Intravenous or intracerebroventricular administration of thyrotropin-releasing hormone (TRH) significantly improved survival in immunized mice subjected to fatal ...
Neuroscience Letters, 46 (1984) 127-130
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Elsevier Scientific Publishers Ireland Ltd. NSL 02669
ANTI-ANAPHYLACTIC ACTION IN THE MOUSE OF THYROTROPINRELEASING HORMONE (TRH) IS MEDIATED THROUGH ~t-ADRENOCEPTIVE EFFECTORS
SHIMON AMIR
Department of lsotope Research, The Weizmann Institute of Science, 76100 Rehovot (lsrael) (Received December 23rd, 1983; Revised version received January 31st, 1984; Accepted February 1st, 1984)
Key words: thyrotropin-releasing hormone - systemic anaphylaxis - /~1- and Bz-adrenoceptors metoprolol - butoxamine - mice
Intravenous or intracerebroventricular administration of thyrotropin-releasing hormone (TRH) significantly improved survival in immunized mice subjected to fatal anaphylaxis by intravenous challenge with an antigen. This protective action of TRH was blocked by pretreatment with the ~/adrenergic antagonist propranolol (5 mg/kg), or by prior administration of the cardioselective ~ antagonist, metoprolol (5 mg/kg), but not by pretreatment with the ~/2-selectiveantagonist, butoxamine (5 mg/kg). It is suggested, based on the present and previous findings that the anti-anaphylactic effect of TRH in the mouse is mediated through activation of fl~-adrenoceptive effectors, secondary to central stimulation of sympathomedullary release of catecholamines.
Thyrotropin-releasing hormone (TRH) has been shown to reverse anaphylactic shock in mouse [5] and guinea pig [13]. In the mouse, TRH appeared to exert its beneficial effect by acting centrally to increase sympathomedullary outflow to ~/adrenoceptive sites [5]. However, as ~/-adrenoceptors have been localized in several tissues implicated in anaphylaxis, including cardiac muscle (~/1-adrenoceptors) and bronchial and vascular smooth muscle (~/2-adrenoceptors) [15] the specific ~adrenergic receptor-effector mechanism involved in the anti-anaphylactic action remains to be elucidated. The present study investigated the differential involvement of ~1- (myocardial) and ~/2- (bronchial, vascular) adrenoceptors in the action of TRH by comparing the effect of the f/l-selective antagonist, metoprolol [1], and the ~/2-selective antagonist, butoxamine [12], on the response to TRH in anaphylactic shock. Subjects were male ICR mice (28-30 g) which were immunized i.p. with 2 mg bovine serum albumin (BSA) in 0.2 ml aluminium hydroxide gel. Fatal systemic anaphylaxis was induced by challenging the mice i.v. with 25/zg BSA in 0.2 ml saline 10 days following immunization. TRH (Sigma) was administered i.v. (5 mg/kg) 0304-3940/84/$ 03.00 © 1984 Elsevier Scientific Publishers Ireland Ltd.
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together with the challenge dose of BSA or i.c.v. (5 tzg in 5 /,1) 2 min following the BSA challenge. These doses of T R H were found previously to significantly improve survival in mouse anaphylactic shock [5]. The i.c.v, injections were made according to the method of Haley and McCormick [8] using a Hamilton microsyringe bearing a 27-gauge needle 2.5 mm long. Propranolol (Sigma), metoprolol (Ciba-Geigy) and butoxamine (Burroughs Wellcome) were administered i.p. at a dose of 5 mg/kg in 0.2 ml saline 30 min before induction of shock. The results are shown in Fig. 1. Eighty-five percent of the challenged mice died of anaphylactic shock; all deaths occurred within 15-30 min after administration of the antigen. Administration of 5 mg/kg T R H together with the challenge dose of BSA significantly improved survival (P < 0.05, X2 test for two independent samples). Similarly, i.c.v, injection of 5 txg T R H 2 min after the induction of shock significantly improved the survival rate. Pretreatment with 5 mg/kg propranolol or 5 mg/kg of the cardioselective /3~antagonist, metoprolol reversed the protective effect of i.v. or i.c.v. TRH. Pretreatment with 5 mg/kg butoxamine, a selective 52-antagonist had no demonstrable effect on the anti-anaphylactic action of i.v. or i.c.v. TRH. In prior work in mice, it has been suggested that the anti-anaphylactic effect of TRH involves central actions which are peripherally mediated through interaction of adrenal medullary catecholamines and 13-adrenoceptive mechanisms. Evidence to
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Fig. 1. The effect o f i.v. or i.c.v, a d m i n i s t r a t i o n o f T R H on survival f o l l o w i n g i n d u c t i o n of a n a p h y l a c t i c shock in saline- (control), p r o p r a n o l o l - , m e t o p r o l o l - or b u t o x a m i n e - p r e t r e a t e d mice. The n u m b e r s a b o v e the bars indicate the n u m b e r o f a n i m a l s in each group• The asterisks indicate significant difference f r o m BSA a l o n e ( P < 0.05, x 2 test for two i n d e p e n d e n t samples).
129 support this comes from the finding that blockade of sympathetic transmission to the adrenal medulla by treatment with the ganglionic blocker chlorisondamine chloride or by surgical denervation of the adrenal glands or blockade of ~adrenergic receptors by propranolol reversed the central beneficial effect of TRH [5]. Moreover, these experiments indicated that the protective action of TRH is independent of its ability to release thyrotropin and prolactin from the pituitary gland as central administration of acid-TRH, a deamidated analogue of TRH lacking hypophysiotropic influences, was as effective as TRH in improving the survival rate [5]. In the present study blockade of myocardial ~-adrenoceptors by the ~l-selective antagonist, metoprolol, but not inhibition of B-adrenoceptors by the 132-selective antagonist, butoxamine, reversed the anti-anaphylactic effect of TRH. Since TRH has been shown to induce the release of adrenal medullary catecholamines [6] and since activation of ~l-adrenoceptors by catecholamines results in myocardial stimulation [11] this finding suggests that TRH may exert its beneficial effect in mouse anaphylaxis by improving cardiac function, secondary to enhancing ~-adrenergic outflow from the adrenal medulla. Previously, it has been demonstrated that TRH can improve cardiovascular performance in experimental shock produced by endotoxin administration, hemorrhage [10] and spinal cord trauma [7]. In these studies, it has been suggested that TRH exerts its beneficial effect by acting centrally to physiologically antagonize the cardiovascular depressive effect of endogenous opiates (endorphins). More recently, it has been demonstrated that endorphins might be implicated in the mechanism of anaphylactic shock in the mouse since treatment with the opiate antagonist naloxone significantly improved survival in this condition [2]. In these experiments, naloxone appeared to exert its protective action by acting centrally to increase ~-adrenergic outflow from the adrenal medulla, presumably by reversing the central sympathoinhibitory effect of endorphins [3, 4]. The present results suggest that TRH may mimic the effect of naloxone by acting centrally to increase sympathomedullary outflow to ~l-adrenoceptive sites thus functionally antagonizing the cardiodepressive effects of endorphins. Propranolol, a ~-antagonist, reversed the anti-anaphylactic effect of TRH (Fig. 1) as well as that of naloxone [4], suggesting that both agents exert their beneficial effect through a common effector mechanism. However, while naloxone's beneficial effect results exclusively from antagonism of the central actions of endorphins [9], TRH might produce cardiovascular effects in shock which are independent of endorphin mechanisms (see ref. 16). The anti-anaphylactic effect of TRH in the guinea pig [14] as well as TRH's ability to reverse leukotriene D4 hypotension in this species [14] are probably due to such endorphin-independent autonomic actions, as endorphins appear not to be involved in the mechanism of anaphylaxis or leukotriene D4 hypotension in the guinea pig [13, 14]. I wish to thank Michal Harel for her technical assistance, and Ms. Shoshana
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Newman for her secretarial assistance. I also thank Burroughs Wellcome for the gift of butoxamine.
S . A . is a n I n c u m b e n t
of the Henry Glasberg Career Development
Chair. 1 Ablad, B., Carlsson, E. and Ek, L., Pharmacological studies of two new cardioselective adrenergic H-receptor antagonists, Life Sci., 12 (1973) 107-119. 2 Amir, S., Opiate antagonists improve survival in anaphylactic shock, Europ. J. Pharmacol., 80 (1982) 161-162. 3 Amir, S., Antianaphylactic effect of naloxone in mice is mediated by increased central sympathetic outflow to sympathetic nerve endings and adrenal medulla, Brain Res., 274 (1983) 180-183. 4 Amir, S., Beneficial effect of i.c.v, naloxone in anaphylactic shock is mediated through peripheral ~-adrenoceptive mechanisms, Brain Res., 290 (1984) 191-194. 5 Amir, S., Harel, M. and Schachar, A., Thyrotropin-releasing hormone (TRH) improves survival in anaphylactic shock: a central effect mediated by the symphato-adrenomedullary-~-adrenoceptive system, Brain Res., in press. 6 Brown, M.R., Thyrotropin-releasing factor: a putative CNS regulator of the autonomic nervous system, Life Sci., 28 (1981) 1789-1795. 7 Faden, A.I., Jacobs, T.P. and Holaday, J.W., Thyrotropin-releasing hormone improves neurologic recovery after spinal trauma in cats, New Engl. J. Med., 305 (1981) 1063-1067. 8 Haley, T.J. and McCormick, W.G., Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse, Brit. J. Pharmacol., 12 (1957) 12-15. 9 Holaday, J.W., Cardiovascular consequences of endogenous opiate antagonism, Biochem. Pharrnacol., 32 (1983) 573-585. 10 Holaday, J.W., D'Amato, R.J. and Faden, A.I., Thyrotropin-releasing hormone improves cardiovascular function in experimental endotoxic and hemorrhagic shock, Science, 213 (1981) 216-218. 1 l Lands, A.M., Arnold, A., McAuliff, J.P., Luduena, F.P. and Brown, T.G., Differentiation of receptor systems activated by sympathomimetic amines, Nature (Lond.), 214 (1967) 597-598. 12 Levy, B., The adrenergic blocking activity ofN-tert.-butylmethoxamine (butoxamine), J. Pharmacol. exp. Ther., 151 (1966) 413-422. 13 Lux, W.E., Feuerstein, G. and Faden, A.I., Thyrotropin releasing hormone reverses anaphylactic shock through non-endorphin related mechanisms, Europ. J. Pharmacol., 90 (1983) 301-302. 14 Lux, W.E., Feuerstein, G. and Faden, A.I., Alteration of leukotriene D4 hypotension by thyrotropin releasing hormone, Nature (Lond.), 302 (1983) 822-824. 15 Minneman, K.P., Pittman, R.N. and Molinoff, P.B., ~-Adrenergic receptor subtypes: properties, distribution and regulation, Ann. Rev. Neurosci., 4 (1981) 419-461. 16 Yarbrough, G.G., On the neuropharmacology of thyrotropin releasing hormone (TRH), Progr. Neurobiol., 12 (1979) 291-312.
