HYPOTENSIVE MECHANISMS OF AMIFOSTINE

Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after similar to 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its meta bolite, WR-1065, induced dose-dependent hypotension in anesthetized ra ts that was not blocked by N-G-methyl L arginine (L-NAME), an NO synth ase inhibitor. WR-1065 but not amifostine induced concentration-depend ent relaxation of isolated rat aortic rings in an endothelium-independ ent fashion. Relaxation was nor associated with increases in cGMP or c AMP and could nor be blocked by L-NAME or indomethacin. Similarly, nei ther amifostine or WR-1065 activated adenylyl, particulate guanylyl, o r soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontr acted with norepinepherine, suggesting a-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazos in or phentolamine to bind to alpha-adrenergic receptors. Further, WR- 1065 had no effect on receptor-mediated increases in intracellular cal cium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to res ult from direct relaxation of Vascular smooth muscle. Smooth muscle re laxation induced by WR-1065 is not related to production of nitric oxi de, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor a ntagonism; or interference with receptor-dependent increases in intrac ellular calcium. Administration of ephedrine, an efficacious adrenergi c agonist, attenuated hypotension induced by amifostine in anesthetize d rats and may be useful in alleviating hypotension associated with am ifostine administration in patients.