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Articles in PresS, published online ahead of print April 25, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.01129.2001
Submitted on January 2, 2002
Accepted on April 15, 2002
1 The iCAPTUR4E Centre, Vancouver Vascular Biology Research Centre, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
2 Cardiac Surgery, University of British Columbia, Vancouver, British Columbia, Canada
* To whom correspondence should be addressed. E-mail: breemen{at}interchange.ubc.ca.
The human saphenous vein (HSV) is the most widely used graft in coronary artery revascularisation 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 [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. Pre-incubation with 5µM nifedipine, a blocker of the L-type voltage-operated Ca2+ channel (VOC), or 50µM SKF-96365, a blocker of both the VOC and the receptor-operated channel (ROC), 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 signal(s) other than Ca2+ must maintain the tonic contraction elicited by PE, such as those that sensitise the myofilaments to Ca2+. Application of HA-1077 (a relatively specific rho kinase inhibitor) at the peak of the contraction completely abolished the plateau phase of the response, while application of genistein (a relatively specific tyrosine kinase inhibitor) reduced this phase by about 50%. The foregoing results suggest that while 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+ sensitisation 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.
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