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J Thorac Cardiovasc Surg 2008;135:131-138
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Isoprostanes constrict human radial artery by stimulation of thromboxane receptors, Ca²⁺ release, and RhoA activation

^a Department of Medicine, McMaster University, Hamilton, Ontario, Canada
^b Department of Surgery, McMaster University, Hamilton, Ontario, Canada.

Received for publication February 7, 2007; revisions received April 27, 2007; accepted for publication June 11, 2007.

^_* Address for reprints: Luke J. Janssen, PhD, Department of Medicine, McMaster University St Joseph’s Hospital, L-314, Research, 50 Charlton Ave East, Hamilton, Ontario, Canada L8N 4A6. (Email: janssenl{at}mcmaster.ca).

Objectives: Radial artery vasospasm remains a potential cause of early graft failure after coronary bypass graft surgery, despite pretreatment with -adrenergic or calcium channel blockers. We examined the roles of isoprostanes and prostanoid receptors selective for thromboxane A₂ in the vasoconstriction of human radial arteries.

Methods: Human radial arterial segments were pretreated intraoperatively with verapamil/papaverine or nitroglycerine/phenoxybenzamine, or not treated. In the laboratory, we measured isometric contractions in ring segments, vasoconstriction in pressurized segments, and changes in [Ca²⁺] and K⁺ currents in single cells.

Results: Although phenoxybenzamine eliminated adrenergic responses, the isoprostane 15-F_2t-IsoP and 2 closely related E-ring molecules (15-E_1t-IsoP and 15-E_2t-IsoP) still evoked powerful contractions; 15-E_2t-IsoP was approximately 10-fold more potent than the other 2 agents. Responses were mediated through thromboxane receptors because they were sensitive to ICI-192605. Furthermore, they were sensitive to the Rho-kinase inhibitors Y-27632 or H-1152 (both 10^–5 mol/L) or to cyclopiazonic acid (which depletes the internal Ca²⁺ pool), but not to nifedipine. In single cells, 15-E_2t-IsoP elevated [Ca²⁺]_i and suppressed K⁺ current.

Conclusions: Isoprostanes accumulate after coronary artery bypass graft surgery, yet none of the currently available antispasm treatments for radial artery grafts is effective against isoprostane-induced vasoconstriction. It is imperative that more specific treatment strategies be developed. We found that isoprostane responses in radial arteries are mediated by prostanoid receptors selective for thromboxane A₂ with activation of Rho-kinase and release of Ca²⁺. Pretreatment of radial artery grafts with Rho-associated kinase inhibitors may potentially reduce postoperative graft spasm. Clinical studies to test this are indicated.

This article has been cited by other articles:

				H. Sauer and M. Wartenberg Circulating Isoprostanes: Gate Keepers in the Route From Oxidative Stress to Vascular Dysfunction Circ. Res., October 24, 2008; 103(9): 907 - 909. [Full Text] [PDF]