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CARDIOVASCULAR

Sirolimus Causes Relaxation of Human Vascular Smooth Muscle: A Novel Action of Sirolimus Mediated via ATP-Sensitive Potassium Channels

Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota (S.G., R.R.T., S.T.O.) and Department of Internal Medicine, University of North Dakota, Grand Forks, North Dakota (S.K., M.R.)

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 [GenBank] (9,11-dideoxy-11,9-epoxymethano-prostaglandin F₂; 10^-8 M) [-log (M) EC₅₀ (pD₂) = 7.28 ± 0.1; E_max = 57 ± 6%] or phenylephrine (10^-6 M) (pD₂ = 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 [GenBank] -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.

Address correspondence to: Dr. Stephen T. O'Rourke, Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105-5055. E-mail: stephen.orourke{at}ndsu.edu