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Using streptozotocin (STZ)-diabetic mice, we examined the respiratory distress induced by arachidonic acid. Male ddY mice were made diabetic by injecting STZ (170 mg/kg, i.p.) 2 weeks prior to the experiment. Control mice received the vehicle (citrate buffer, pH 4.6). The duration of respiratory distress was observed by a slow i.v.-injection of sodium arachidonic acid (AA) into the caudal vein of mice at the dose of 50 mg/kg. Aspirin was i.p.-administered 30 min before AA. OKY-046 (specific thromboxane A2 (TXA2) synthetase inhibitor), OP-41483 (stable prostacyclin analog) and 9, 11 epithia-11, 12-methano-TXA2 (STA2, stable TXA2 analog) were i.v.-administered 30 min before AA. The duration of respiratory distress induced by AA was significantly reduced in STZ-diabetic mice. Aspirin (10-50 mg/kg) and OKY-046 (25-100 mg/kg) enhanced the AA-induced respiratory distress in STZ-diabetic mice. OP-41483 (1-100 micrograms/kg) reduced the AA-induced effect in both control and STZ-diabetic mice. STA2 (10 micrograms/kg) enhanced the AA-induced effect in both control and STZ-diabetic mice. ONO-1078 (1-10 mg/kg) did not affect the AA-induced effect in both control and STZ-diabetic mice. TMK-688 (0.01-1 mg/kg) reduced the AA-induced effect in the control mice, but not in the STZ-diabetic mice. These results suggest an involvement of leukotriene in the respiratory response to AA in diabetic mice, especially when cyclooxygenase and TXA2 synthetase are inhibited.

N-methyl-D-aspartate (NMDA) receptors are known to play an important role in learning and memory and to be involved in neuron cell death accompanying cerebral ischemia, seizures, and Alzheimer's disease. The NMDA receptor complex has been considered to consist of an L-glutamate recognition site, a strychnine-insensitive glycine modulatory site, and a voltage-dependent cation channel. In the present study, effects of age on an L-glutamate recognition site and a glycine site were examined in rat brain by quantitative in vitro autoradiography with [3H]-CPP and [3H]-glycine. Both [3H]-glycine and [3H]-CPP binding sites were most abundant in the hippocampus and cerebral cortex, and they showed a similar distribution pattern throughout the brain. [3H]-glycine binding sites were severely decreased in the telencephalic regions, including the hippocampus and cerebral cortex, in aged brain. Conversely, [3H]-CPP binding sites were well preserved in these brain areas. In the mid-brain regions and cerebellum, neither [3H]-glycine nor [3H]-CPP binding sites changed in the aged brain. Our results indicate that within the NMDA receptor complex, glycine receptors are primarily affected in the aging process.

The analgesic effects of μ-and κ-opioid agonists, including morphine, FK33,824, U50,488H, tifluadom and bremazocine, have been determined in C57BL/6J-bgJ (beige) and CXBK mice which are hyporesponsive to μ-opioid receptor-mediated analgesia compared with those of control mice (C57BL/6J (C6J), C57BL/6By (C6By), BALB/cBy (BALB)) using an abdominal constriction assay. The analgesic effect of subcutaneously administered morphine and FK33,824 in both beige and CXBK mice was significantly reduced compared with the controls and the analgesic effect of U50,488H and tifluadom in beige mice was significantly reduced compared with the wild strain (C6J). No reduction of analgesic effect of U50,488H and tifluadom was seen in CXBK compared with its progenitor strains, C6By and BALB, except for a reduction of the effect of tifluadom in CXBK compared with C6By. There was no strain difference in the bremazocine-induced analgesia. These results suggest that the beige mouse has a deficit in analgesia mediated by both μ-and κ-opioid receptors, whereas the CXBK is deficient only in the μ-opioid receptor-mediated analgesia.

Significance of the intercapsular brown adipose tissue (IBAT) in the thermal response to chlorpromazine (CPZ) during acute and chronic cold exposure was studied in rats. Adult male Wistar-Imamichi rats were exposed to 4 degrees C for 1 (cold-exposed) or 30 days (cold-acclimated). Intraperitoneal injection of 10 mg/kg CPZ caused a more marked and lasted hypothermia in acute cold-exposed rats as compared with that seen in control or in cold-acclimatized rats. Hypothermia induced by CPZ was unaffected by removal of IBAT either in control or acute cold-exposed rats. But in cold-acclimated rats, the removal of IBAT potentiated the hypothermia by CPZ. The relative weight of IBAT in cold-acclimated rats was about 3 times heavier than that in control and acute cold-exposed rats. CPZ had no effect on the relative weight of IBAT in all groups examined. Total lipids in IBAT showed no significant changes following CPZ administration in rats of all groups. In acute cold-exposed rats, serum FFA level progressively decreased after CPZ injection. The noradrenaline concentration in IBAT increased after chronic cold exposure and CPZ suppressed this elevation. The results suggest that the thermogenesis related sympathetic activity in the IBAT plays a mediatory role in thermal response to CPZ during cold acclimation.

1 The effects of adenosine and adenine nucleotides were studied in rat duodenum from postnatal day 1 to day 70. The mechanical activity of duodenal segments was recorded through an isotonic transducer connected to a polygraphic recorder. 2 In rat duodenal segments, adenosine-5′-triphosphate (ATP, 10−4m) and adenosines-5′-diphosphate (ADP, 10−4m) produced a contractile response on postnatal day 1. This response increased with age, peaking on day 7, followed by a gradual decrease and was non-existent by day 21. In contrast, a relaxant response to ATP and ADP was apparent on day 21, and continued to increase up to day 70. 3 The contraction caused by ATP was inhibited by indomethacin or the P2y-purinoceptor antagonist, reactive blue-2 but not by tetrodotoxin or hyoscine. Thus, it may be mediated by production of prostaglandin through the P2y-purinoceptor. The relaxation produced by ATP was inhibited by reactive blue-2 but not by tetrodotoxin, guanethidine or the P1-purinoceptor antagonist, 8-phenyltheophylline indicating that ATP acts on smooth muscle directly through the P2y-purinoceptor. The pD2 for the contractile response to ATP was 5.15 on day 7 and that for the relaxant response, 6.64 on day 70. 4 Adenosine (10−4m) and adenosine-5′-monophosphate (AMP, 10−4m) elicited no response before day 14. On day 14, both adenosine and AMP produced a small relaxant response which increased with age. The relaxation produced by adenosine was inhibited by 8-phenyltheophylline but not by tetrodotoxin or guanethidine, indicating that it is mediated by an action on the P1-purinoceptor of smooth muscle. 5 It is evident from these results that in neonatal rat, a contractile response to ATP and ADP occurs initially in the duodenum, followed by a relaxant response to adenosine and AMP on day 14 and to ADP and ATP on day 21. 6 The smooth muscle of rat duodenum may tentatively be concluded to contain separate purinoceptors for adenosine and AMP (P1) and ADP and ATP (P2) and the responses to P1- and P2-agonists change during the course of development.

The present study deals with the hypnotic effect of pentobarbital (Pento) in relation to its metabolism in hepatic microsomes in streptozotocin (STZ, 170 mg/kg, i.p.) injected mice. Liver weight (mg/10 g body wt.) of STZ-treated mice was larger than that of the controls throughout the experimental period. Although the shortening of sleeping time induced by Pento (60 mg/kg, i.p.) was always observed, Pento-metabolizing enzyme activity (by the method of Kato et al., 1964) increased in mice with diabetes for 2 and 4 weeks but decreased in mice with diabetes for 8 weeks. Induction following phenobarbital (100 mg/kg, s.c.) and inhibition by SKF 525-A (10 mg/kg, i.p.) of hepatic metabolizing enzyme were found in both control and mice with diabetes for 2, 4 and 8 weeks, but these were not definitely correlated to their hepatic Pento-metabolizing enzyme activities. STZ-induced hyperglycemia and shortening of sleeping time by Pento were completely prevented by the pretreatment with nicotinamide (500 mg/kg, i.p.). NPH-insulin injection partially decreased hyperglycemia in STZ-diabetic mice, but sleeping time by Pento was not significantly affected. These results suggest that the hyposensitivity to Pento in STZ-diabetic mice is partially related to an abnormality of metabolism in liver such as the hyperglycemic state.

To investigate the hyperthermic effect of thyrotropin releasing hormone (TRH) and its potentiation by exogenous catecholamines (CA), the role of the adrenal medulla and of the pituitary gland was studied in unoperated, adrenal-demedullated or hypophysectomized mice. In unoperated mice, TRH 40 mg kg-1 i.p. produced a hyperthermia which was accompanied by an increase in plasma noradrenaline (NA) and adrenaline (Ad). NA or Ad, both at a dose of 1 mg kg-1 i.p., enhanced the TRH-induced hyperthermia. Adrenal demedullation suppressed the hyperthermia and the increase of plasma CA produced by TRH but not the potentiation of this hyperthermia by exogenous CA. Hypophysectomy abolished the TRH-induced hyperthermia but not the increase of plasma CA or the potentiation of this hyperthermia by exogenous CA. These results suggest that, in mice, both the adrenal medulla and the pituitary gland play an essential role in TRH-induced hyperthermia but not in its potentiation.

Administration of streptozotocin (STZ, 200 mg/kg, i.p.) to pregnant mice during either the early or middle stages of pregnancy produced diabetic conditions in the mother mice. It reduced the litter size, but did not induce diabetes in the pups. The weights of the liver and kidney per unit body weight of the infants of STZ-treated mother mice were slightly larger, though not significantly, than that of infants from control mothers; however, no increase was observed in the blood glucose or glycosylated hemoglobin (HbA1) values.

The blood flow of thyroid, adrenal cortex and renal cortex in the pentobarbital anesthetized rat was assessed from hydrogen gas desaturation curve. The microcirculation of thyroid was markedly augmented within 2 min after an intraventricular injection of Thyrotropin-Releasing Hormone (TRH) while Met-Enkephalin (ENK) failed to influence. Both TRH and ENK stimulated the microcirculation of adrenal cortex moderately. ENK diminished the microcirculation of renal cortex whereas TRH did not exert any effect. The response of thyroid to TRH was abolished by vagotomy, thus the existence of a specific TRH-vagus -thyroid connection was indicated.

The effect of pretreatment with reserpine (1 mg kg−1 i.p. daily for 7 days) on the regulation of iodothyronine 5′-deiodinase (5′D) in mouse brown adipose tissue (BAT) has been examined. 5′D activity of BAT homogenate was assessed by the in-vitro formation of 3,5,3′-triiodothyronine from thyroxine and 3,3′-diiodothyronine from 3,3′,5′-triiodothyronine in the presence of 20 mM dithiothreitol. Reserpine treatment decreased the stimulation of BAT 5′D induced by acute cold exposure (4°C, 2h) without a significant decrease in the basal 5′D activity, whereas stimulation of BAT 5′D elicited by noradrenaline (0.4 and 0.8 mg kg−1 s.c. 2 h previously) was not augmented after reserpine treatment. Although both noradrenaline and acute cold exposure increase BAT 5′D through α1-adrenoceptors, our results show that chronic reserpine treatment prevents the effect of cold, but does not induce α1-adrenoceptor supersensitivity in BAT.

STZ-diabetic mice showed the shortening of sleeping time and inhibition of hypothermia induced by pentobarbital(PB)(Tsukahara et al.,1983). TRH has been known to antagonize such PB actions. Therefore, we investigated the effects of TRH on PB hypnosis and hypothermia in STZ-diabetic mice. Diabetes was induced in male ddY mice by STZ(170mg/kg, i.p.). Some of them were injected with NPH-insulin(Ins,4-10U/kg/day, s.c.) twice daily for 3 days, and the last injection was given 15 min prior to PB experiment. Control mice were injected with citrate buffer in which STZ was dissolved. After TRH(10mg/kg, i.p.) was given immediately prior to PB(60mg/kg, i.p.), sleeping time and rectal temperature were determined at 2(STZ-2W), 4(STZ-4W) and 8 wk(STZ-8W) following the injection of STZ. TRH given simultaneously with PB antagonized PB-induced hypothermia but did not modify the hypnotic effect of PB in STZ-2W and STZ-4W mice. Although it did not show significant alterations in hypothermia, sleeping time was prolonged by TRH in STZ-8W mice. Pretreatment with Ins blocked the antagonistic effect of TRH on PB hypnosis in STZ-8W mice. The results suggest that the effect of TRH on the PB hypnosis and hypothermia in STZ-diabetic mice is partially related to an abnormality of metabolism such as the hyperglycemic state.

Since recent reports have demonstrated that triiodothyronine (T3) generated from thyroxine(T4) within the pituitary has an important role in the regulation of thyrotropin(TSH) secretion, it is of value to observe the effect of various pharmacological manipulations on pituitary T4 metabolism. Effects of propylthiouracil (PTU), an antithyroid drug, and thyrotropin-releasing hormone(TRH) were examined in this study. Bisected pituitaries and liver slices from the same rats were incubated with 125I-T4 in Krebs-Ringer phosphate buffer, pH7.4, in the presence of lOmM dithiothreitol. T4 metabolites in their homogenates were analyzed by paper chromatography, the results being related to tissue protein content. T3 formation from T4(T3-neogenesis) in the liver was remarkably inhibited by PTU added in vitro (0.ImM), In contrast, PTU(up to ImM) did not show any inhibitory effect on pituitary T3-neogenesis, the results being not affected by~ altered thyroid status. Varying doses of TRH in vitro (1.4×10, 1.4, 140μM) did not affect pituitary T3-neogenesis in both hypo- and euthyroid rats. Pituitary T3-neogenesis following TRH administration(i.v.,lng/g b.w.) was also studied at 0,15,30 and 240min. TRH given in vivo did not affect T3-neogenesis in the pituitaries of hypo- and euthyroid rats. The results suggest that T4 metabolism in the pituitary is not easily affected compared to that in the liver and thus appears to have important thyroregulatory significance.