Vasculoprotective role of inducible nitric oxide synthase at inflammatory coronary lesions induced by chronic treatment with interleukin-1 beta in pigs in vivo

Background We recently developed a porcine model in which chronic, local treatment with interleukin-1 beta (IL-1 beta) causes coronary arteriosclerotic changes and hyperconstrictive responses. Inflammatory cytokines are known to induce inducible NO synthase (iNOS) in the vascular smooth muscle. This study was designed to examine whether or not the production of NO by iNOS has a protective or deleterious effect on the coronary artery in vivo. Methods and Results A segment of the porcine coronary artery was aseptically wrapped with cotton mesh absorbing IL-1 beta suspension. We inhibited both eNOS and iNOS activity by cotreatment with L-NAME (a nonspecific inhibitor of NOS) and iNOS activity alone by aminoguanidine (a selective inhibitor of iNOS). Immunostaining showed that iNOS was absent in the normal coronary artery, whereas it was highly expressed 1 day after the application of IL-1 beta and thereafter downregulated until 14 days. In contrast, eNOS was well maintained throughout the study period. Two weeks after the operation, hyperconstrictive responses to intracoronary serotonin and neointimal formation were noted at the IL-1 beta-treated site, and both responses were significantly greater at the site cotreated with either L-NAME or aminoguanidine. Conclusions These results indicate that iNOS is transiently induced in vivo in response to local inflammation and that NO produced by iNOS exerts an inhibitory effect against the cytokine-induced proliferative/vasospastic changes of the coronary artery in vivo.