Differences in activities of thromboxane A 2 receptor antagonists in smooth muscle cells

Abstract

Thromboxane A 2/prostaglandin H 2 (TXA 2/PGH 2) receptors were characterized in rat vascular smooth muscle cells (VSMC). The specific binding of [ 3H]SQ 29,548 was inhibited by KW-3635, a novel non-prostanoic TXA 2 antagonist, SQ 29,548 and BM-13505 (daltroban). SQ 29,548 showed a single class of binding sites with a K i value of 1.6 nM. The inhibition patterns were better fit to two-component curves for KW-3635 (K i values of 0.45 nM and 42 nM) and BM-13505 (2.3 nM and 20 nM). U46619, a TXA 2 agonist, induced an increase in intracellular calcium concentration ([Ca 2] i), which was inhibited by these antagonists. KW-3635 and SQ 29,548 did not induce any increase in [Ca 2+] i, whereas BM-13505 was found to induce a smaller increase in [Ca 2+] i. The BM-13505-induced increase in [Ca 2+] i was also inhibited by pretreatment with KW-3635, SQ 29,548 and BM-13505. The results demonstrate that BM-13505 has partial agonistic activity on TXA 2/PGH 2 receptors, and KW-3635 and SQ 29,548 do not. SQ 29,548 and BM-13505 inhibited both U-46619- and BM-13505-induced increases in [Ca 2+] i to a similar degree. Alternatively, KW-3635 inhibited a U46619-induced increase in [Ca 2+] i more effectively than a BM-13505-induced increase. These results suggest the heterogeneity of functional binding sites or subtypes of TXA 2/PGH 2 receptors present in VSMC.