Mechanism of ITF 296-induced vasorelaxation compared to nitroglycerin and 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 to nitroglycerin (NTG) and isosorbide dinitrate (ISDN). In norepinephrine-contracted arteries, ITF 296, NTG, and ISDN elicited maximal and concentration-dependent vasodilation with pD2 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 microM methylene blue (MB) and 3 microM oxyhemoglobin (HbO2), whereas a significant shift to the left (p < 0.01) was observed in the presence of 10 microM M&B-22948 (a specific cGMP phosphodiesterase inhibitor). When KCl (60 mM) was used as contracting agent, a weak relaxation was observed with ITF 296, suggesting the absence of activity on the voltage-dependent Ca2+ channels. A time-dependent increase in cGMP content and a positive correlation between cGMP and vasodilation were observed in norepinephrine-contracted arteries after exposure to a single submaximal concentration of ITF 296 (1 microM). Similar results were obtained with NTG and ISDN, although NTG was found to be more active than ITF 296 or ISDN. The presence of either MB or HbO2 almost completely abolished the increase in cGMP induced by ITF 296, whereas a further increase 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 semipurified 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 compounds NTG and ISDN, ITF 296-induced vasorelaxation in rabbit aortic rings is mediated by an NO-cGMP mechanism.
Donà
G
G
Italfarmaco Research Center, Italfarmaco S.p.A., Milan, Italy.
Giuliani
P
P
Cremonesi
P
P
Passaro
A
A
Stella
P
P
Tursi
F
F
Mizrahi
J
J
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D048588:Benzoxazines; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis*; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology*; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D048588:Benzoxazines; D009566:Nitrates; D010078:Oxazines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000242:Cyclic AMP; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; C091726:sinitrodil