DECREASE IN VASCULAR TXA(2) RECEPTORS IN A SUBGROUP OF RABBITS UNRESPONSIVE TO A TXA(2) MIMETIC

In rabbit pulmonary artery, endothelium-dependent contractions to arac hidonic acid and methacholine are mediated by thromboxane (Tx) A(2). T he TxA(2) mimetics U-46619 and {1S-[1 alpha,2 beta(5Z),3 alpha(1E,3R( )),4 alpha]}-7-{3-[3- tenyl]-7-oxabicyclo(2.2.1)heptan-2-yl}-5-hepteno ic acid (I-BOP), norepinephrine, and endothelin produced endothelium-i ndependent contractions. Arachidonic acid, methacholine, U-46619, and I-BOP failed to produce contractions in a subgroup of rabbits (25%). N onresponder arteries contracted similarly to norepinephrine and endoth elin as responder arteries. The affinity (K-d) and density (B-max) of TxA(2) receptors in crude pulmonary artery membranes were assessed via equilibrium binding studies using I-125-BOP. There was no difference in K-d between the two groups (0.49 +/- 0.17 vs. 0.32 +/- 0.14 nM, res ponder vs. nonresponder). There was a significant decrease in B-max (1 23 +/- 21 VS. 28 +/- 11 fmol/mg protein, responder vs. nonresponder; P < 0.01) of receptors in the nonresponders. Nonresponder aortas also d id not contract to U-46619 and exhibited a decrease in TxA(2) receptor s, indicating that the difference is not specific for the pulmonary ar tery. Nonresponder platelets aggregated to U-46619, suggesting that th e platelet receptor is not altered. TxA(2)-receptor expression may be regulated in vivo. Nonresponder rabbits may provide a useful model for studying these receptors in vascular disease.