Tissue- and species-specific differences in ligand binding to thromboxane A2 receptors

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Abstract

The ligand binding site of vascular smooth muscle (VSM) and platelet thromboxane A2 (TxA2) receptors was characterized in humans and rabbits using the TxA2 mimetic [125I]BOP. Vessel contraction and platelet aggregation studies demonstrated that unlabeled I-BOP and the prostaglandin H2 (PGH2) mimetic U-46619 were potent agonists in rabbit aortas, human saphenous veins, and washed human and rabbit platelets. [125I]BOP bound saturably to a single site on cultured vascular smooth muscle (VSM) cells from rabbit aortas and human saphenous veins with dissociation constants (K(d)) of 392 ± 8 (n = 5) and 390 ± 120 pM (n = 6) and binding capacities (B(max)) of 5,322 ± 200 and 2,017 ± 322 sites/cell, respectively. [125I]BOP also bound saturably to one site on rabbit platelets (K(d) = 415 ± 15 pM, B(max) = 594 ± 43 sites/platelet, n = 4) but, in agreement with previous studies, to two sites on human platelets (high-affinity K(d) = 118 ± 24 pM, B(max) = 121 ± 33 sites/platelet; low-affinity K(d) = 1.1 1/4 0.47 nM, B(max) 232 ± 23 sites/platelet, n = 4). [125I]BOP was displaced from its binding site on rabbit and human VSM and platelets by stable TxA2/PGH2 analogues possessing either agonist or antagonist activity but not by other prostaglandins. The rank orders of the binding inhibition constants (IC50) for the TxA2/PGH2 analogues were compared among the four tissues and were highly correlated (r = 0.963) in VSM and platelets from rabbits but not humans (r = 0.699), suggesting that human VSM TxA2 receptors may be distinct from platelet TxA2 receptors. The IC50 rank order was also highly correlated (r = 0.935) between human and rabbit platelets. However, the human and rabbit VSM IC50 rank orders differed significantly (r = 0.466), suggesting that VSM TxA2 receptors are dissimilar in these species. Collectively, these receptor binding studies strongly suggest the existence of TxA2 receptors that are both tissue and species specific.

Original languageEnglish
Pages (from-to)R145-R153
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume261
Issue number1 30-1
StatePublished - Sep 17 1991
Externally publishedYes

Keywords

  • Platelets
  • Vascular smooth muscle

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