Interleukin-1 receptor antagonist displays intrinsic agonist activity on rat gastric fundus motility in vitro.
It has been shown previously that both forms of interleukin-1, 1 alpha and 1 beta, produce dose-dependent relaxation of the rat gastric fundus in vitro, accompanied by an increased production and release of eicosanoids. This effect appears to be mediated, at least in part, by leukotrienes, since the inhibition of 5-lipoxygenase by specific drugs counteracts interleukin-1-induced gastric relaxation. In the present study, we attempted to antagonize interleukin-1-induced inhibition of gastric fundus motility with a interleukin-1 receptor antagonist. Surprisingly, the interleukin-1 receptor antagonist itself possessed interleukin-1-like agonist activity, since: (a) it produced rapid, dose-dependent relaxation of the rat gastric fundus, with an estimated EC50 of 70 pg/ml and a maximal effect at 10 ng/ml; (b) interleukin-1 receptor antagonist-induced relaxation was dose dependently inhibited by N-(3-phenoxycinnamyl)acetohydroxamic acid (BW A4c), a specific inhibitor of 5-lipoxygenase; (c) in the first 5 min after its addition to the bath solution, interleukin-1 receptor antagonist produced a significant increase in prostaglandin E2 release from the gastric strips. This evidence suggests that, shortly after receptor occupancy, in this experimental model interleukin-1 and interleukin-1 receptor antagonist share the same pattern of mechanical and biochemical activities.
Montuschi
P
P
Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
Tringali
G
G
Mirtella
A
A
Parente
L
L
Preziosi
P
P
Navarra
P
P
D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000819:agonists* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011863:Radioimmunoassay; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology
D044482:Benzeneacetamides; D006877:Hydroxamic Acids; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; D015232:Dinoprostone