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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 28, 2006; DOI: 10.1124/jpet.106.109363

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Received for publication June 16, 2006.
Revised November 1, 2006.
Accepted for publication November 6, 2006.

Potent Inhibition of Arterial Smooth Muscle Tonic Contractions by the Selective Myosin II Inhibitor, Blebbistatin

Thomas J. Eddinger 1, Daniel P. Meer 2, Amy S. Miner 3, Joel Meehl 1, Arthur S. Rovner 4, Paul H. Ratz 3*

1 Marquette University 2 Cardinal Stritch University 3 Virginia Commonwealth University School of Medicine 4 University of Vermont School of Medicine

* Address correspondence to: E-mail: phratz{at}vcu.edu

Abstract

Blebbistatin is reported to be a selective and specific small molecule inhibitor of the myosin II isoforms expressed by striated muscles and non-muscle (IC50 = 0.5-5 µM), but is a poor inhibitor of purified turkey smooth muscle myosin II (IC50 ~80 µM). We found that blebbistatin potently (IC50 ~3 µM) inhibited the actomyosin ATPase activities of expressed "slow" (SMA) and "fast" (SMB) smooth muscle myosin II heavy chain isoforms. Blebbistatin also inhibited the KCl-induced tonic contractions produced by rabbit femoral and renal arteries that express primarily SMA, and the weaker tonic contraction produced by saphenous artery that expresses primarily SMB, with an equivalent potency comparable to that identified for non-muscle myosin IIA (IC50 ~5 µM). In femoral and saphenous arteries, blebbistatin had no effect on unloaded shortening velocity (Vus) or the tonic increase in myosin light chain phosphorylation produced by KCl, but potently inhibited {beta}-escin permeabilized artery contracted with calcium at pCa 5, suggesting that cell signaling events upstream from KCl-induced activation of cross bridges were unaffected by blebbistatin. Notably, KCl-induced contractions of chicken gizzard were less-potently inhibited (IC50 ~20 µM). Adult femoral, renal and saphenous arteries did not express significant levels of non-muscle myosin. These data together indicate that blebbistatin is a potent inhibitor of smooth muscle myosin II, supporting the hypothesis that the force-bearing structure responsible for tonic force maintenance in adult mammalian vascular smooth muscle is the cross bridge formed from the blebbistatin-dependent interaction between actin and smooth muscle myosin II.


Key words: blebbistatin, blood vessels, contraction, latch, myosin, vascular smooth muscle


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