The antiinflammatory effects of adenosine receptor agonists on the carrageenan-induced pleural inflammatory response in rats.
Adenosine and adenosine receptor agonists have a variety of inhibitory effects on the generation of inflammatory mediators by neutrophils and other cell types. In human neutrophils stimulated with the chemotactic peptide FMLP, adenosine agonists inhibit O2- generation and degranulation. Because these findings suggest that the agonists may have potential as antiinflammatory agents, several compounds were evaluated for effects on the exudative and cellular phases of carrageenan-induced pleural inflammation in rats. All of the agonists tested inhibited both parameters of the inflammatory response. Inhibition appeared to correlate better with binding to the A1 than to the A2 receptor and was reversible by a known adenosine receptor antagonist, 8-phenyltheophylline. In mechanistic studies, R-N-(1-methyl-2-phenylethyl)adenosine, a standard A1 selective agonist, reversed the drop in circulating neutrophil count that occurs after injection of carrageenan. These results suggest that the agonists may prevent cell emigration by inhibiting adhesion to the endothelium or diapedesis. In addition (R)-N-(1-methyl-2-phenylethyl)adenosine had weak inhibitory effects on superoxide production by FMLP-stimulated rat neutrophils. Control studies showed that the effects of the agonists were not the result of agonist-induced hypotension nor corticosterone production by the adrenal glands. These findings indicate that adenosine receptor agonists are effective new pharmacologic tools for the study of inflammatory processes.
Schrier
D J
DJ
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Lesch
M E
ME
Wright
C D
CD
Gilbertsen
R B
RB
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000315:Adrenalectomy; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D002351:Carrageenan; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D008914:Minoxidil / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D010998:Pleurisy / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D011983:Receptors, Purinergic / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D011983:Receptors, Purinergic; D013481:Superoxides; C047235:N-(1-methyl-2-phenylethyl)adenosine; D008914:Minoxidil; D002351:Carrageenan; D002216:Captopril; D013806:Theophylline; C028322:8-phenyltheophylline; C022192:alinidine; D000241:Adenosine; D003000:Clonidine