatment. Inhibition of guanylyl cyclase with ODQ mimicked the effects exerted by L‐NAME and losartan also reduced these effects. Conclusions: NOS inhibition for 4‐h results in the attachment of leukocytes to the arterial endothelium, a critical event in disease states such as hypertension and atherosclerosis, which could be prevented by the administration of AT₁Ang‐II receptor antagonists.