Differences in activities of thromboxane A2 receptor antagonists in smooth muscle cells.
Thromboxane A2/prostaglandin H2 (TXA2/PGH2) 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 TXA2 antagonist, SQ 29,548 and BM-13505 (daltroban). SQ 29,548 showed a single class of binding sites with a Ki value of 1.6 nM. The inhibition patterns were better fit to two-component curves for KW-3635 (Ki values of 0.45 nM and 42 nM) and BM-13505 (2.3 nM and 20 nM). U46619, a TXA2 agonist, induced an increase in intracellular calcium concentration ([Ca2+]i), which was inhibited by these antagonists. KW-3635 and SQ 29,548 did not induce any increase in [Ca2+]i, whereas BM-13505 was found to induce a smaller increase in [Ca2+]i. The BM-13505-induced increase in [Ca2+]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 TXA2/PGH2 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 [Ca2+]i to a similar degree. Alternatively, KW-3635 inhibited a U46619-induced increase in [Ca2+]i more effectively than a BM-13505-induced increase. These results suggest the heterogeneity of functional binding sites or subtypes of TXA2/PGH2 receptors present in VSMC.
Miki
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Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Kase
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Ishii
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D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001584:Benzoxepins / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001562:Benzimidazoles; D001584:Benzoxepins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010648:Phenylacetates; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D013928:Thromboxane A2; C045749:SQ 29548; C051762:daltroban; D002118:Calcium; C065729:KW 3635