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

Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
Microcirculation (Impact Factor: 2.57). 07/2005; 12(5):443-53. DOI: 10.1080/10739680590960962
Source: PubMed


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.
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 AT(1) Ang-II receptor antagonist.
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.
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 AT(1)Ang-II receptor antagonists.

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    • "Although eNOS-NO production is a minor part of total brain NOS activity, this enzyme is critical for the regulation of cerebrovascular hemodynamics and for the protection of endothelium integrity from inflammatory, oxidative, and procoagulant stimuli. It has been demonstrated that eNOS-derived NO scavenges ROS [44] and inhibits the expression of cellular adhesion molecules [45], platelet aggregation [46], and leukocyte adhesion [47]. "
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    ABSTRACT: Cerebral ischemia initiates a cascade of detrimental events including glutamate-associated excitotoxicity, intracellular calcium accumulation, formation of Reactive oxygen species (ROS), membrane lipid degradation, and DNA damage, which lead to the disruption of cellular homeostasis and structural damage of ischemic brain tissue. Cerebral ischemia also triggers acute inflammation, which exacerbates primary brain damage. Therefore, reducing oxidative stress (OS) and downregulating the inflammatory response are options that merit consideration as potential therapeutic targets for ischemic stroke. Consequently, agents capable of modulating both elements will constitute promising therapeutic solutions because clinically effective neuroprotectants have not yet been discovered and no specific therapy for stroke is available to date. Because of their ability to modulate both oxidative stress and the inflammatory response, much attention has been focused on the role of nitric oxide donors (NOD) as neuroprotective agents in the pathophysiology of cerebral ischemia-reperfusion injury. Given their short therapeutic window, NOD appears to be appropriate for use during neurosurgical procedures involving transient arterial occlusions, or in very early treatment of acute ischemic stroke, and also possibly as complementary treatment for neurodegenerative diseases such as Parkinson or Alzheimer, where oxidative stress is an important promoter of damage. In the present paper, we focus on the role of NOD as possible neuroprotective therapeutic agents for ischemia/reperfusion treatment.
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    • "NO has been shown to modulate the expression of selectins [17] which mediate tethering and rolling during leukocyte recruitment. L-NAME treatment may enhance the expression of endothelial adhesion molecules [13] such as P-selectin expression and enhance leukocyte rolling and adhesion [18]. NO inhibition may also stimulate degranulation of mast cells which release pro-inflammatory mediators that upregulate P-selectin expression [19,20]. "
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    • "Morris et al. [4] showed an association between sVCAM-1 and arginase levels. NO acts as an anti-inflammatory mediator, affecting endothelial cell function by preventing leukocyte adhesion to the endothelium through the inhibition of adhesion molecule expression [22]. However, no correlation was found between such molecules in our results. "
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