Decrease in vascular TxA2 receptors in a subgroup of rabbits unresponsive to a TxA2 mimetic.
In rabbit pulmonary artery, endothelium-dependent contractions to arachidonic acid and methacholine are mediated by thromboxane (Tx) A2. The TxA2 mimetics U-46619 and (1S-[1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha])-7-[3- [3-hydroxy-4-(4'-iodophenoxy)-1-butenyl]-7-oxabicyclo(2.2.1)hep tan-2-yl]- 5-heptenoic acid (I-BOP), norepinephrine, and endothelin produced endothelium-independent contractions. Arachidonic acid, methacholine, U-46619, and I-BOP failed to produce contractions in a subgroup of rabbits (25%). Nonresponder arteries contracted similarly to norepinephrine and endothelin as responder arteries. The affinity (Kd) and density (Bmax) of TxA2 receptors in crude pulmonary artery membranes were assessed via equilibrium binding studies using 125I-BOP. There was no difference in Kd between the two groups (0.49 +/- 0.17 vs. 0.32 +/- 0.14 nM, responder vs. nonresponder). There was a significant decrease in Bmax (123 +/- 21 vs. 28 +/- 11 fmol/mg protein, responder vs. nonresponder; P < 0.01) of receptors in the nonresponders. Nonresponder aortas also did not contract to U-46619 and exhibited a decrease in TxA2 receptors, indicating that the difference is not specific for the pulmonary artery. Nonresponder platelets aggregated to U-46619, suggesting that the platelet receptor is not altered. TxA2-receptor expression may be regulated in vivo. Nonresponder rabbits may provide a useful model for studying these receptors in vascular disease.
Buzzard
C J
CJ
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas 75235.
Pfister
S L
SL
Halushka
P V
PV
Campbell
W B
WB
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D004351:Drug Resistance; D004730:Endothelium, Vascular / Q000502:physiology; D006728:Hormones / Q000097:blood; D008297:Male; D010974:Platelet Aggregation; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011817:Rabbits; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000378:metabolism*; D013928:Thromboxane A2 / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D006728:Hormones; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D013928:Thromboxane A2