Abstract
The role of endothelin B (ETB) receptors in inflammation and nociception was examined using ETB receptor knockout mice. Genotyping studies were used with tissues from ETB(+/+), ETB(+/−), and ETB(−/−) mice to confirm the loss of ETB receptors. Algesia induced by phenylbenzoquinone was evident in the (+/+) mice, reduced by ∼80% in the (+/−) mice, and absent in the (−/−) mice. Phenylbenzoquinone-induced algesia in (+/+) mice was inhibited 74% by the ETB receptor-selective antagonist A192621 (25 mg/kg p.o.), but unaffected by the ETA receptor-selective antagonist SB 234551 (25 mg/kg p.o.). Noninflammatory pain, induced by hotplate, was equivalent between (+/+) and (−/−) mice. The cutaneous inflammatory response to topical arachidonic acid (AA) also was evaluated. Whereas (+/+) mice had a marked inflammatory response to AA, the (+/−), and (−/−) mice had significantly reduced fluid phase responses (37 and 65% inhibition, respectively). Neutrophil infiltration also was reduced in the (+/−) and (−/−) mice (51 and 65% reduction, respectively). Topical administration of A192621 (500 μg/ear) in (+/+) mice inhibited AA-induced swelling (39%), whereas SB 234551 (500 μg/ear) was without effect. Collectively, these results implicate the ETB receptor in mediation of inflammatory pain and cutaneous inflammatory responses in mice.
Footnotes
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Send reprint requests to: Douglas W. P. Hay, Ph.D., Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, King of Prussia, PA 19406-0939. E-mail: douglas_w_hay{at}sbphrd.com
- Abbreviations:
- ET
- endothelin
- ETA
- endothelin A receptor
- ETB
- endothelin B receptor
- IL
- interleukin-8
- PBQ
- phenylbenzoquinone
- AA
- arachidonic acid
- PCR
- polymerase chain reaction
- MPO
- myeloperoxidase
- Received April 1, 1999.
- Accepted July 16, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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