Characterization of receptors involved in the direct and indirect actions of prostaglandins E and I on the guinea-pig ileum.
1. A study of the effects of prostaglandin E2 (PGE2) and eleven synthetic analogues on the guinea-pig isolated ileum preparation has revealed three distinct contractile actions, each associated with a different prostaglandin E (EP-) receptor subtype. In addition, PGI2 (prostacyclin) and its stable analogues can activate prostaglandin I (IP-) receptors to elicit both contraction and relaxation of the ileum. 2. Two of the PGE actions involve direct stimulation of the smooth muscle, being unaffected by 1 microM morphine treatment. One action is blocked by AH 6809 at micromolar concentrations and ICI 80205 and 16,16-dimethyl PGE2 are particularly potent agonists. Activation of EP1-receptors appears to be involved. The second action is unaffected by AH 6809; sulprostone and MB 28767 are potent agonists. Comparison with agonist potency rankings on the guinea-pig vas deferens indicates that EP3-receptors may be involved. 3. The third PGE effect and the stimulant PGI effect are blocked by morphine, indicating enteric neurones and/or sensory nerve terminals as sites of action. EP2-receptors may be involved in the PGE action, in view of the marked effect of morphine on the contractile actions of misoprostol, 11-deoxy PGE2-1-alcohol, 11-deoxy PGE1 and butaprost, all of which show some selectivity for EP2-receptors. The PGI action is most easily studied with cicaprost (EC25 = 1.3 nM), since iloprost, carbacyclin and to a lesser extent PGI2 also have agonist activity at EP1-receptors. 4. The contractile action of 17-phenyl-omega-trinor PGE2 on the ileum is unaffected by morphine. Since this analogue shows only weak agonist activity on the rabbit jugular vein (EP2 preparation) and guinea-pig vas deferens (EP3), it may be a more useful standard agonist than PGE2 in EPl1-receptor studies.5. In the presence of morphine and AH 6809, cicaprost inhibits histamine-induced contractions (IC25 = 22 nM). PGI2 and iloprost show mixed inhibitory/potentiating actions, whereas carbacyclin only potentiates histamine contractions. This IP-receptor-mediated inhibition may account for the bell-shaped log concentration-response curve of cicaprost (no inhibitors present) and the very marked block of iloprostinduced contractions by AH 6809.6. We have found no evidence for either IP-receptors mediating direct contraction or EP-receptors mediating inhibition of the ileum longitudinal smooth muscle, as has been suggested in the literature.7. In view of the complexity of prostanoid action on the guinea-pig ileum we feel that the preparation must be used with caution to ascertain the EPl agonist or antagonist potencies of novel compounds.
Lawrence
R A
RA
Department of Pharmacology, University of Edinburgh.
Jones
R L
RL
Wilson
N H
NH
D000818:Animals; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011458:Prostaglandins E / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D014132:Trachea / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D006633:Histamine Antagonists; D011448:Prostaglandin Antagonists; D011458:Prostaglandins E; D011459:Prostaglandins E, Synthetic; D011982:Receptors, Prostaglandin; D014966:Xanthenes; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; C026678:carboprostacyclin; D009020:Morphine; D011464:Epoprostenol