Is the pressor response to strychnine centrally mediated?

European Journal o f Pharmacology, 60 (1979) 365--368

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© Elsevier/North-Holland Biomedical Press Short communication IS T H E P R E S S O R R E S P O N S E T O S T R Y C H N I N E C E N T R A L L Y M E D I A T E D ? DANITA TSOUCARIS-KUPFER, LOLA LIBLAU and HENRI SCHMITT Laboratoire de Pharmacologie, Facult~ de Mddecine, 15 rue de l'Ecole de Mgdecine, 75270 Paris Cedex 06, France

Received 29 October 1979, accepted 1 November 1979

D. TSOUCARIS-KUPFER, L. LIBLAU and H. SCHMITT, Is the pressor response to strychnine centrally mediated?, European J. Pharmacol. 60 (1979) 365--368.

Intravenous administration of strychnine (0.003-0.300 m g - k g -1) to curarized, chloralosed dogs induced hypertension and tachycardia. In spinal cord-transected dogs, intravenous administration of strychnine no longer elicited a rise in blood pressure and heart rate. Intracisternal injections of strychnine also produced hypertension and tachycardia but at lower doses. Similar results were obtained after intrathecal administration of strychnine in doses significantly different from those effective on intravenous and intracisternal administration. These findings suggest that the central nervous system may be involved in the haemodynamic changes induced by strychnine, but did not allow the site of action to be located. Blood pressure

Heart rate

CNS

Strychnine

1. I n t r o d u c t i o n S t r y c h n i n e is k n o w n t o r e d u c e t h e inhib i t o r y p o s t s y n a p t i c p o t e n t i a l s in t h e spinal c o r d (Eccles, 1 9 6 2 ; Tebecsis a n d Philis, 1 9 6 9 ) . I t is t h o u g h t t h a t t h e alkaloid is a c o m p e t i t i v e a n t a g o n i s t o f glycine w h i c h has b e e n suggested t o b e t h e i n h i b i t o r y t r a n s m i t t e r at this level (Curtis a n d J o h n s t o n 1 9 7 4 ; Curtis et al., 1971). However, the effects of strychnine on t h e c a r d i o v a s c u l a r s y s t e m are as y e t p o o r l y k n o w n . S t r y c h n i n e h a s b e e n r e p o r t e d to increase b l o o d p r e s s u r e as a result o f seizures induced by the drug (Abreu and Woodbury, 1 9 7 3 ) . H o w e v e r , s t r y c h n i n e increases b l o o d pressure in c u r a r i z e d a n i m a l s ( S o f o l a a n d O d u s o t e , 1 9 7 6 ) , b u t t h e m e c h a n i s m o f this p r e s s o r r e s p o n s e is n o t k n o w n . T h e p r e s e n t w o r k was carried o u t t o f u r t h e r investigate t h e p r e s s o r r e s p o n s e to s t r y c h n i n e in dogs. 2. Materials a n d m e t h o d s Dogs o f e i t h e r sex weighing 8-10 kg w e r e a n a e s t h e t i z e d w i t h c h l o r a l o s e ( 0 . 1 0 0 g • kg -1

i.v.). T h e d o g s w e r e i n t u b a t e d a n d v e n t i l a t e d w i t h a Bird M a r k V I I p u m p . B l o o d p r e s s u r e was m e a s u r e d in t h e f e m o r a l a r t e r y b y m e a n s o f a S t a t h a m P 23 D b pressure t r a n s d u c e r a n d r e c o r d e d o n a S a n ' E i r e c o r d e r . H e a r t r a t e was c o u n t e d o n t h e pulse pressure. I n t r a v e n o u s injections w e r e m a d e i n t o t h e s a p h e n o u s vein. I n j e c t i o n s i n t o t h e cisterna m a g n a w e r e given b y m e a n s o f an 18 gauge n e e d l e i n t r o d u c e d p e r c u t a n e o u s l y . Drugs w e r e injected in a v o l u m e o f 0.2-0.5 ml. I n t r a t h e c a l a d m i n i s t r a t i o n was p e r f o r m e d in t h e f o l l o w i n g w a y : t h e m u s c l e s o f t h e n e c k w e r e incised and t h e o c c i p i t o - a t l a n t o i d m e m b r a n e was e x p o s e d . A p o l y e t h y l e n e c a t h e t e r 10 c m long, 0.45 m m i n n e r d i a m e t e r a n d 0 . 6 5 m m o u t e r d i a m e t e r was i n t r o d u c e d i n t o t h e t h e c a l s p a c e t h r o u g h a small h o l e m a d e in t h e o c c i p i t o - a t l a n t o i d m e m b r a n e . T h e spinal c o r d was s e c t i o n e d at C1 a f t e r incision o f t h e muscles o f t h e n e c k a n d o f t h e o c c i p i t o - a t l a n toid membrane. G r o u p s o f 5-9 dogs w e r e used. T h e results s h o w values o b t a i n e d at t h e t i m e o f t h e

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D. T S O U C A R I S - K U P F E R ET AL.

3.1. Intravenous administration

maximal response which occurred after 10-15 min whatever was the route. T h e y are expressed as the mean _+ S.E.M. The statistical significance o f th e results was ascertained using Student's t-test for paired comparisons. Strychnine sulfate used; t he alkaloid was diluted to an appropriate volume with saline. In order to prevent seizures, pancuronium (Pavulon@) was administered at a dose o f 0.04 mg- kg -~ and injections of 0.02 mg • kg -~ were added when necessary.

Strychnine administered intravenously in doses o f 0.001, 0.003 and 0.030 m g . kg -1 did not significantly change the blood pressure. However the heart rate was increased significantly. Strychnine in doses of 0.1 and 0.3 m g . kg -I induced a significant rise in mean blood pressure from 130 + 9 to 204-+ 1 9 m m H g and from 133-+ 12 to 1 8 3 + 1 7 mm Hg respectively. With b o t h doses there was a significant increase in heart rate from 182-+ 16 to 224-+ 11 and from 129-+ 18 to 207 -+ 13 beats/min respectively. Bradycardia occurred in some dogs when the rise in blood pressure was particularly steep.

3. Results The results presented in this r e p o r t show t h e variation in mean blood pressure, but it should be pointed o u t t hat no m a t t e r which r o u t e of administration was used the rise in systolic blood pressure was greater than the increase in diastolic blood pressure.

3.2. Injections o f strychnine into the cisterna magna Strychnine injected into the cisterna magna in doses o f 0.001-0.003 m g - k g -1 did not

TABLE 1 E f f e c t s o n m e a n b l o o d pressure and h e a r t rate o f a d m i n i s t r a t i o n o f s t r y c h n i n e by t h e intravenous, intracisternal, intrathecal r o u t e s and after s e c t i o n o f t h e spinal c o r d . The m e a n s -+ S.E.M. o f n e x p e r i m e n t s are given. T h e n u m ber o f m a r k s indicates the degree o f statistical significance; 1 p < 0.05; 2 p < 0.01 ; 3 p < 0.001. Route of administration

n

m g • kg -1

Mean b l o o d pressure (ram Hg)

Heart rate (beats/rain)

before injection

after injection

before injection

after injection

Intravenous

5 5 5 5 5

0.001 0.003 0.030 0.100 0.300

110_+ 9 130_+ 9 127 + 14 130_+ 9 133 -+ 12

125_+ 5 134+ 4 145 _+ 10 204+191 183 _+ 17 2

97_+10 92_+ 5 152 _+ 17 182-+16 129 + 18

122+141 154-+34 208 _+ 6 224-+11 1 207 -+ 13 2

Intracisternal

5 5 6 9 8

0.001 0.003 0.030 0.100 0.300

122_+ 117_+ 115-+ 120_+ 116_+

135_+ 9 148_+10 154_+132 173-+142 173+132

94_+17 106-+16 136-+ 9 110_+14 103_+16

110_+10 105+10 185_+ 3 1 150-+192 162+183

Intrathecal

5 5 9 6 6

0.001 0.003 0.030 0.100 0.300

134 _+ 12 126_+ 8 121_+ 5 144-+ 9 144 _+ 15

145 _+ 12 154_+15 1 151_+ 9 2 209_+112 199 -+ 13 2

137 _+ 16 101_+21 113-+ 3 104_+ 9 116-+ 25

167 -+ 10 127_+27 146-+112 141-+15 1 155 + 31 1

Intravenous a f t e r section at C1

4 4

0.300 1.000

86-+ 80+

3 9 9 6 8

7 6

86+ 82-+

8 9

78_+ 66-+

6 8

74-+ 68+

7 7

PRESSOR RESPONSE TO STRYCHNINE

significantly change blood pressure and heart rate: 0.030 mg • kg -1 significantly increased the blood pressure from 115 + 3 to 154 -+ 13 mm Hg and the heart rate from 136 +- 9 to 185 +- 63. Higher doses also produced a significant increase in blood pressure and in the heart rate.

3.3. Intrathecal injections Strychnine injected into the theca at the dose of 0.003 mg • kg -1 significantly increased the blood pressure but the tachycardia was not significant. Higher doses induced greater increases in blood pressure and also caused a significant rise in heart rate.

3.4. Effects of strychnine in spinal dogs Section of the spinal cord at C~ lowered arterial blood pressure from 98 + 7 mm Hg to 86 + - 7 m m Hg. In these spinal cordtransected dogs, intravenous injections of strychnine in doses of 0.3 and 1 mg • kg -~ no longer changed the blood pressure and heart rate. The results are summarized in table 1.

4. Discussion The present work confirmed that strychnine increases the blood pressure and heart rate of dogs. In addition, it showed that the seizures induced b y the alkaloid were not the cause of the cardiovascular changes; in fact, in dogs treated with pancuronium, a curare-like agent, strychnine did n o t produce seizures, but increased blood pressure. The pressor and tachycardic responses to strychnine were dose-related. The change in systolic blood pressure was usually greater than the increase in diastolic blood pressure. These results agree with those reported by Sofola and Odusote (1976). In dogs with the spinal cord transected at C1 strychnine no longer increased the blood pressure and heart rate. Therefore a change in

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vagal tone does not appear to be involved in the tachycardia induced by the drug. In addition, strychnine did not seem to stimulate the spinal cord or the peripheral sympathetic system directly. Thus, supraspinal structures may be involved in the cardiovascular actions of strychnine, or the presence of the sympathetic tone may be a prerequisite for these effects of the drug. However, there are no clearcut indications of the site(s) of action of strychnine in our experiments. Blood pressure and heart rate did not significantly increase after injections of low doses of strychnine (0.001 and 0.003 mg • kg -1 ) into the cisterna magna. There was a significant rise in blood pressure after intracisternal injection at the dose of 0.030 m g . kg -1 whereas this dose injected intravenously did not change the blood pressure significantly. Intrathecal administration of strychnine significantly increased the blood pressure at doses as low as 0.003 mg • kg -I and 0.030 m g . k g -1 which induced no change or no significant rise in blood pressure after intravenous administration. However intracisternal of intrathecal injections of the drug did n o t appear to be more effective for increasing heart rate than was intravenous administration. These results seem on the whole, at least for the pressor response, to favour an action of strychnine on the central nervous system. As glycine has been recognized as the inhibitory transmitter at the spinal level, the spinal cord appears to be a possible site for a centrally mediated effect of the drug. Were this effect of the alkaloid due to the suppression of tonic inhibition of the central sympathetic tone, it would disappear after abolition of this tone as found in spinal dogs. The dose-response curve for strychnine appeared to be steep and there is a possibility that the difficulty in demonstrating a centrally mediated effect of strychnine was due to this phenomenon. Schaeppi (1969) has reported that low doses of strychnine injected into the fourth ventricle of cats induced both a pressor response and arousal. Some experiments suggest that strychnine

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inhibits and does not stimulate peripheral sympathetic structures. Strychnine has been reported to reduce ganglionic transmission inhibition of acetylcholine release (McKinstry and Koelle, 1969) and also to exert an inhibitory action on the postganglionic sympathetic fibres (Chieppa and Siro-Brigianni 1965). On the other hand, strychnine elicits a dose-related negative chronotropic effect (Bortignon et al., 1970). These results contraindicate a facilitation of sympathetic tone by strychnine at peripheral sites. It is therefore tempting to suggest that strychnine abolished the inhibitory activity of glycine, which is found in spinal cord interneurones (Curtis and Johnston, 1974; Curtis et al., 1971) by increasing the firing rate of preganglionic sympathetic neurones and therefore blood pressure and heart rate.

Acknowledgement The authors are grateful to Organon-Teknika Laboratories for their gift of pancuronium (Pavulon®).

References Abreu, B.E. and R.A. Woodbury, 1943, Blood pressure and respiration changes produced by strychnine

D. TSOUCARIS-KUPFER ET AL. convulsions, J. Pharmacol. Exp. Ther. 7 8 , 3 2 1 . Bortignon, C., Carpendo, F., Maragnon, I., SantiSoncin, E., Stella, G.D. and M. Gerrari, 1970, The cardiac effects of strychnine and their mechanisms, J. Pharm. Pharmacol. 22,380. Chieppa, D.D. and G. Siro-Brigianni, 1965, The action of strychnine o n peripheral sympathetic transmlssion, Arch. Sci. Biol. 4 9 , 2 1 7 . Curtis, D.R. and G.A.R. Johnston, 1974, Amino acid transmitters in the mammalian central nervous system, Ergebn. Physiol. 69, 97. Curtis, D.R., Duggan, A.W. and G.A.R. Johnston, 1971, The specificity of strychnine as a glycine antagonist in the mammalian spinal cord, Exp. Brain Res. 12,547. Eccles, J.C. 1962, Spinal neurons: synaptic connexions in relation to chemical transmitters, In proceedings of the First International Pharmacological Meeting; Vol. 8, Pharmacological Analysis of Central Nervous Action, ed. W.D.M. Patton (Pergamon Press, Oxford). McKinstry, D.N. and G.B. Koelle, 1967, Inhibition of release of acetylcholine by strychnine and its implication regarding transmission by the olivocochlear bundle, Nature (London) 213, 505. Schaeppi, V., 1967, Drug injection into the cat's fourth ventricule. Effect upon E.E.G. and ~utonomic system, Arch. Int. Pharmacodyn. Ther. 169, 44. Sofola, A., Olusoga and Kayode, A. Odusote, 1976, Sympathetic cardiovascular effects of experimental strychnine poisoning in dogs, J. Pharmacol. Exp. Tjer. 196, 29. Tebecsis, A.K. and J.W. Phillis, 1969, The use of convulsivants in studying possible functions of amino acids in the toad spinal cord, Comp, Biochem. Physiol. 28, 1303.