Isoprostanes constrict human radial artery by stimulation of thromboxane receptors, Ca2+ release, and RhoA activation.
OBJECTIVE
Radial artery vasospasm remains a potential cause of early graft failure after coronary bypass graft surgery, despite pretreatment with alpha-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.
Mueed
Irem
I
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Tazzeo
Tracy
T
Liu
Ciaqiong
C
Pertens
Evi
E
Zhang
Yongde
Y
Cybulski
Irene
I
Semelhago
Lloyd
L
Noora
Joseph
J
Lamy
Andre
A
Teoh
Kevin
K
Chu
Victor
V
Janssen
Luke J
LJ
D002118:Calcium / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D028421:Isoprostanes / Q000494:pharmacology*; D017534:Radial Artery / Q000187:drug effects* / Q000503:physiopathology; D017482:Receptors, Thromboxane / Q000187:drug effects; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D015398:Signal Transduction; D020858:Tissue and Organ Harvesting; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D028421:Isoprostanes; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein; D002118:Calcium