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1 iCAPTURE4 Centre, Vancouver Vascular Biology Research Centre, St. Paul's Hospital, University of British Columbia, Vancouver V6Z 1Y6; and 2 Department of Cardiac Surgery, University of British Columbia, Vancouver, British Columbia, V5Z 4E3 Canada
The human saphenous vein (HSV) is the most widely used graft in coronary artery revascularization procedures and is susceptible to spasm perioperatively. The aim of this study is to elucidate the mechanism(s) of agonist-induced excitation-contraction coupling in this vessel. Isometric contraction experiments were combined with in situ smooth muscle intracellular Ca2+ concentration ([Ca2+]i) imaging by confocal microscopy of intact undistended HSV segments during activation with phenylephrine (PE; 50 µM). Stimulation with PE produced a sustained contraction. Preincubation with 5 µM nifedipine, a blocker of the L-type voltage-operated Ca2+ channel, or 50 µM SKF-96365, a blocker of both the voltage- and receptor-operated channels, reduced force generation by 25-30%. Ca2+ imaging revealed that PE elicited only a transient rise in [Ca2+]i, suggesting that Ca2+ plays only a minor role. However, a requirement for basal Ca2+ levels was demonstrated when PE contractions could not be maintained in Ca2+-free medium. In light of the transient Ca2+ response, it appears that signals other than Ca2+ must maintain the tonic contraction elicited by PE, such as those that sensitize the myofilaments to Ca2+. Application of HA-1077 (a Rho kinase inhibitor) at the peak of the contraction completely abolished the plateau phase of the response, whereas application of genistein (a tyrosine kinase inhibitor) reduced this phase by ~50%. The foregoing results suggest that, whereas the transient Ca2+ signal can contribute to the development of force, maintenance of the plateau phase of the PE contraction in the HSV is the result of myofilament Ca2+ sensitization by Rho kinase and tyrosine phosphorylation. The elucidation of the mechanisms of excitation-contraction coupling in the HSV may be useful for the development of therapeutic strategies for the alleviation of vein graft spasm.
calcium; Rho kinase; tyrosine kinase; smooth muscle; 
1-adrenergic receptor agonist
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