EFFECT OF THROMBOXANE A(2) ANTAGONIST GR32191B ON PROSTANOID AND NONPROSTANOID RECEPTORS IN THE HUMAN INTERNAL MAMMARY ARTERY

Arterial grafts have been demonstrated to be very effective for coronary artery bypass surgery. Thromboxane A(2) (TXA(2)) is a potent vasoconstrictor for arterial grafts. To determine whether the specific TXA(2) (TP) receptor antagonist GR32191B is effective in inhibition of prostanoid or nonprostanoid receptors, we studied the effect of GR32191B in human internal mammary artery (IMA) segments, taken from coronary bypass patients, in organ chambers. In IMA precontracted with U46619 (10 nM, n = 7), prostaglandin F-2 alpha (PGF(2 alpha) 1 mu M, n = 7), or potassium chloride (K+ 25 mu M, n = 6). GR32191B induced 100.0 + 0, 97.86 +/- 2.14, or 45.87 +/- 7.63% relaxation. In other experiments, one IMA ring taken from each patient was used as a control and others from the same patient were allocated to other groups treated with different concentrations of GR32191B [3-300 nM for U466I9, 30 nM-3 mu M for PGF(2 alpha) 300 nM-100 mu M for K+, 3 mu M norepinephrine (NE), and 3 mu M for 5-hydroxytryptamine (5-HT)] for 1 h before concentration-contraction curves to these vasoconstrictors (expressed as percentage of K+-induced contraction force) were established. Treatment with GR32191B (300 nM) significantly decreased the contraction induced by U46619 (from 306.4 +/- 22.1 to 61.9 +/- 24.9%, p < 0.01) and that induced by PGF(2 alpha) (from 208.2 +/- 13.5 to 1.4 +/- 1.4%, p < 0.0001). However, higher concentrations of GR32191B did not significantly inhibit the contraction induced by NE (from 135.0 +/- 20.0 to 89.0 +/- 30.4%, p > 0.05), 5-HT (from 149.4 +/- 27.4 to 118.8 +/- 30.8%, p > 0.05), or K+ (from 185.7 +/- 23.9 to 152.7 +/- 22.8%, p > 0.05). Our results suggest that GR32191B is a highly potent and specific TXA(2) receptor antagonist for the human IMA. These findings may have important clinical implications in coronary artery bypass grafting surgery.