title: Sirolimus causes relaxation of human vascular smooth muscle: a novel action of sirolimus mediated via ATP-sensitive potassium channels.
abstract: Little is known about the vasomotor effects of sirolimus, and preliminary studies using animal models have provided conflicting results. The present study was designed to determine the effects of sirolimus on vasomotor tone in human blood vessels. Human radial artery segments were cut into rings, denuded of endothelium, and placed into organ chambers for isometric tension recording. Sirolimus (10(-10) to 10(-6) M) caused concentration-dependent relaxation of human arteries contracted with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha); 10(-8) M) [-log (M) EC(50) (pD(2)) = 7.28 +/- 0.1; E(max) = 57 +/- 6%] or phenylephrine (10(-6) M) (pD(2) = 7.16 +/- 0.4; E(max) = 45 +/- 9%). Sirolimus-induced relaxation was unaffected by treatment with indomethacin (10(-5) M) but was nearly abolished in tissues contracted by depolarization with elevated K(+) (60 mM). In U46619-contracted rings, the response to sirolimus was markedly inhibited in the presence of the specific ATP-sensitive potassium (K(ATP)) channel blocker, glyburide (10(-6) M), but was unaffected by treatment with blockers of large conductance, calcium-activated potassium channel (iberiotoxin, 10(-7) M), small conductance, calcium-activated potassium channel (apamin, 10(-6) M), or voltage-gated potassium channel (4-aminopyridine, 10(-3) M). The K(ATP) channel opener, aprikalim (10(-7) to 10(-5) M), caused concentration-dependent relaxations that were inhibited by glyburide (10(-6) M) and abolished in tissues contracted with elevated K(+) (60 mM), thus confirming that K(ATP) channel opening causes relaxation of these arteries. These data suggest that sirolimus, at concentrations attained in vivo, causes relaxation of human arteries, and this effect is mediated by opening of K(ATP) channels in vascular smooth muscle. Reduced vasomotor tone is a heretofore unrecognized action of sirolimus that could potentially contribute to its efficacy in drug-eluting stents.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ghatta
authors.forename: Radhika R
authors.initials: RR
authors.lastname: Tunstall
authors.forename: Sohail
authors.initials: S
authors.lastname: Kareem
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahman
authors.forename: Stephen T
authors.initials: ST
authors.lastname: O'Rourke
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D017534:Radial Artery / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D020123:Sirolimus