Effect of clonidine (catapresan, St-155) on sympathetic reflexes

Neuroscience Lette~ 4 (1977) 281--286 © Elsevier/North-Holland Scientific Publishers, Ltd.

281

E F F E C ~ O F C L O N I D I N E ( C A T A P R E S A N , St-155) O N S Y M P A T H E T I C REFLEXES IL I~ItSZ/~Z-GIBISZER, J.PORSZASZ, Jr.and J.P6RSZASZ Department of Pharmacology and Department of Biology, University Medical School, P~c~ (Hungary) (Received January 17th, 1977) (Accepted February 2nd, 1977)

SUMMARY The e f f ~ t of clonidine on sympathetic vasomotor reflexes elicited by electrical stimulation of visceral and somatic nerves was studied. C~onidine was proved to shift the sympathetic vasomotor reflex processes towards excitation.

Hoefke and Kobinger [6] were the first to demonstrate clonidine to cause a lasting fall in blood pressure. This effect is primarily attributed to a central site of action [7,9,16]. The m e d u l l ~ location of the hypotensive effect was substantiated by the investigations of Schmitt and Schmitt [17], as well as Klupp et al. [8] and Haeusier [4,5]. A constant tonic activity can be observed in the efferent sympathetic fibres, and also in those running to the kidney [1,20,25]. The changes in blood pressure are synchronously modulated by the activity of these fibres, and, more exactly, by alterations of pulse waves. Stimulation of the autonomic and somatic afferents induces an inhibition of sympathetic activity and a fall in blood pressure in the case of animals anaesthetized with chloralose-urethane. The vasomotor neurones receive both stimulatory and inhibitory impulses from the hypothalamic reticular formation and also from the periphery [13, 14]. Dynamics of the visceral and somatic inhibitory reflexes was elucidated by Pbrsz~sz et al. [15]. Neurohumoral transmission in the vasomotor neurones was studied by means of drugs with well-defined site of action [10,12]. These experiments demonstrated the frequency-dependence of sympathetic reflexes elicited by stimulation of the central end of the cut tibial, vagal and median nerve and elucidated the effect of various drugs (diazepam, chlorpromazine, phentolamine, dihydroergotamine, reserpine) on these reflexes [10,12]. The present paper describes the effect of clonidine (Catapres~n, St-155, 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride) on the sympathetic vasomotor reflexes. The experiments were performed on 19 cats under chloralose-urethane

282

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Bl0od p ~ m u ~ was measured through a polyethylene c~mul~ ~ into the ~ o r a l o r ~ o n carotid a~.eW by means of ~'strain gauge" transducer ( S ~ P-23 Db) connected to one chsnnel of a Beckman dynograph (type RM). The postganglionic sympathetic activity of the ~ f t renal plexus was r~orded according to the met'~od of Pbrsz~z [12]. The animals were immobilized with f,allsmine and respirated artificially. The c h _ ~ in the integrated sympathetic activity were expr~.~d in per cent of the pre-stimulation basal activity, always ~ identical periods of time. I ~ the experimental period the noises of the transmission channel were kept canstant, because neither the amplification nor the frequency transmission band were altered; furthermore, the experiments were followed up to the resist,race between the nerve bundle and the platinum loop electrode which did not alter in a great manner. So the noise level of resulting registration is constant. Stimulation of the central end of. the cut vaga] nerve elicited an inhibition of sympathetic activity and a fall in blood pressure*. These effects were frequency-related, a~ described previously [15]. Intravenous administration of clonidine fi~t enhanced, but 20--30 mitt after the injection inhibited, these effects. Fig. I shows the effect of 20 #g/kg c l o n ~ given intravenously on the %

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Fig. 1. Effect of eionidine on the viscero-inbAbitory sympathetic vasomotor reflex. Sympatbet,.'~ efferent activity is expressed in per cent of the pre-stimula~on basal activity. , - - : - ~ : response before treatment (n = 15); • . . . . . o: response 20 rain after 20 ug/kg i.v. clonidine (n = 7). Stimulation: 5 msec, 5 V, 10 see (vagai nerve). Mean ± S.E.M. * •P < 0.01. * The reflex responses ~f untreated animals remained unchanged during the 3--4-h experimental period.

283

~ . e r a l inhibitory sympathetic reflex in the phase of inhibition. Except for stimulations of 80--160 Hz the inhibition is statistically significant. If the response is investigated at a later point of time (one hour) following clonidine administration an excitation and also an increase in blood pressure can be seen in the first few seconds followed b y an inhibition in the further course of stimulation. If more than one hour had elapsed from the application of clonidine, excitations rather than inhibitions could mainly be observed. Stimulation of the central end of the cut ischiadic nerve (0.1 msec, 2 V, varying frequencies) inhibited efferent sympathetic activity and decreased blood pressure. This inhibition was counteracted by clonidine (20 u g/kg i.v. ) immediately after the injection. Twenty minutes after clonidine actmin~stration, however, the responses first became biphasic and then only augmentations were seen. Table I shows the biphasic character of the response. Stimulation of the central end of the cut ulnar nerve increased sympathetic activity and the blood pressure. Intravenous application of 20 pg]kg clonidine enhanced this excitatory response (Fig. 2). The difference is obviously significant at stimulations of 10--20 Hz; significance at 40--80 Hz is at a level of P < 0.05. According to the investigations of Pbrszgsz [I1,12] the electrophysio!ogical TABLE I E ~ OF CLONIDINE ON THE ~OMATO-SYM_PATHO-|NHIBITORY REFLEX R I ~ F O N B ~ ELICITED BX STIMULATION OF THE CENTRAL PART OF ISCHIADIC NERVE The r ~ I t ~ are e x p r ~ d 8etivity.,

u per cent ( m e a n -~ S.E.Mo) of the prestimu|ation values of basal

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Fig. 2. Effect of elonidine on the ~xcitatory sympathetic vasomotor reflex. • - - ~: respvnse before treatment (n = 11); s . . . . . • : r ~ p o r a e 20 min after Lv. a d m ~ i s t r a t i o n o f 20 ~g/k~; clonidine (n ffi 7). Stimulation: 10 n~ee, 10 V, 10 lee (ulnar nerve). Heart ± S.E.M. *: P < 0.01, °: P < 0.05.

analysis of vasomotor reflexes gives information on the function of the vasomotor centre. From the study of the temporal and spatial summation of the r e f l ~ responF~ he concluded that the central organization of the visceral pathway ~ystem contained many more synapses than did t]mt of the somatic on~, He put forward a hypothesi~ regarding the excitatory and inhibitory convections of the bulbar sympathetic neurone$, and demonstzated by pharmacological analysis that the inhibitory transmitter of the vasomotor neurone i3 most probably noradrenaline. Kobinger and Walland [9], Schmitt et al. [18,19], and also other authors, have demonstrated that clonidine inhibits efferent sympathetic activity through a cer, tral alpha.adrenergic stimulation. In the present experiments the effect of clonidine on inhibitory and excitatory sympathetic reflexes was studied. The results can be summarized as follows. (1) The visceral inhibitory reflexes are transiently enhanced, then inhibited and later reverser into excitatory ones by clonidine. (2) The somatic inhibitory reflexes are transiently inhibited than made biphasic and later revered by clonidine. (3) The excitatory ~eflexes are enhanced by clonidine. It was demonstrated in our previous investigations [2,3] that tachyphylaxis developed to the vasodepressor effect of clonidine. The clonidine may act through norad~enaline ~elease and/or uptake mechanisms, in addition to a direct excitatory effect on adrenergic alpha-receptors and the phenomenon of tachyphylaxis might be connected with these processes. The initial increase in

285 visceral reflexes corresponds t o the central alpha-adrenergic e x c i t a t i o n [5 ], however, t h e i n h i b i t i o n a n d reversal o f the reflexes c a n n o t be explained on this basis. According t o Pbrsz~sz's analysis [12] t h e visceral reflexes are inhibited b y alpha-receptor blocking agents. T h e s o m a t o - i n h i b i t o r y reflexes are less sensitive t o drugs t h a n are t h e visceral ones. In thi~ respect it seems in our present experiments t h a t clonidine also has an a-adrenergic neurone-blocKinglike action. This corresponds with the ,~pinion o f Starke et al., t h a t the neuroneblocking-like action o f clonidine is due t o an e x c i t a t i o n of presynaptics ~phaadrenoceptors [ 2 1 - - 2 3 ] . The present results show clonidine t o shift t h e i n h o m o g e n e o u s v a s o m o t o r reflex processes [24] towards excitation. This m a y a c c o u n t for the finding t h a t clonidine inhibits i n h i b i t o r y b u t enhances e x c i t a t o r y reflex responses, by a mechanism n o t fully elucidated at present. REFERENCES

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