L-NAME induces direct arteriolar leukocyte adhesion, which is mainly mediated by angiotensin-II.
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 AT(1) 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 AT(1)Ang-II receptor antagonists.
Nabah
Yafa Naim Abu
YN
Department of Pharmacology, University of Valencia, Valencia, Spain.
Mateo
Teresa
T
Cerdá-Nicolás
Miguel
M
Alvarez
Angeles
A
Martinez
Maria
M
Issekutz
Andrew C
AC
Sanz
Maria-Jesus
MJ
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001160:Arterioles / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000187:drug effects; D036904:Leukocyte Rolling / Q000187:drug effects*; D007962:Leukocytes / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018715:Microscopy, Video; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation; D014699:Venules / Q000502:physiology
D015815:Cell Adhesion Molecules; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester