Nc. Gocan et al., Nitric oxide produced via neuronal NOS may impair vasodilatation in septicrat skeletal muscle, AM J P-HEAR, 278(5), 2000, pp. H1480-H1489
Citations number
52
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Impaired vascular responsiveness in sepsis may lead to maldistribution of b
lood flow in organs. We hypothesized that increased production of nitric ox
ide (NO) via inducible nitric oxide synthase (iNOS) mediates the impaired d
ilation to ACh in sepsis. Using a 24-h cecal ligation and perforation (CLP)
model of sepsis, we measured changes in arteriolar diameter and in red blo
od cell velocity (V-RBC) in a capillary fed by the arteriole, following app
lication of ACh to terminal arterioles of rat hindlimb muscle. Sepsis atten
uated both ACh-stimulated dilation and V-RBC increase. In control rats, art
eriolar pretreatment with the NO donors S-nitroso-N-acetylpenicillamine or
sodium nitroprusside reduced diameter and V-RBC responses to a level that m
imicked sepsis. In septic rats, arteriolar pretreatment with the "selectite
" iNOS blockers aminoguanidine (AG) or S-methylisothiourea sulfate (SMT) re
stored the responses to the control level. The putative neuronal NOS (nNOS)
inhibitor 7-nitroindazole also restored the response toward control. At 24
-h post-CLP, muscles showed no reduction of endothelial NOS (eNOS), elevati
on of nNOS, and, surprisingly, no induction of iNOS protein; calcium-depend
ent constitutive NOS (eNOS+nNOS) enzyme activity was increased whereas calc
ium-independent iNOS activity was negligible. We conclude that 1) AG and SM
T inhibit nNOS activity in septic skeletal muscle, 2) NO could impair vasod
ilative responses in control and septic rats, and 3) the source of increase
d endogenous NO in septic muscle is likely upregulated nNOS rather than iNO
S. Thus agents released from the blood vessel milieu (e.g., NO produced by
skeletal muscle nNOS) could affect vascular responsiveness.