Characterization of the EP-receptor mediating dilatation and potentiation of inflammation in rabbit skin.
The interactions of bradykinin (BK) and FMLP (a leukocyte-dependent mediator of inflammation) with thirteen prostaglandin E analogs have been investigated in a rabbit skin model of inflammation. The PGE analogs were chosen with a view to defining the EP-receptor subtypes involved. Five analogs, PGE2, misoprostol, 16,16-dimethyl PGE2, nocloprost, and enisoprost, were potent vasodilators (133Xe clearance method) and potent potentiators of both BK and FMLP exudation ([125I]albumin method). A further four analogs, butaprost, 11-deoxy PGE1, mexiprostil, and AH 13205, were weaker vasodilators and weaker potentiators of exudation. The remaining four analogs, 11-deoxy PGE2-1-alcohol, MB 28767, sulprostone, and GR 63779X did not induce vasodilatation and did not potentiate FMLP exudation. However, the latter three prostanoids (which are all potent and moderately selective EP3 agonists) produced a modest potentiation of BK exudation at low doses (1 and 10 ng), with no greater effect at higher doses (100 and 1000 ng). Statistical correlation of vasodilator responses with potentiation of FMLP exudation responses was highly significant. A similar correlation for vasodilation/BK exudation, although statistically significant, was not as convincing. The analyses suggested that vasodilatation is a major mechanism of PGE-induced potentiation of plasma exudation and that an EP2-receptor subtype is involved. However, the possibility of a second non-dilator mechanism could not be ruled out.
Armstrong
R A
RA
Department of Pharmacology, University of Edinburgh, Scotland.
Marr
C
C
Jones
R L
RL
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001783:Blood Flow Velocity; D001920:Bradykinin / Q000494:pharmacology; D003872:Dermatitis / Q000503:physiopathology*; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D005480:Flurbiprofen / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D016595:Misoprostol / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D011461:Prostaglandins F, Synthetic; D018078:Receptors, Prostaglandin E; D016595:Misoprostol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005480:Flurbiprofen; C048895:nocloprost; D000527:Alprostadil; C060013:vapiprost; C054594:enisoprost; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D001920:Bradykinin