MECHANISM OF ITF 296-INDUCED VASORELAXATION COMPARED TO NITROGLYCERINAND ISOSORBIDE DINITRATE - RELATIONSHIP BETWEEN RELAXATION OF RABBIT AORTA AND TISSUE CGMP

The vasorelaxant properties of ITF 296, a new mononitrate ester, were studied in endothelium-denuded rabbit aortic rings and were compared t o nitroglycerin (NTG) and isosorbide dinitrate (ISDN). In norepinephri ne-contracted arteries, ITF 296, NTG, and ISDN elicited maximal and co ncentration-dependent vasodilatation with pD(2) values of 7.07, 7.95, and 7.2, respectively. The concentration-relaxation curves of ITF 296 were shifted markedly to the right (p < 0.01) in the presence of 10 mu M methylene blue (MB) and 3 mu M oxyhemoglobin (HbO(2)), whereas a si gnificant shift to the left (p < 0.01) was observed in the presence of 10 mu M M&B-22948 (a specific cGMP phosphodiesterase inhibitor). When KCl (60 mM) was used as contracting agent, a weak relaxation was obse rved with ITF 296, suggesting the absence of activity on the voltage-d ependent Ca2+ channels. A time-dependent increase in cGMP content and a positive correlation between cGMP and vasodilatation were observed i n norepinephrine-contracted arteries after exposure to a single submax imal concentration of ITF 296 (1 mu M). Similar results were obtained with NTG and ISDN, although NTG was found to be more active than ITF 2 96 or ISDN. The presence of either MB or HbO(2) almost completely abol ished the increase in cGMP induced by ITF 296, whereas a further incre ase in cGMP was observed in the presence of isobutylmethylxanthine. No changes in cAMP levels were observed after exposure of the tissues to a concentration of ITF 296 that induced significant elevation in the cGMP content. In the presence of L-cysteine, ITF 296 stimulated semipu rified rat lung guanylate cyclase at higher concentrations than those of NTG or ISDN, probably because of its lower rate of nitric oxide (NO ) release. These results suggest that, in common with the reference co mpounds NTG and ISDN, ITF 296-induced vasorelaxation in rabbit aortic rings is mediated by an NO-cGMP mechanism.