Mechanism of the hyperthermic effect of the novel thyrotropin-releasing hormone analogue Na- ( (1S,2R) -2-methyl-4-oxocyclopentylcarbonyl) -L-histidyl-L- prolinamide monohydrate in mice with reserpine-induced hypothermia
Matsushita, M.; Yonemori, F.; Ohta, A.; Iwata, K.
Arzneimittel-Forschung 45(6): 708-711
1995
ISSN/ISBN: 0004-4172 PMID: 7646576 Document Number: 440324
To investigate the mechanism of the antagonistic effect of Na-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prolin amide monohydrate (CAS 131404-34-7, JTP-2942) on reserpine-induced hypothermia, the role of the autonomic nervous system, adrenal gland, and thyroid gland regarding the effects of JTP-2942 has been studied in mice. Both phenoxybenzamine and propranolol significantly attenuated the hyperthermic effect of JTP-2942 on reserpine-induced hypothermia, although neither drug caused complete inhibition. A high dose of hexamethonium also significantly antagonized the hyperthermic effect of JTP-2942. The hyperthermic effect of JTP-2942 was almost abolished by adrenal demedullation. In mice with thiouracil-induced hypothyroidism, both thyrotropin-releasing hormone (TRH) and JTP-2942 significantly increased the rectal temperature. However, the increase induced by TRH was smaller in hypothyroid mice than in control mice, while the temperature increase induced by JTP-2942 was similar in both hypothyroid and control mice. These results suggest that the hyperthermic effect of JTP-2942 is mainly mediated by the adrenal gland and the autonomic nervous system. In addition, the hypothalamic-pituitary-thyroid axis does not regulate the hyperthermic effect of JTP-2942, unlike that of TRH.