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.
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.
Matsushita
M
M
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka.
Yonemori
F
F
Ohta
A
A
Iwata
K
K
D000313:Adrenal Medulla / Q000502:physiology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D018738:Hexamethonium / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007037:Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012110:Reserpine; D013889:Thiouracil; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology
D010643:Phenoxybenzamine; C080784:JTP 2942; D018738:Hexamethonium; D013889:Thiouracil; D013973:Thyrotropin-Releasing Hormone; D012110:Reserpine; D011433:Propranolol