DUAL ROLE FOR NITRIC-OXIDE IN THE REGULATION OF PLASMA-VOLUME AND ALBUMIN ESCAPE DURING ENDOTOXIN-SHOCK IN CONSCIOUS RATS

To assess the role of nitric oxide (NO) produced by the constitutive ( cNOS) and inducible NO synthase (iNOS) in the regulation of vascular f unctions, we compared the effects of aminoguanidine, a relatively sele ctive inhibitor of iNOS, and N-G-nitro-L-arginine methyl ester (L-NAME ), a nonselective NOS inhibitor on blood pressure, plasma volume, and albumin escape during the early and delayed phases of endotoxin shock in conscious, chronically catheterized rats. Red blood cell volume and plasma volume were determined by using chromium-51-tagged erythrocyte s and iodine-125-labeled albumin, respectively. Injection of lipopolys accharide (LPS) 10 mg/kg IV resulted in a fall in blood pressure, hemo concentration, and increased total-body albumin escape, which is refle cted by a 25% reduction in plasma volume. When LPS was injected into a nimals pretreated with L-NAME (7.4 mu mol/kg IV 15 minutes before LPS) , losses in plasma volume and albumin escape were significantly greate r than in rats that received LPS alone, despite that L-NAME attenuated the hypotensive action of LPS. Aminoguanidine pretreatment (162 mu mo l/kg) had no effect on the early responses to LPS, whereas it was as p otent as L-NAME in reversing hypotension when injected 70 minutes afte r LPS. Aminoguanidine treatment also prevented further losses in plasm a volume and markedly attenuated total-body and organ albumin escape r ates elicited by LPS. L-NAME produced only a slight attenuation of LPS -induced losses in plasma volume and albumin escape in most organs stu died, whereas it potentiated albumin extravasation in the lung. These results demonstrate that inhibition of cNOS potentiates, whereas inhib ition of iNOS markedly attenuates, losses in plasma volume and albumin escape elicited by LPS, and suggest that selective inhibitors of iNOS may be more effective than nonselective-inhibitors of all forms of NO S in the therapy of septic shock.