Inhibition of vasoconstriction by the thromboxane A2 antagonist GR32191B in the human radial artery

Aims The newly revived coronary bypass graft, the radial artery (RA), is more spastic than the internal mammary artery. Thromboxane A(2) is a potent vasoconstrictor for arterial grafts. This study was therefore designed to determine whether the specific thromboxane A(2) (TP) receptor antagonist, GR32191B, is effective in inhibition of prostanoid or nonprostanoid receptors in the RA. Methods The effect of GR32191B was studied in human RA segments, taken from coronary bypass patients, in organ chambers. Two effects of GR32191B were tested: (1) the relaxation induced by GR32191B in the RA precontracted with the TP receptor agonists U46619 and PGF(2 alpha) or nonprostanoid vasoconstrictors (noradrenaline [NA], angiotensin II [AII], and K+) and (2) the inhibitory effect of GR32191B on TP receptor agonists and nonprostanoid vasoconstrictors. Results In U46619 (10 nM, n=7) and PCF2 alpha (1 mu M n=7) precontracted RA, GR32191B induced 100% relaxation (10-100 mu M) but not after precontraction with nonprostanoid stimuli (5.8% for K+, 25 mM, n=6, 24.4% for NA, 3 mu M, n=8, and 53.2% for AII, 3 nM, n=5) (P<0.001). Treatment with GR32191B (3 nM) significantly depressed the contraction with U46619 (from 160.1+/-11.0% to 116.8+/-13.1%, P<0.05) or PCF2 alpha (from 91.3+/-12.3% to 42.2+/-9.2%, P<0.01). The contraction was further abolished by 3 mu M GR32191B. However, GR32191B at 3 mu M did not significantly inhibit the contraction induced by either NA, Ail, or K+ Conclusions GR32191B is a highly potent acid specific TP receptor antagonist for the human RA. It may be particularly useful in inhibiting TXA(2)-mediated vasoconstriction and therefore in reducing the complications related to vasospasm in this graft.