INHIBITION
OF
CAT
BY D E P O L A R I Z I N G A.
F.
Danilov
SKELETAL MUSCLE and
MUSCLE
CHOLINESTERASES
RELAXANTS
V. V. Malygin
UDC 615.785.3 : 612.815.2
It is believed that postsynaptic m u s c l e relaxants do not inhibit the c h o l i n e s t e r a s e (CE) of a n e u r o m u s c u l a r synapse if their a n t i c h o l i n e s t e r a s e activity in vitro is lower than the activity of c l a s s i c inhibitors of CE, for example neostigmine methylsulfate [1-3]. However, in recently published r e p o r t s [4, 5] the t h e o r y has been advanced that decamethonium, disufene, and i m b r e t i l in blocking doses cause profound inhibition of synaptic CE of the skeletal m u s c l e s . A d i r e c t determination of the CE activity is not possible in this c a s e , since a m m o n i u m compounds f o r m an unstable complex with CE, which b r e a k s down during p r e p a r a t i o n and dilution of a homogenate. T h e r e f o r e for an evaluation of the state of CE on exposure to m u s c l e relaxants we c o m p a r e d the blocking effect of acetylcholine (AC) and carbocholine (CC) on n e u r o m u s c u l a r t r a n s m i s s i o n [4]. In experiments on anesthetized (chloralose and urethan) cats a r e c o r d i n g was made of the c o n t r a c tions of the m u s c u l u s tibialis a n t e r i o r in r e s p o n s e to e l e c t r i c a l stimulation of the p e r i p h e r a l region of the peroneal n e r v e with single s u p r a m a x i m a l impulses. Acetylcholine and carbocholine w e r e injected intra-a r t e r i a l l y into a b r a n c h of the c o r r e s p o n d i n g f e m o r a l a r t e r y . The m u s c l e relaxants and all of the other compounds w e r e injected into the jugular vein. The inhibitory activity of AC and CC was determined b e fore injection of a m u s c l e relaxant and in the period of partial (30-50%) r e c o v e r y of n e u r o m u s c u l a r t r a n s mission. Under n o r m a l conditions inhibition of the n e u r o m u s c u l a r t r a n s m i s s i o n of single impulses developed a f t e r the injection of AC in a dose of 15-20 g m o l e s / k g and of CC in a dose of 0.1-0.15 g m o l e / k g . In the period of incomplete b l o c k i n g by decamethonium, imbretil, disufene, or diacetylcholine for the development of complete inhibition it was sufficient to inject AC in a dose of 0.2-0.4 p m o l e s / k g and CC in a dose of 0.01-0.02 p m o l e / k g . Thus, the blocking activity of AC i n c r e a s e d 50-100-fold, w h e r e a s the activity of CC i n c r e a s e d only 5 - 1 0 , f o l d . In the p r e s e n c e of t e t r a m e t h y l a m m o n i u m (TMA) and compound PK-93, d e polarizing agents with the lowest a n t i a c e t y l c h o l i n e s t e r a s e activity (Table 1), the blocking activity of AC i n c r e a s e d only 20-foId, while the activity of CC as b e f o r e i n c r e a s e d 5-10-fold. If the s t r o n g e r potentiating effect of AC as c o m p a r e d with CC is due to inhibition of synaptie CE, this difference should be d e c r e a s e d
T A B L E 1. Effect of Neostigmine Methylsulfate on Blocking Effect of Depolarizing Muscle Relaxants (In. tibialis a n t e r i o r of cat) AmiacetylBlocking Neostigrnine methylsulfate, m g / k p Depolarizing cholinesterase (50%) dose. agent activity (Ki), /~mole/kg * 03)1 0.02--0,0J ; i mole/liter * TMA 1-10-3 3,0 PK-93 I 3. t0 -4 + 3.0 DiacetylchoHne[ t t0 ~ 0.08 PK-I07 ] 1.8.t0 -~ 0.4 Deeamethonium] ' 4. t0-6 0.05 0 Disufene [ 3.t0-6 0,05 0 Imbretil [ I- t0-8 0,005 0 Neostigmine !. meth~lsulfate ,1.t0-7 *Data f r o m [8]. ?A minus sign m e a n s weakening of blocking effect, 0 means no e f fect, plus sign m e a n s intensification.
I. M. Sechenov Institute of Evolutionary Physiology and B i o c h e m i s t r y , A c a d e m y of Sciences of the USSR, Leningrad. ( P r e s e n t e d by Academician E. M. Kreps, July 29, 1975.} T r a n s l a t e d f r o m Doklady Akademii Nauk SSSR, Vol. 226, No. 1, pp. 227-229, January, 1976. Original a r t i c l e submitted July29, 1975.)
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o r eliminated b y d i p y r o x i m e (TMB-4), which has the c a p a c i t y to weaken the a n t i c h o l i n e s t e r a s e activity of s o m e m u s c l e r e l a x a n t s in e x p e r i m e n t s with purified bovine e r y t h r o c y t e a c e t y l c h o l i n e s t e r a s e [6]. in e x p e r i m e n t s in Which d i p y r o x i m e * w a s injected in a dose of 2 m g / k g 2 rain a f t e r the injection o f i m b r e t i l , * d e c a m e t h o n i u m , o r disufene* the potentiation of the blocking activity of AC and CC w a s identical, 5 - 1 0 fold. Since the blocking activity of CC did not change, it is difficult to find a n o t h e r explanation of the d e c r e a s e in the potentiating effect of m u s c l e r e l a x a n t s on the activity of AC caused by d i p y r o x i m e . * T h e a n t i c h o l i n e s t e r a s e activity of d e c a m e t h o n i u m , i m b r e t i l , and disufene in o u r e x p e r i m e n t s was m o r e pronourtced than the effect of diacetylcholine, TMA, and PK-93, which is in a c c o r d with t h e i r a n t i c h o l i n e s t e r a s e activity in v i t r o (Table 1). M o r e o v e r , as was shown e a r l i e r [7, 8], d i p y r o x i m e in a dose of 2 m g / k g e l i m i n a t e s the blocking effect of d e e a m e t h o n i u m , i m b r e t i l , and disufene, but does not affect the activity of o t h e r m u s c l e r e l a x a n t s . T h e s e f a c t s can b e u n d e r s t o o d if one c o m p a r e s t h e m with the effect of inhibitors of CE on n e u r o m u s c u l a r t r a n s m i s s i o n . It is known that only profound (higher than 90%) inhibition of synaptic CE leads to blockage of the t r a n s m i s s i o n of single i m p u l s e s . I f the inhibition of CE r e a c h e s the level of 50-90%, the amplitude of the m u s c l e c o n t r a c t i o n s i n c r e a s e s . M o d e r a t e inhibition of the e n z y m e (up to 50%) does not have an effect on m u s c l e c o n t r a c t i o n s [9-11]. Such inhibition of synaptic CE is also quite likely in the p r e s e n c e of m u s c l e r e l a x a n t s . The inhibition of CE c a u s e d b y d e c a m e t h o n i u m , i m b r e t i l , and disufene r e a c h e s the level at which inhibition of n e u r o m u s c u l a r t r a n s m i s s i o n o c c u r s . This a n t i c h o l i n e s t e r a s e inhibitory m e c h a n i s m is in a d dition to t h e i r d i r e c t action on the p o s t s y n a p t i c m e m b r a n e . An injection of d i p y r o x i m e , by weakening t h e i r a n t i c h o l i n e s t e r a s e activity, leads to the elimination of this m e c h a n i s m and, consequently, to r e s t o r a t i o n of t r a n s m i s s i o n . If a m u s c l e r e l a x a n t c a u s e s l e s s pronounced inhibition of c h o l i n e s t e r a s e , its blocking e f f e c t can r e m a i n unchanged o r be weakened b y the n a t u r a l a n t i e h o l i n e s t e r a s e activity. It has n a t u r a l l y b e e n a s s u m e d that in this c a s e the intensification of the a n t i c h o l i n e s t e r a s e activity of a depolarizing agent by the additional injection of an inhibitor of CE will lead, depending on the d e g r e e of inhibition of the CE, to weakening o r intensification of the blocking. On the b a s i s of this a s s u m p t i o n a s e r i e s of e x p e r i m e n t s w a s set up on c a t s in which the effect of n e o s t i g m i n e m e t h y l s u l f a t e in d o s e s of 0.01-0.1 m g / k g on the blocking action of d e p o l a r i z i n g agents was studied. It w a s e s t a b l i s h e d in p r e l i m i n a r y e x p e r i m e n t s that n e o s t i g m i n e in a dose of 0.01 m g / k g does not a f fect the c o n t r a c t i o n of a m u s c l e in r e s p o n s e to i n d i r e c t single stimulation and, consequently, does not c a u s e profound inhibition of CE. A f t e r the injection of n e o s t i g m i n e in a dose of 0.02-0.05 m g / k g an i n c r e a s e w a s o b s e r v e d in the amplitude of the m u s c l e c o n t r a c t i o n s , while in a dose of 0.1 m g / k g n e o s t i g m i n e c a u s e d blocking of n e u r o m u s c u l a r t r a n s m i s s i o n . T h e blocking effect of d e c a m e t h o n i u m , i m b r e t i l , and disufene was not changed by n e o s t i g m i n e in any of the d o s e s used. T h e s e c o m p o u n d s , as was shown above, have a m a r k e d capacity to inhibit CE and the injection of an inhibitor can add little to t h e i r a n t i c h o l i n e s t e r a s e effect. The injection of n e o s t i g m i n e in a dose of 0.01 m g / k g led to weakening of the blocking effect of TMA and PK-93, depolarizing agents with the lowest a n t i a c e t y l c h o l i n e s t e r a s e activity, and did not affect the activity of diaeetylcholine and PK-107, c o m pounds with higher a n t i e h o l i n e s t e r a s e activity. When the dose of n e o s t i g m i n e was i n c r e a s e d to 0.02-0.03 9m g / k g the blocking activity of TMA and PK-93 did not differ f r o m the control (before the injection of n e o stigmine), while that of diacetylcholine and PK-107 i n c r e a s e d twofold. At the highest dose of n e o s t i g m i n e the blocking activity of all four d e p o l a r i z i n g agents i n c r e a s e d two- to fourfold. T h e weakening of the blocking effect of TMA and PK-93 by n e o s t i g m i n e in a dose of 0.01 m g / k g is a p p a r e n t l y due to s u m m a t i o n of t h e i r w e a k a n t i c h o l i n e s t e r a s e effects, as a r e s u l t of which the inhibition of CE r e a c h e s the level at which m u s c l e c o n t r a c t i o n s a r e intensified. Analogous s u m m a t i o n can also be expected in the p r e s e n c e of diacetylcholine or PK-107 in combination with neostigmine. However, this does not lead to a change in the blocking activity of t h e s e compounds b e c a u s e the inhibition of CE caused b y diaeetylcholine and PK-107 a p p a r e n t l y r e a c h e s a level which c o r r e s p o n d s to the m a x i m u m i n c r e a s e in the amplitude of the m u s c l e c o n t r a c t i o n s . Intensification of the a n t i c h o l i n e s t e r a s e activity of m u s c l e r e l a x a n t s can lead only to intensification of t h e i r blocking capacity, which we o b s e r v e d with an i n c r e a s e in the dose of n e o s t i g m i n e . Thus, a l t o g e t h e r the data obtained m a k e p o s s i b l e the conclusion that the m u s c l e r e l a x a n t s investigated in a blocking dose c a u s e inhibition of the synaptic CE of the s k e l e t a l m u s c l e s and that the a n t i c h o l i n e s t e r a s e activity of d e c a m e t h o n i u m , i m b r e t i l , and disufene is so pronounced that it leads to blocking of n e u r o m u s c u l a r t r a n s m i s s i o n . T h i s a n t i c h o l i n e s t e r a s e blocking m e c h a n i s m is in addition to t h e i r d i r e c t d e p o l a r i z i n g effect on the p o s t s y n a p t i c m e m b r a n e .
192
LITERATURE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
CITED
W . D . M . Paton and E. J. Zaimis, Brit. J. Pharmacol., 4, 381 (1949). A . G . Karczmar, in: Pr e c . Symp. on Comp. Bioelectrogenesis (1962), G . B . Koelle (editor), Cholinesterases and Anticholinesterase Agents, Pharmakologie, Vol. 15, Berlin (1963). A . F . Danilov, Eksp. Khir. Anesteziol., 1, 59 (1969). A . F . Danilov, Farmakol. Toksikol., 30, No. 6, 664 (1967). R . I . Volkova, Biokhimiya, 33, No. 4, 604 (1968). R . S . Rybolovlev, Doctoral Dissertation, Leningrad {1964). A . F . Danilov and V. V. Lavrent'eva, Farmakol. Toksikol., 30, No. 5, A . N . Davison, Biochem. J., 60, 339 (1955). J . A . B . Barstad, Arch. Int. Pharmacodyn., 128, No. 1-2, 143 (1960). T . M . Mittag, S. Ehrenpreis, and R. M. Hehir, Biochem. Pharmacol.,
FORMATION
OF T O N I C
IN S E G M E N T A L
AND P H A S I C
TYPE
p. 320. Handbuch der Experimental
567 (1967).
20, No. 9, 2263 (1971).
REACTIONS
INTERNEURONS
K . S. P r e d t e c h e n s k a y a , a n d V. I . S a f ' y a n t s
UDC 612
S. A . E v d o k i m o v ,
According to c u r r e n t information, the spinal cord interneuron apparatus plays a leading role in the formation of locomotor reactions [1-5]. Activation of interneurons through a f f e r e n t a n d i n t e r c e n t r a l channels normally occurs not by a single impulse, but by a rhythmic s e r i e s . Any investigation of the properties of interneurons t h e r e f o r e must place special emphasis on study of their reactions during rhythmic activation [6-8]. In the present study the t r a n s f o r m e r effect of the most numerous group of interneurons in the i n t e r mediate zone and the ventral horn, the interneuron groups of the afferent flexor reflex (a.f.r.), w ere studied. Interneurons of this group a r e c h a r a c t e r i z e d by a broad convergence of afferent and descending influences [9, 10] and participate not only in the formation of the generalized flexor reflex, but also other polysynaptic locomotor reactions. The objective of the investigation centered on the reactions of interneurons to rhythmic activation from suprathreshold v i s c e r a l motor and somatic motor afferents converging on them and also on an explanation of the conditions and mechanisms of their formation. a
b
c
Fig. I . Types of reactions of spinal cord interneurons during rhythmic stimulation of visceral motor and somatic motor afferent nerves of the rear extremities, a) Reaction of tonic type (without:inhibition); b) phasic type r e action (complete inhibition); c) intermediate type (partial inhibition). Upper tracing - interneuron response; l o w e r - dorsal surface potential. Discharge frequency 50 imp/sec,~ force 20T. Amplitude calibration 10 mV (a) and 4 mV (b, c); time calibration 20 msec.
I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. (Presented by Academician V. N. Chernigovskii, July 17, 1975.) Translated from Doklady Akademii Nauk, SSSR, Vol. 226, No. 1, pp. 238-240, January, 1976. Original article submitted June 30, 1975.
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193
OF
CAT
BY D E P O L A R I Z I N G A.
F.
Danilov
SKELETAL MUSCLE and
MUSCLE
CHOLINESTERASES
RELAXANTS
V. V. Malygin
UDC 615.785.3 : 612.815.2
It is believed that postsynaptic m u s c l e relaxants do not inhibit the c h o l i n e s t e r a s e (CE) of a n e u r o m u s c u l a r synapse if their a n t i c h o l i n e s t e r a s e activity in vitro is lower than the activity of c l a s s i c inhibitors of CE, for example neostigmine methylsulfate [1-3]. However, in recently published r e p o r t s [4, 5] the t h e o r y has been advanced that decamethonium, disufene, and i m b r e t i l in blocking doses cause profound inhibition of synaptic CE of the skeletal m u s c l e s . A d i r e c t determination of the CE activity is not possible in this c a s e , since a m m o n i u m compounds f o r m an unstable complex with CE, which b r e a k s down during p r e p a r a t i o n and dilution of a homogenate. T h e r e f o r e for an evaluation of the state of CE on exposure to m u s c l e relaxants we c o m p a r e d the blocking effect of acetylcholine (AC) and carbocholine (CC) on n e u r o m u s c u l a r t r a n s m i s s i o n [4]. In experiments on anesthetized (chloralose and urethan) cats a r e c o r d i n g was made of the c o n t r a c tions of the m u s c u l u s tibialis a n t e r i o r in r e s p o n s e to e l e c t r i c a l stimulation of the p e r i p h e r a l region of the peroneal n e r v e with single s u p r a m a x i m a l impulses. Acetylcholine and carbocholine w e r e injected intra-a r t e r i a l l y into a b r a n c h of the c o r r e s p o n d i n g f e m o r a l a r t e r y . The m u s c l e relaxants and all of the other compounds w e r e injected into the jugular vein. The inhibitory activity of AC and CC was determined b e fore injection of a m u s c l e relaxant and in the period of partial (30-50%) r e c o v e r y of n e u r o m u s c u l a r t r a n s mission. Under n o r m a l conditions inhibition of the n e u r o m u s c u l a r t r a n s m i s s i o n of single impulses developed a f t e r the injection of AC in a dose of 15-20 g m o l e s / k g and of CC in a dose of 0.1-0.15 g m o l e / k g . In the period of incomplete b l o c k i n g by decamethonium, imbretil, disufene, or diacetylcholine for the development of complete inhibition it was sufficient to inject AC in a dose of 0.2-0.4 p m o l e s / k g and CC in a dose of 0.01-0.02 p m o l e / k g . Thus, the blocking activity of AC i n c r e a s e d 50-100-fold, w h e r e a s the activity of CC i n c r e a s e d only 5 - 1 0 , f o l d . In the p r e s e n c e of t e t r a m e t h y l a m m o n i u m (TMA) and compound PK-93, d e polarizing agents with the lowest a n t i a c e t y l c h o l i n e s t e r a s e activity (Table 1), the blocking activity of AC i n c r e a s e d only 20-foId, while the activity of CC as b e f o r e i n c r e a s e d 5-10-fold. If the s t r o n g e r potentiating effect of AC as c o m p a r e d with CC is due to inhibition of synaptie CE, this difference should be d e c r e a s e d
T A B L E 1. Effect of Neostigmine Methylsulfate on Blocking Effect of Depolarizing Muscle Relaxants (In. tibialis a n t e r i o r of cat) AmiacetylBlocking Neostigrnine methylsulfate, m g / k p Depolarizing cholinesterase (50%) dose. agent activity (Ki), /~mole/kg * 03)1 0.02--0,0J ; i mole/liter * TMA 1-10-3 3,0 PK-93 I 3. t0 -4 + 3.0 DiacetylchoHne[ t t0 ~ 0.08 PK-I07 ] 1.8.t0 -~ 0.4 Deeamethonium] ' 4. t0-6 0.05 0 Disufene [ 3.t0-6 0,05 0 Imbretil [ I- t0-8 0,005 0 Neostigmine !. meth~lsulfate ,1.t0-7 *Data f r o m [8]. ?A minus sign m e a n s weakening of blocking effect, 0 means no e f fect, plus sign m e a n s intensification.
I. M. Sechenov Institute of Evolutionary Physiology and B i o c h e m i s t r y , A c a d e m y of Sciences of the USSR, Leningrad. ( P r e s e n t e d by Academician E. M. Kreps, July 29, 1975.} T r a n s l a t e d f r o m Doklady Akademii Nauk SSSR, Vol. 226, No. 1, pp. 227-229, January, 1976. Original a r t i c l e submitted July29, 1975.)
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o r eliminated b y d i p y r o x i m e (TMB-4), which has the c a p a c i t y to weaken the a n t i c h o l i n e s t e r a s e activity of s o m e m u s c l e r e l a x a n t s in e x p e r i m e n t s with purified bovine e r y t h r o c y t e a c e t y l c h o l i n e s t e r a s e [6]. in e x p e r i m e n t s in Which d i p y r o x i m e * w a s injected in a dose of 2 m g / k g 2 rain a f t e r the injection o f i m b r e t i l , * d e c a m e t h o n i u m , o r disufene* the potentiation of the blocking activity of AC and CC w a s identical, 5 - 1 0 fold. Since the blocking activity of CC did not change, it is difficult to find a n o t h e r explanation of the d e c r e a s e in the potentiating effect of m u s c l e r e l a x a n t s on the activity of AC caused by d i p y r o x i m e . * T h e a n t i c h o l i n e s t e r a s e activity of d e c a m e t h o n i u m , i m b r e t i l , and disufene in o u r e x p e r i m e n t s was m o r e pronourtced than the effect of diacetylcholine, TMA, and PK-93, which is in a c c o r d with t h e i r a n t i c h o l i n e s t e r a s e activity in v i t r o (Table 1). M o r e o v e r , as was shown e a r l i e r [7, 8], d i p y r o x i m e in a dose of 2 m g / k g e l i m i n a t e s the blocking effect of d e e a m e t h o n i u m , i m b r e t i l , and disufene, but does not affect the activity of o t h e r m u s c l e r e l a x a n t s . T h e s e f a c t s can b e u n d e r s t o o d if one c o m p a r e s t h e m with the effect of inhibitors of CE on n e u r o m u s c u l a r t r a n s m i s s i o n . It is known that only profound (higher than 90%) inhibition of synaptic CE leads to blockage of the t r a n s m i s s i o n of single i m p u l s e s . I f the inhibition of CE r e a c h e s the level of 50-90%, the amplitude of the m u s c l e c o n t r a c t i o n s i n c r e a s e s . M o d e r a t e inhibition of the e n z y m e (up to 50%) does not have an effect on m u s c l e c o n t r a c t i o n s [9-11]. Such inhibition of synaptic CE is also quite likely in the p r e s e n c e of m u s c l e r e l a x a n t s . The inhibition of CE c a u s e d b y d e c a m e t h o n i u m , i m b r e t i l , and disufene r e a c h e s the level at which inhibition of n e u r o m u s c u l a r t r a n s m i s s i o n o c c u r s . This a n t i c h o l i n e s t e r a s e inhibitory m e c h a n i s m is in a d dition to t h e i r d i r e c t action on the p o s t s y n a p t i c m e m b r a n e . An injection of d i p y r o x i m e , by weakening t h e i r a n t i c h o l i n e s t e r a s e activity, leads to the elimination of this m e c h a n i s m and, consequently, to r e s t o r a t i o n of t r a n s m i s s i o n . If a m u s c l e r e l a x a n t c a u s e s l e s s pronounced inhibition of c h o l i n e s t e r a s e , its blocking e f f e c t can r e m a i n unchanged o r be weakened b y the n a t u r a l a n t i e h o l i n e s t e r a s e activity. It has n a t u r a l l y b e e n a s s u m e d that in this c a s e the intensification of the a n t i c h o l i n e s t e r a s e activity of a depolarizing agent by the additional injection of an inhibitor of CE will lead, depending on the d e g r e e of inhibition of the CE, to weakening o r intensification of the blocking. On the b a s i s of this a s s u m p t i o n a s e r i e s of e x p e r i m e n t s w a s set up on c a t s in which the effect of n e o s t i g m i n e m e t h y l s u l f a t e in d o s e s of 0.01-0.1 m g / k g on the blocking action of d e p o l a r i z i n g agents was studied. It w a s e s t a b l i s h e d in p r e l i m i n a r y e x p e r i m e n t s that n e o s t i g m i n e in a dose of 0.01 m g / k g does not a f fect the c o n t r a c t i o n of a m u s c l e in r e s p o n s e to i n d i r e c t single stimulation and, consequently, does not c a u s e profound inhibition of CE. A f t e r the injection of n e o s t i g m i n e in a dose of 0.02-0.05 m g / k g an i n c r e a s e w a s o b s e r v e d in the amplitude of the m u s c l e c o n t r a c t i o n s , while in a dose of 0.1 m g / k g n e o s t i g m i n e c a u s e d blocking of n e u r o m u s c u l a r t r a n s m i s s i o n . T h e blocking effect of d e c a m e t h o n i u m , i m b r e t i l , and disufene was not changed by n e o s t i g m i n e in any of the d o s e s used. T h e s e c o m p o u n d s , as was shown above, have a m a r k e d capacity to inhibit CE and the injection of an inhibitor can add little to t h e i r a n t i c h o l i n e s t e r a s e effect. The injection of n e o s t i g m i n e in a dose of 0.01 m g / k g led to weakening of the blocking effect of TMA and PK-93, depolarizing agents with the lowest a n t i a c e t y l c h o l i n e s t e r a s e activity, and did not affect the activity of diaeetylcholine and PK-107, c o m pounds with higher a n t i e h o l i n e s t e r a s e activity. When the dose of n e o s t i g m i n e was i n c r e a s e d to 0.02-0.03 9m g / k g the blocking activity of TMA and PK-93 did not differ f r o m the control (before the injection of n e o stigmine), while that of diacetylcholine and PK-107 i n c r e a s e d twofold. At the highest dose of n e o s t i g m i n e the blocking activity of all four d e p o l a r i z i n g agents i n c r e a s e d two- to fourfold. T h e weakening of the blocking effect of TMA and PK-93 by n e o s t i g m i n e in a dose of 0.01 m g / k g is a p p a r e n t l y due to s u m m a t i o n of t h e i r w e a k a n t i c h o l i n e s t e r a s e effects, as a r e s u l t of which the inhibition of CE r e a c h e s the level at which m u s c l e c o n t r a c t i o n s a r e intensified. Analogous s u m m a t i o n can also be expected in the p r e s e n c e of diacetylcholine or PK-107 in combination with neostigmine. However, this does not lead to a change in the blocking activity of t h e s e compounds b e c a u s e the inhibition of CE caused b y diaeetylcholine and PK-107 a p p a r e n t l y r e a c h e s a level which c o r r e s p o n d s to the m a x i m u m i n c r e a s e in the amplitude of the m u s c l e c o n t r a c t i o n s . Intensification of the a n t i c h o l i n e s t e r a s e activity of m u s c l e r e l a x a n t s can lead only to intensification of t h e i r blocking capacity, which we o b s e r v e d with an i n c r e a s e in the dose of n e o s t i g m i n e . Thus, a l t o g e t h e r the data obtained m a k e p o s s i b l e the conclusion that the m u s c l e r e l a x a n t s investigated in a blocking dose c a u s e inhibition of the synaptic CE of the s k e l e t a l m u s c l e s and that the a n t i c h o l i n e s t e r a s e activity of d e c a m e t h o n i u m , i m b r e t i l , and disufene is so pronounced that it leads to blocking of n e u r o m u s c u l a r t r a n s m i s s i o n . T h i s a n t i c h o l i n e s t e r a s e blocking m e c h a n i s m is in addition to t h e i r d i r e c t d e p o l a r i z i n g effect on the p o s t s y n a p t i c m e m b r a n e .
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LITERATURE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
CITED
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FORMATION
OF T O N I C
IN S E G M E N T A L
AND P H A S I C
TYPE
p. 320. Handbuch der Experimental
567 (1967).
20, No. 9, 2263 (1971).
REACTIONS
INTERNEURONS
K . S. P r e d t e c h e n s k a y a , a n d V. I . S a f ' y a n t s
UDC 612
S. A . E v d o k i m o v ,
According to c u r r e n t information, the spinal cord interneuron apparatus plays a leading role in the formation of locomotor reactions [1-5]. Activation of interneurons through a f f e r e n t a n d i n t e r c e n t r a l channels normally occurs not by a single impulse, but by a rhythmic s e r i e s . Any investigation of the properties of interneurons t h e r e f o r e must place special emphasis on study of their reactions during rhythmic activation [6-8]. In the present study the t r a n s f o r m e r effect of the most numerous group of interneurons in the i n t e r mediate zone and the ventral horn, the interneuron groups of the afferent flexor reflex (a.f.r.), w ere studied. Interneurons of this group a r e c h a r a c t e r i z e d by a broad convergence of afferent and descending influences [9, 10] and participate not only in the formation of the generalized flexor reflex, but also other polysynaptic locomotor reactions. The objective of the investigation centered on the reactions of interneurons to rhythmic activation from suprathreshold v i s c e r a l motor and somatic motor afferents converging on them and also on an explanation of the conditions and mechanisms of their formation. a
b
c
Fig. I . Types of reactions of spinal cord interneurons during rhythmic stimulation of visceral motor and somatic motor afferent nerves of the rear extremities, a) Reaction of tonic type (without:inhibition); b) phasic type r e action (complete inhibition); c) intermediate type (partial inhibition). Upper tracing - interneuron response; l o w e r - dorsal surface potential. Discharge frequency 50 imp/sec,~ force 20T. Amplitude calibration 10 mV (a) and 4 mV (b, c); time calibration 20 msec.
I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. (Presented by Academician V. N. Chernigovskii, July 17, 1975.) Translated from Doklady Akademii Nauk, SSSR, Vol. 226, No. 1, pp. 238-240, January, 1976. Original article submitted June 30, 1975.
0097-0549/78/0902-0193507.50
9 1979 Plenum Publishing Corporation
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