BQ-153, a novel endothelin (ET)A antagonist, attenuates the renal vascular effects of endothelin-1.
Endothelin (ET)-1, leukotriene D4 and the thromboxane analogue, U-44069, were all shown to produce dose-dependent reductions in renal blood flow after direct injection into the renal artery of anaesthetized pigs. The effects of ET-1 differed from the other two mediators in that ET-1 caused a transient vasodilator followed by a prolonged vasoconstrictor response. The pressor response was not mediated by the secondary release of either leukotriene D4 or thromboxane A2 as evidenced by the lack of effect of appropriate receptor antagonist MK571 (3-[-2(7-chloro-2 quinolinyl) ethenyl]phenyl[3-(dimethylamino-3-oxopropyl)thio]methyl thio propionic acid) and L-670,596 respectively. This response, however, could be inhibited in a dose-dependent fashion by the selective ETA antagonist, BQ-153 (cyclo-D-sulphalanine-L-Pro-D-Val-L-Leu-D-Trp-). Following blockade by BQ-153 the vasodilator response was unaffected and a residual pressor response remained, suggesting that either or both of these effects were mediated either through an ETB or a novel, as yet undefined, endothelin receptor.
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.
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Cirino
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Motz
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Maw
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Ford-Hutchinson
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Yano
D000595:Amino Acid Sequence; D000818:Animals; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012079:Renal Circulation / Q000187:drug effects*; D013189:SRS-A / Q000494:pharmacology; D013552:Swine
D016232:Endothelins; D010456:Peptides, Cyclic; D011450:Prostaglandin Endoperoxides, Synthetic; D013189:SRS-A; C072485:cyclo(sulfoalanyl-prolyl-valyl-leucyl-tryptophyl); C028429:U 44069