EXCESS NITRIC-OXIDE DOES NOT CAUSE CELLULAR, VASCULAR, MUCOSAL DYSFUNCTION IN THE CAT SMALL-INTESTINE

The overproduction of nitric oxide in the small bowel has been invoked as a cytotoxic event in the vascular, mucosal, and whole organ dysfun ction associated with inflammation. We assessed whether exogenous admi nistration of nitric oxide in the form of nitric oxide donors (CAS 754 , SIN-1) could cause microvascular and mucosal barrier dysfunction in vivo or epithelial and endothelial cell permeability alterations and c ell injury in vitro. Increasing concentrations of CAS 754 or SIN-1 wer e infused locally into autoperfused segments of cat ileum at 30-min in tervals. Baseline epithelial permeability (blood-to-lumen clearance of Cr-51-EDTA) was not affected by CAS 754, whereas vascular protein cle arance was reduced. The latter effect could almost entirely be explain ed by a decrease in intestinal capillary hydrostatic pressure. Therefo re, in some experiments venous pressure was elevated and the microvasc ular reflection coefficient for total proteins was estimated at filtra tion-independent rates. This direct measurement of microvascular perme ability was unaffected by exogenous nitric oxide. CAS 754 did not incr ease permeability across monolayers of endothelial or epithelial cells and did not cause cell injury. Next, we assessed the possibility that excess nitric oxide may be detrimental, but only in inflamed intestin e, by infusing CAS 754 with platelet-activating factor; the latter dir ectly increases microvascular and mucosal permeability. CAS 754 did no t exacerbate but rather reduced platelet-activating factor-induced ris e in microvascular and mucosal permeability. These results suggest tha t high concentrations of nitric oxide do not cause breakdown of mucosa l or microvascular barrier integrity under normal inflammatory conditi ons.