title: Hypotensive mechanisms of amifostine.
abstract: Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.
authors.affiliation: Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Ryan
authors.forename: S L
authors.initials: SL
authors.lastname: Carrithers
authors.forename: S J
authors.initials: SJ
authors.lastname: Parkinson
authors.forename: C
authors.initials: C
authors.lastname: Skurk
authors.forename: C
authors.initials: C
authors.lastname: Nuss
authors.forename: P M
authors.initials: PM
authors.lastname: Pooler
authors.forename: C S
authors.initials: CS
authors.lastname: Owen
authors.forename: A M
authors.initials: AM
authors.lastname: Lefer
authors.forename: S A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D004999:Amifostine / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004809:Ephedrine / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008624:Mercaptoethylamines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011837:Radiation-Protective Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D008024:Ligands; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; D011942:Receptors, Adrenergic, alpha; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D004809:Ephedrine; D006152:Cyclic GMP; D004999:Amifostine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester