James F. Kachur

Bradykinin-stimulated electrolyte secretion in rabbit and guinea pig intestine. Involvement of arachidonic acid metabolites.

Bradykinin (BK) increases short-circuit current (Isc) when added to the serosal side of rabbit or guinea pig ileum or rabbit colon. Significant effects on Isc are seen at concentrations as low as 10(-10) M. Anion substitution experiments and unidirectional 36Cl flux measurements indicate that this effect of BK on Isc is due to Cl secretion. The effect of BK on Isc can be partially blocked (60-70% inhibition) by cyclooxygenase inhibitors (indomethacin and/or naproxen) and completely blocked by the phospholipase inhibitor, mepacrine. The combined cyclooxygenase/lipoxygenase inhibitors BW 755 and eicosa-5,8,11,14-tetraynoic acid (ETYA) also completely block the effect of BK on Isc but the slow-reacting substance of anaphylaxis (SRS-A) antagonist FPL 55712 has no effect. None of the above inhibitors diminish the effect on Isc of other exogenously added secretory stimuli such as vasoactive intestinal peptide (VIP), theophylline, or prostaglandin E2 (PGE2). Prior desensitization of rabbit ileum to PGE2 blocks the effect on Isc of BK but not those of VIP or theophylline. Conversely, prior desensitization of rabbit ileum to BK greatly reduces the effect of PGE2 on Isc. BK also stimulates the synthesis of PGE2 in rabbit ileal and colonic mucosa and this effect can be blocked by prior addition of either indomethacin or mepacrine. These effects of BK are similar to those of exogenously added arachidonic acid (AA). AA also stimulates Cl secretion and increases PGE2 synthesis and its effect on Isc can be inhibited by prior desensitization to PGE2 or by prior addition of indomethacin. The above results indicate that BK stimulates active Cl secretion in both small and large intestine and suggest that this effect is due to the intracellular release of AA. Although the prostaglandins appear to be the major products of AA metabolism contributing to the secretory response, lipoxygenase products may also play a role.

Characterization of the opiate receptor in the guinea-pig ileal mucosa

Several opioid peptides and narcotic drugs reduced transepithelial potential difference (PD) and short circuit current (Isc) in guinea-pig ileal mucosa measured in vitro in Ussing chambers. [D-Ala2,D-Leu5]enkephalin was the most potent peptide tested. Enkephalin analogues with altered C-terminal amino acids were less potent, as were beta-endorphin and dermorphin. Etorphine produced potent effects whereas morphine and SKF 10,047 were inactive. Ethylketazocine produced a biphasic dose-response curve. When added by themselves diprenorphine and naloxone produced small increases in Isc. This effect was not seen when Cl- and HCO3- in the Ringer were replaced by SO42-. Diprenorphine and naloxone were able to shift the dose response curves for all agonists to the right, with the exception of that for ethylketazocine. Diprenorphine was a more potent antagonist than naloxone. SKF 10,047 also acted as a pure antagonist. Morphine and ethylketazocine had no antagonist effects. It is concluded that the opiate receptor in the guinea-pig ileal mucosa is similar to a delta-opiate receptor as defined by ligand binding studies, but that some differences also exist.

OPIATE RECEPTORS IN THE GUINEA-PIG ILEAL MUCOSA

Enkephalins and their analogues reduced transepithelial potential difference (PD) and short circuit current (Isc) across guinea-pig ileal mucosa. These effects were blocked by naloxone, diprenorphine and SKF 10,047. Diprenorphine was the most potent antagonist used.