Fujiyama, Katsumi

Hoshino, Tazue

Ikeda, Tadasu

Mashiba, Hiroto

Ochi, Hiroshi

Ohtani, Izumi

Takeuchi, Tatsuo

Tanaka, Yasushi

Tottori University Research Result Repository

lullTMCT 17, 1-6, 1991 Possible role of the adrenergic mechanism in experimental hyperketonemia caused by thyrotoxicosis and starvation in rats Tadasu IKEDA, Hiroshi OCHI*, Izumi OHTANI~ Katsumi FUJIYAMA*, Tazue HOSHINO*, Yasushi TANAKA*, Tatsuo TAKEUCHI* and Hiroto MASHIBA* Tottori University College of Medical Care Technology, and *The First Department of Internal Medicine, Tottori University School of Medicine, Yonago 683, Japan Catecholamine is well known to have an important role to metabolize ketone bodies. P-ractically, hyperketonemia is frequently observed both in hyperthyroidism 1nd starvation of various species l-71. Besides, several investigators have reported 1n increase of catecholamine in serum and ur-ine during starvation of animals 8- 101. Beylot et al. 51 have reported an implication that catecholamine affects some symptoms. of hyperthyroidism through S-receptors. However, the role of the adrenergic mech-anism in hyperketonemia involved in hyperthyroidism and starvation remains to be fully elucidated. In this study, we investigated the possible role of the adrenergic mechanism in experimental hyperketonemia in thyrotoxic or starved rats. Materials and Methods Animals and chemicals Male Wistar albino rats were used in this study. L-Thyroxine was purchased from Sigma Chemical, St Louis. Phentolamine from Ciba Geigy, Takarazuka, Japan, and propranolol from ICI Pharma., Osaka, Japan. L-Thyroxine was dissolved in a small amount of 0.01N NaOH, then brought to a concentration of 100.Ug/ml with saline. Adrenergic blockers administration into thyrotoxic rats Into an experimental group of rats, thyroxine ( T4 ) was first administered sub-cutaneously at a dose of lOO.ug/kg/day for 7 days. While into a control group, sole saline was first injected under the same schedule. Into some of both groups, 2 Ikeda T et al either a 2 mg/kg dose of phentolamine or a 0.1 mg/kg dose of propranolol wa secondly administered subcutaneously twice a day for 7 days. Consequently, tb rats were left to fast overnight to consume the drugs, then drawn blood fron femoral vein, after being anesthetized with a 30 mg./kg dose of intraperitone~ pentobarbital sodium solution. Adrenergic blockers administration into starved rats One group of rats was forced to fast 96 hr, except with a dilute electrolyt solution consisted of 78mEq/l sodium salts and 15mEq/l potassium salts t prevent rats from the depletion of sodium ions. The other group of fed rats wa used as control. Into some of both groups, either phentolamine or propranolo was administered at the same dose as above, this time, every 12 hr for 96 hr. Measurement Blood glucose was measured by a glucose oxidase method. Plasma insulin glucagon, triiodothyronine (T3 ), and thyroxine (T4 ) were measured by respectiv radioimmunoassay. Amount of plasma free fatty acid (FF A) was measured enzyma tically with a commercial kit (NEFA C-Test, Wako, Osaka, Japan). Plasm: acetoacetate (AcAc), and /1-hydroxybutyrate (BOHB) were measured enzymatically 11 Statistical analysis Analysis of variance and two tailed Student's non-paired t test was applied t< verify the values obtained with the measurements, presenting them as means ± SD Results Relation among body weight, amount of blood glucose, and of plasma insulin, glucagon, T3 , T4 , FFA, AcAc, and BOHB in thyrotoxic rats Table 1 shows that the mean value of body weight in thyrotoxic rats is lower than that of control rats. On the contrary, the mean values of blood glucose, plasma insulin, T 3 , T4 , FFA, AcAc, and BOHB in thyrotoxic rats are significantly higher than those in control. Plasma glucagon level in thyrotoxic rats was similar to it in control. In both groups of rats, phentolamine administered induced to in· crease the level of plasma insulin, but not of blood glucose, plasma FFA, AcAc, and BOHB. Propranolol could not change the levels of these parameters at all. Relation among body weight, amount of blood glucose, and of Plasma insulin, glucagon, FFA, AcAc, and BOHB in starved rats Table 2 shows that body weight, blood glucose and plasma insulin in starved rats are significantly lower than those in fed rats. Table 2 also shows that, on the contrary, plasma FF A, AcAc, BOHB in starved rats are significantly higher than those in fed rats. Plasma glucagon level was not different between starved and fed Hyperketonemia in rats 3 ats. Phentolamine administered induced to increase the levels of plasma insulin in ny rat. Besides, it lifted up significantly the levels of plasma FF A, AcAc, and IOHB only in starved rats. Propranolol could not change the levels of these para-neters at all. Table 1 Amounts of various parameters after operating adrenergic blockers to experimentally thyrotoxic rats Adrenergic BW BG IRI IRG T, T, FFA AcAc blockers (g) (mg/dl) (.uU/ml) (pg/ml) (ng/dl) (.ug/dl) (mmol/1) (mmol/l) administration [ Contcol ( n~6) ) 162± 11 74±4 12±5 71±23 80±10 3.1±0.5 !.0±0.3 !.10±0.26 [ Thycotoxic ( n~ 6) ) 130± 10* 82±5* 25±9* 70±22 148±44* 10.9±0. 7* 1.7±0.3* 1.85±0.47* propranolol (n=6) 125± 12* 82±6* 24±9* 69±25 139±51 * 10.8±0.8* 1.6±0.3* !.87:±-0.51* phentolamine (n=6 )1 129±11* 83±7* 47 ± 15* 73±24 140±42* 1!.0±0.9* !. 7 ± 0.3* !.84±0.55* BOHB (mmol/l) 0.46±0.11 !.06±0.24* 1.17±0.23* !.09±0.27* After overnight fast, thyrotoxic rats were induced with either propranolol or phentolamine according to the schedule shown in Materials and Methods. Then, amounts of various parameters were measured with respective procedures shown in Materials and Methods. Symbols show; BW, body weight of rats; BG, blood glucose; IRI, plasma insulin; IRG, plasma glucagon; T3 , triiodothyronine; T4 , thyroxine; FF A, free fatty acid; AcAc, acetoacetata; BOHB, S-hydroxybutyrate; *P <0.05 in being significantly different from value in control. Discussion Hyper ketonemia was sure to be observed in the thyrotoxic or starved ats in this study, according to many reports that an increased ketogenesis nd subsequent hyper ketonemia were observed in hyperthyroidism or starvation n several species J-'i). Phentolamine or propranolol could not change the tmount of plasma FF A, AcAc, and BOHB in thyrotoxic rats, suggesting that the tdrenergic mechanism did not operate to eliminate hyperketonemia at least at the 1yperthyroid state. Although phentolamine administration increased plasma level of nsulin, the amount of plasma FFA, AcAc, and BOHB were not changed, suggesting ha:t the insulin resistance may partly be involved in hyperketonemia of thyrotoxic :ats. Bey lot et al. 61 have reported that propranolol does not have a direct, inhibitory ~£feet on ketogenesis as it is, but on that of hyperthyroid patients so far, being pro-Jably due to the decrease of the triiodothyronine level. Several investigators rz-Js) 1ave reported that S-adrenergic blockade inhibits the conversion of T 4 to T 3 in pe. ·ipheral tissues. In this study, the plasma T 3 level was not changed in propranolol-:reated thyrotoxic rats. Therefore, propranolol may not inhibit the conversion of ex-Jgenous thyroxine into T 3 in rats. 4 Ikeda T et al Propranolol could not change the amount of plasma FFA, AcAc, and BOHB in starved rats, suggesting that the S-adrenergic mechanism have no important role in ketogenesis caused by the starvation. On the other hand, phentolamine administered lifted up the levels of plasma FFA and ketone bodies in starved rats. The current results suggest that a-adrenergic mechanism has an inhibitory effect on lipolysis and ketogenesis in the starvation. This is partly supported by the fact that catecholamine exerts not only S-lipolytic action but also a 2 -antilipolytic action I6-IS), though Carpene' et al. 19 ) have reported that the starvation induces a significant decrease of a 2-adrenoceptors in number and an antilipolytic effect of a 2 -agonists in male golden hamsters. The mechanism, by which phentolamine increases the amount of plasma ketone bodies in starved rats but not in fed rats, is unknown. Phentolamine may reduce the metabolic clearance rate of ketone bodies in the starvation. studies are necessary to clarify the current phenomena. Further Concisely speaking, the adrenergic mechanism my not contribute to hyper ketone-mia of thyrotoxic rats, but to the slight inhibition of ketogenesis in starved rats, probably being due to a-antilipolytic action. Table 2 Amounts of various parameters after operating adrenergic blockers to starved rats Adrenergic BW BG IRI IRG FFA AcAc BOHB blockers (g) (mg/dl) (ttU/ml) (pg/ml) (mmol/1) (mmo]/1) (mmo]/1) administration ( Fed (n=6) J 179±10 114± 10 49±9 78±20 0.5±0.1 0.05±0.01 0.07±0.01 propranolol (n=6) 181±11 117±8 44±8 85±25 0.5±0.1 0.05±0.01 0.08±0.01 phentolamine (n=6) 182± 11 112±8 78± 15* 81±24 0.5±0.1 0.05± 0.01 0.08±0.01 ( 96hr starved (n=6)) 113±8 72±5 10±3 80±21 !.1±0.2 1.41±0.24 2.32±0.51 propranolol (n=6) 123±9 80±6 11±3 94±24 !.0±0.3 1.45±0.25 2.17±0.53 phentolamine (n=6) 129±9 71±5 19±4* 90±24 1.8±0.4* 2.00±0.31* 3.49± 1.00* For legend, see the fo,Jtnote of Table 1. *P <0.02 in being significantly different from value in corresponding control. Summary To elucidate the possible role of the adrenergic mechanism in hyperketonemia observed in hyperthyroidism and starvation, two groups of rats were first forced to a series of thyroxine (T 4 )-intoxication for 7 days and of starvation for 96 hr, respec-Hyperketonemia in rats 5 vely. Each of the groups was secondly administered subcutaneously with phentola-tine or propranolol to make operate the adrenergic mechanism. As several parame-~rs were measured, both of phentolamine and propranolol did not change the am-unt of plasma FFA, AcAc, and BOHB in thyrotoxic rats. Phentolamine lifted the mount of plasma FFA, AcAc, and BOHB in starved rats, though propranolol did ot change the amount of them. These results indicate that the adrenergic mechanism D the hyperketonemia may not contribute to it in case of thyrotoxic rats, but in case f starved rats, probably being due to a-antilipolytic action. 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LO) Klein S, Young VR, Blackburn GL, Bistrian BR and Wolfe RR, J Clin Invest, 78, 928-933, 1986. 11) Harano Y, Kosugi K, Hyosu T, Uno S, Ichikawa Y and Shigeta Y, Clin Chim Acta, 134, 327-336, 1983. 12) Wiersinga WM and Touber SL, J Clin Endocrinol Metab, 45, 293-298, 1977. 13) Heyma P, Larkins RG and Higgenbotham L, Br Med J, 3, 24-26, 1980. 14) VanNoorden CJF, Wiersinga MW and Touber JL, Horm Metab Res, 11, 366-370, 1979. 15) Shulkin BL, Peele ME and Utiger RD, Endocrinology, 115, 858-861, 1984. 16) Mauriege P, Galitzky J, Berlan M and Lafontan M, Eur J Clin Invest, 17, 156-165, 1987. 17) Katovich MJ and Barney CC, Life Sci, 33, 1385-1393, 1983. 18) Burns TW, Langley PE, Terry BE, Bylund DM, Hoffman BB, Lefkowitz RJ, Garcia-Sainz JA and Fain JN, J Clin Invest, 1981. Tharp MD, 67' 467-475, 6 Ikeda T et al 19) Carpene C, Galitzky J, Saulnier-Blache J-S and Lafon tan M, Amer J Physiol, 259, E80-E88, 1990. (Received July 25, 1991) 

Possible role of the adrenergic mechanism in experimental hyperketonemia caused by thyrotoxicosis and starvation in rats

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Possible role of the adrenergic mechanism in experimental hyperketonemia caused by thyrotoxicosis and starvation in rats

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