AJP - Regulatory, Integrative and Comparative Physiology, Vol 272, Issue 3 969-R974, Copyright © 1997 by American Physiological Society

ARTICLES

Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to endothelin-1 in septic rats

S. M. Hollenberg, M. J. Piotrowski and J. E. Parrillo
Section of Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.

Persistent vasodilation refractory to vasopressor agents is the hemodynamic abnormality characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines has been hypothesized to play a pathogenetic role in this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure responses of resistance arterioles (15-20 microm) to topical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), in rat cremaster muscle. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats before and after superfusion of the muscle with the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induced vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentrations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sham controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing arteriolar constriction at 1 and 10 nM. This effect was reversed with superfusion of excess L-arginine (1 mM). This study demonstrates that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition. Taken together with previous studies showing sepsis-induced impairment of vasoconstriction with norepinephrine, a vasopressor with a mechanism of action different from ET-1, these findings suggest a generalized abnormality in the responsiveness of resistance arterioles in sepsis. Reversal of hyporesponsiveness to both of these vasopressor agents by NOS inhibition suggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.

This article has been cited by other articles:

				S. M. HOLLENBERG, A. DUMASIUS, C. EASINGTON, S. A. COLILLA, A. NEUMANN, and J. E. PARRILLO Characterization of a Hyperdynamic Murine Model of Resuscitated Sepsis Using Echocardiography Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 891 - 895. [Abstract] [Full Text] [PDF]

				D. W. Landry and J. A. Oliver The Pathogenesis of Vasodilatory Shock N. Engl. J. Med., August 23, 2001; 345(8): 588 - 595. [Full Text] [PDF]

				P. Wiesel, A. P. Patel, N. DiFonzo, P. B. Marria, C. U. Sim, A. Pellacani, K. Maemura, B. W. LeBlanc, K. Marino, C. M. Doerschuk, et al. Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1-Deficient Mice Circulation, December 12, 2000; 102(24): 3015 - 3022. [Abstract] [Full Text] [PDF]

				S. M. Hollenberg, M. Broussard, J. Osman, and J. E. Parrillo Increased Microvascular Reactivity and Improved Mortality in Septic Mice Lacking Inducible Nitric Oxide Synthase Circ. Res., April 14, 2000; 86(7): 774 - 778. [Abstract] [Full Text] [PDF]