NICOTINE IMPAIRS HISTAMINE-INDUCED INCREASES IN MACROMOLECULAR EFFLUX- ROLE OF OXYGEN RADICALS

Nicotine, a major component of cigarettes and smokeless tobacco, has t oxic effects on endothelium and impairs reactivity of resistance arter ioles in response to agonists that stimulate the synthesis and/or rele ase of nitric oxide. However, the effect of nicotine on nitric oxide s ynthase-dependent increases in macromolecular transport is not known. Thus our first goal was to determine the effect of nicotine on histami ne-induced increases in macromolecular efflux. We used intravital micr oscopy and FITC dextran (mol wt 70,000) (FITC-dextran-70K) to examine macromolecular extravasation from postcapillary venules in response to histamine before and after intravenous infusion of vehicle or nicotin e. Extravasation of macromolecules was quantitated by counting venular leaky sites and calculating clearance (ml/s x 10(-6)) of FITC-dextran -70K. Histamine elicited reproducible increases in venular leaky sites and clearance in hamsters infused with vehicle. In contrast, nicotine infusion inhibited histamine-induced increases in macromolecular effl ux. Histamine (1.0 and 5.0 mu M) elicited 19 +/- 2 and 34 +/- 4 vs. 3 +/- 1 and 11 +/- 5 leaky sites per 0.11 cm(2), before vs. after nicoti ne infusion, respectively (P < 0.05. Histamine-induced clearance of FI TC-dextran-70K was also impaired after infusion of nicotine. Our secon d goal was to examine whether alterations in histamine-induced increas es in macromolecular efflux by nicotine may be related to the producti on of oxygen radicals. Application of superoxide dismutase (150 U/ml) to the hamster cheek pouch restored histamine-induced increases in ven ular leaky sites and clearance of FITC-dextran-70K during infusion of nicotine. Thus nicotine alters agonist-induced increases in microvascu lar permeability, via the formation of oxygen radicals, to presumably inactivate nitric oxide.