In vitro thyrotrophin release with thyrotropin-releasing hormone and an analogue, DN-1417

Using dispersed and primarily cultured cells of rat pituitary glands, thyrotrophin (TSH) release by TSH-releasing hormone (TRH) and an analogue, gamma-butyrolactone-gamma-carbonyl-L-histidyl-L- prolinamide (DN-1417) which is more potent than TRH on central nervous system behavioural paradigms, was examined under conditions of static incubation and superfusion. Static incubations of the cells with different concentrations of DN-1417 (10(-7)-10(-4) M) and TRH (10(-10)-10(-6) M) resulted in a dose-related increase of TSH release and the response to both peptides, in logarithmic doses, was in parallel. The potency of DN-1417 related to TSH release was 0.14-0.26% that of TRH. Maximal TSH release induced by DN-1417 (10(-5) M) was slightly but significantly greater than that by TRH (10(-7) M). In the presence of 3-isobutyl-1-methylxanthine, the TSH response to either of the peptides was augmented, and the difference in the maximal TSH release by either peptide became insignificant, suggesting that TRH as well as DN-1417 act through the same mechanism of mediation by the cyclic nucleotides. In the superfusion study, a biphasic profile of TSH release was observed during a continuous exposure (100 min) to maximal doses of either the analogue or TRH. The biphasic release of TSH was thought to be specific to TRH action because high K+ produced a different profile of the release. These results indicate that the potency of DN-1417 in TSH release is considerably lower than that of TRH, and also suggest that the direct action of DN-1417 on TSH release is qualitatively similar to that of TRH.