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Eur J Cardiothorac Surg 2004;26:1149-1155
© 2004 Elsevier Science NL

Inhibition of myosin light chain kinase provides prolonged attenuation of radial artery vasospasm

^a Cardiothoracic Research Lab, Division of Cardiothoracic Surgery, Emory University School of Medicine, 550 Peachtree Street, NE, Atlanta, GA 30308-2225, USA
^b Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA

Received 7 May 2004; received in revised form 21 August 2004; accepted 24 August 2004.

^* Corresponding author. Tel.: +1 404 686 2511; fax: +1 404 686 4888. (E-mail: jvinten{at}emory.edu).

Objective: Current treatments for conduit vessel vasospasm are short-acting and do not inhibit all vasospastic stimuli. This study tests the hypothesis that irreversible inactivation of myosin light chain kinase provides sustained inhibition of arterial vasoconstriction stimulated by a spectrum of vasopressors. Methods: Canine radial artery segments were soaked for 60min in control buffer or buffer with wortmannin, an irreversible inhibitor of myosin light chain kinase. The vessels were then thoroughly washed and contractile responses were quantified in response to a spectrum of vasopressors at 2 and 48h after treatment. After 48h, selected vessels were examined for morphologic changes and development of apoptosis. Results: Two hours after treatment, wortmannin-soaked vessels contracted significantly less than controls in response to norepinephrine (0.19±0.07g vs. 7.22±0.37g, P<0.001), serotonin (0.92±0.35g vs. 9.64±0.67g, P<0.001), thromboxane-mimetic U46619 (1.25±0.17g vs. 10.99±0.50g, P<0.001), and KCl (1.98±0.27g vs.15.00±0.48g, P<0.001). At 48h, vasoconstriction remained significantly inhibited in wortmannin-treated vessels compared to control vessels in response to norepinephrine (2.36±0.17 vs. 6.95±0.47g, P<0.001), serotonin (4.67±0.39 vs. 12.42±0.70g, P<0.001), U46619 (5.42±0.34 vs. 9.29±0.74g, P=0.008), and KCl (7.49±0.48 vs. 13.32±0.60g, P<0.001). Histology of wortmannin-treated vessels revealed no overt smooth muscle or endothelial cell damage. TUNEL staining revealed a significantly greater proportion of apoptotic smooth muscle and endothelial cells in wortmannin-treated vessels as compared to controls. Conclusions: Disengaging the smooth muscle contractile apparatus by irreversibly binding myosin light chain kinase with wortmannin significantly attenuates radial artery vasoconstriction up to 48h after brief treatment. This novel strategy may prevent vasospasm of arterial grafts from all causes for several postoperative days.