Nitric oxide synthase inhibition increases venular... : Critical Care Medicine (original) (raw)

Laboratory Investigations

Nitric oxide synthase inhibition increases venular leukocyte rolling and adhesion in septic rats

Sundrani, Rohit MD; Easington, Cordus R. MS; Mattoo, Anil MD; Parrillo, Joseph E. MD, FCCM; Hollenberg, Steven M. MD, FCCM

From the Sections of Critical Care (Drs. Parrillo and Hollenberg) and Cardiology (Drs. Sundrani, Mattoo, Parrillo, and Hollenberg and Mr. Easington), Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois.

Address requests for reprints to: Steven M. Hollenberg, MD, Section of Critical Care Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612. E-mail: [email protected]

Supported, in part, by a Schweppe Foundation Career Development Award to Dr. Hollenberg.

Abstract

Objective

Excess production of nitric oxide (NO) has been implicated in hypotension and blood flow abnormalities in sepsis, but NO is also an important inhibitor of leukocyte rolling and adhesion. Leukocyte adhesion is increased in sepsis despite elevated NO production. We hypothesized that inhibition of NO synthase (NOS) could increase leukocyte adhesion in sepsis.

Design

Prospective animal study.

Setting

Experimental animal laboratory.

Subjects

Twenty-five male rats, anesthetized with ketamine and acepromazine.

Interventions

Topical superfusion of the nonselective NOS inhibitor NG-monomethyl-l-arginine (NMA) on skeletal muscle postcapillary venules.

Measurements and Main Results

Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Leukocyte rolling and adhesion were measured in cremasteric postcapillary venules of septic and control rats using in vivo videomicroscopy. The effects of NOS inhibition on leukocyte rolling and adhesion were also measured. After a stable baseline was reached, 1 μM of the nonselective NOS inhibitor NMA was suffused topically followed by physiologic buffer. The effects of l-arginine on leukocyte rolling and adhesion were also measured, both before and after suffusion of NMA.

Leukocyte rolling and adhesion was increased in septic rats as compared with controls (control 5.5 ± 0.9 rolling cells/min, 1.0 ± 0.3 adherent cells/min; septic 13.7 ± 2.0 rolling cells/min, 3.1 ± 0.6 adherent cells/min;p < .001), and NOS inhibition further increased leukocyte rolling and adhesion in both septic and control rats (control 14.0 ± 1.7 rolling cells/min, 2.8 ± 0.5 adherent cells/min; septic 25 ± 2.1 rolling cells/min, 5.4 ± 0.5 adherent cells/min; both _p_ < .001 vs. baseline). Prior suffusion of excess l-arginine prevented the increase in leukocyte adhesion with NMA in septic rats (2.6 ± 0.4 adherent cells/min vs. 3.0 ± 0.6 adherent cells/min; n = 3;_p_ > .05). When administered after NMA, excess l-arginine partially reversed leukocyte adhesion in septic rats (5.4 ± 0.7 adherent cells/min, with NMA vs. 4.3 ± 0.7 adherent cells/min, after l-arginine; n = 5;p < .05). Venular shear did not differ between septic and control rats (600 ± 109 (sec−1) vs. 620 ± 37 (sec−1);_p_ > .05).

Conclusions

Although NOS inhibition may ameliorate hypotension in sepsis, such therapy may be deleterious by increasing leukocyte adhesion.