BIOLOGICAL-ACTIVITY OF METABOLITES OF PGD2 ON CANINE PROXIMAL COLON

The responses of the canine colonic epithelium to the metabolites of p rostaglandin D2 (PGD2) Were compared with those elicited by the parent prostanoid. Dose-response relations to PGD2 showed three distinct pat terns: 1) a dose-dependent decrease in short-circuit current (I(sc)) a t lower concentrations followed by a dose-dependent increase at higher concentrations; 2) dose-dependent decreases, with no increase even at the highest concentrations tested; and 3) dose-dependent increases in I(sc), with no decreases at any concentration. The colon responded di fferently to the two enzymatically derived metabolites 13,14-dihydro-1 5-keto-PGD2 (DK) and 11beta-PGF2alpha. The former consistently produce d only dose-dependent decreases in I(sc), while the latter elicited on ly dose-dependent increases. Pretreatment of tissues with 11beta-PGF2a lpha altered the responses to PGD2 such that only decreases were noted . Conversely, pretreatment with DK caused PGD2 to elicit only increase s in I(sc). The nonenzymatically derived PGJ2 elicited responses compa rable to those seen with PGD2. Pretreatment of tissues with indomethac in abolished responses to 11beta-PGF2alpha as well as its isomer, PGF2 alpha, suggesting the involvement of a cyclooxygenase product. Respons es to PGE2 were, however, amplified. Cross-desensitization was noted b etween the two isomers. Tissues desensitized to either 11beta-PGF2alph a or PGF2alpha, were responsive to DK as well as PGE2; however, tissue s desensitized to PGE2 were unresponsive to 11beta-PGF2alpha. Thus the canine colonic epithelium responds not only to PGD2 but also to its d erived metabolites. Variability in the response to PGD2 between animal s could stem from differences at the receptor level and/or differentia l production of these metabolites.