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Effects of α-adrenoceptor-stimulating drugs on baroreceptor reflexes in conscious cats
European Journal o f Pharmacology, 67 (1980) 75--83
75
© Elsevier/North-Holland Biomedical Press
EFFECTS OF a-ADRENOCEPTOR-STIMULATING REFLEXES IN CONSCIOUS CATS
DRUGS ON BARORECEPTOR
VITALIY A. TSYRLIN and MICHAIL F. BRAVKOV Division o f Pharmacology, The Central Scientific Research Laboratory, I.P. Pavlov 1st Medical Institute, 197089 Leningrad, U.S.S.R.
Received 25 March 1980, revised MS received 8 July 1980, accepted 17 July 1980
V.A. TSYRLIN and M.F. BRAVKOV, Effects o f o~-adrenoceptor-stirnulating drugs on baroreceptor reflexes in conscious cats, European J. Pharmacol. 67 (1980) 75--83. The action of some ~-adrenoceptor stimulating drugs with a central effect (clonidine, ~-methyldopa, reserpine) on baroreceptor reflexes was studied in conscious cats (both in the resting condition and when influenced by emotional tension or electrical stimulation of the hypothalamus). The sedative effect of these drugs was observed simultaneously with bradycardia and the increase of baroreceptor reflexes. Clonidine and reserpine (in 6-24 h after injection) lowered blood pressure while ~-methyldopa (40 mg/kg) increased it. Confrontation with a dog or electrical hypothalamic stimulation produced hypertensive reactions and diminished the baroreflexes. All drugs reduced the emotional and hypertensive reactions caused by natural stress situations and restored baroreceptor reflexes. On the other hand, neither clonidine nor ¢t-methyldopa changed the decrease of baroreceptor reflexes caused by electrical hypothalamic stimulation. It is supposed that central ~-adrenoceptor stimulating drugs do not influence processes of hypothalamic modulation of baroreceptor reflexes. The increase in baroreflex activity after clonidine, (~-methyldopa and reserpine appears to be due to a direct effect of the drugs on the central neurones mediating baroreceptor reflexes and to the tranquillizing action of these drugs. ~-Adrenoceptor-stimulating drugs
Baroreceptor reflexes
1. I n t r o d u c t i o n Administration of noradrenaline and a-methylnoradrenaline into the area of the nucleus t r a c t u s solitarii was s h o w n t o i n d u c e h y p o t e n sion a n d b r a d y c a r d i a in a n e s t h e t i z e d a n i m a l s (De J o n g , 1 9 7 4 ; De J o n g a n d N i j k a m p , 1976). C l o n i d i n e , d u e t o its c e n t r a l a - a d r e n o c e p t o r s t i m u l a t i n g e f f e c t ( S c h m i t t et al., 1 9 7 1 ; V a n Zwieten, 1973; Starke and Altman, 1973; S k o l n i k a n d D a l y , 1 9 7 6 ) , increases b a r o r e c e p t o r r e f l e x e s ( A n t o n a c c i o et al., 1 9 7 5 ; Sleight a n d West, 1 9 7 5 ) . T h e s a m e e f f e c t is s u p p o s e d to b e r e s p o n s i b l e f o r t h e h y p o t e n s i v e a c t i o n o f c l o n i d i n e , since n o r e d u c t i o n o f arterial b l o o d p r e s s u r e was o b s e r v e d w h e n t h e d r u g was a d m i n i s t e r e d to a n i m a l s w h o s e n u c l e u s
Blood pressure
Emotional tension
t r a c t u s solitarii h a d b e e n d e s t r o y e d (Lipski et al., 1976). T h e a b o v e p a p e r s p r o v i d e i n s u f f i c i e n t data, h o w e v e r , as t o t h e i m m e d i a t e cause o f baror e c e p t o r reflex a c t i v a t i o n a f t e r t h e a d m i n i s t r a t i o n o f clonidine. T h e a c t i v a t i o n m a y b e d u e t o a c h a n g e in t h e r e g u l a t i o n o f b a r o r e c e p t o r r e f l e x e s b y t h e u p p e r s t r u c t u r e s o f t h e brain, as well as t o t h e i m m e d i a t e a c t i v a t i o n o f neurones which mediate the h y p o t e n s i o n and bradycardia resulting from the stimulation of b a r o r e c e p t o r s . T h e c e n t r a l links o f t h e b a r o r e c e p t o r r e f l e x arc s i t u a t e d in t h e brain s t e m are k n o w n to be i n h i b i t e d t o n i c a l l y b y h y p o t h a l a m i c s t r u c t u r e s ( K o r n e r et al., 1972). Stimulation of the hypothalamic 'defence area' enhances the hypothalamic inhibition of
76 baroreceptor reflexes (Hilton, 1963; Coote et al., 1979), a factor in the production of hypertensive reactions to emotional stress (Tsyrlin et al., 1978). Direct connections were described between the hypothalamic structures containing a large number of adrenergic neurones (Vogt, 1959; Bloom, 1970; Snyder et al., 1970) and the neurones of the nucleus tractus solitarii (Saper et al., 1976). Histochemical data indicate that noradrenaline is not released from the ending of the primary afferent fibers in the IX-X pairs of cranialis nerves converging on the neurones of the nucleus tractus solitarii (Chiba and Doba, 1976). This allows the suggestion (Chalmers et al., 1977) t h a t the activation of barorecept o t reflexes induced by clonidine may be due to the effect of the drug on the processes of hypothalamic modulation of baroreceptor reflexes, rather than to the direct action on the central link of the baroreceptor reflex arc. There are no adequate studies on the regulation of these processes or on the manner in which drugs with a central aadrenoceptor stimulating effect affect the character of baroreceptor reflexes when the hypothalamus is stimulated. It should be noted that the problem can hardly be solved by experimenting with anesthetised animals as general anesthetics add to the disturbances in the processes of hypothalamic modulation of baroreceptor reflexes (Tsyrlin and Yekimov, 1976). The purpose of the present experiments was to use conscious animals in a s t u d y of the effects produced by clonidine, a - m e t h y l d o p a and reserpine u p o n baroreceptor reflexes under both resting conditions and emotional tension caused by either electrical stimulation of the h y p o t h a l a m u s or a natural stress.
2. Materials and methods
V.A. TSYRLIN, M.F. BRAVKOV mg/kg i.p.) and two blood vessels were cannulated under sterile conditions: the aorta (via the c o m m o n carotid artery) and the jugular vein. Steel electrodes (150-200 pm in diameter) were inserted stereotaxically in the hypothalamic ventromedial nucleus and their localization was later found histologically. After 6-8 days following the operation, each cat was placed in a chamber (150 × 65 × 50 cm) divided by a partition, and its movements there were only limited by two light thin catheters connecting a system fixed to the cat's head with the Statham transducer for measuring blood pressure and the syringe for injecting the drugs. This system (Medvedev, 1974) was connected with distal ends of the vessel catheters. After the main part of each experiment, some cats were operated anew; this time the animals either had their aortic and synocarotid nerves cut or had an electromagnetic flow transducer ('Nihon Kodem') fixed to the ascending aorta. After a few days following the operation the cat was placed into the experimental chamber a second time. Blood pressure, pulse interval and cardiac o u t p u t were recorded (by a photowriting polygraph) and baroreceptor reflexes tested. Measurements were made with the animals either at rest or under emotional tension caused by a a dog barking in the same chamber or by electrical stimulation (50-100 pA, 100 Hz, I msec, 15-30 sec) of the hypothalamus. Baroreflexes were evaluated quantitatively by a m e t h o d described by Smyth et al. (1969). The linear regression coefficient was calculated as a ratio of the rates at which changes occurred in the pulse intervals and blood pressure values. A rise in blood pressure was induced by intravenous (i.v.) injection of phenylephrine (0.03-0.04 mg/kg).
2.2. Drugs
2.1. General Male mongrel cats weighing 3-4 kg were anesthetized with sodium pentobarbital (30
The following drugs were used in the study: clonidine, ~-methyldopa and reserpine. The e f f e c t of clonidine and ~-methyldopa were
a - A D R E N O C E P T O R S T I M U L A T I N G D R U G S ON B A R O R E F L E X E S
estimated for 6 h after injection and the effect of reserpine for 24 h.
77
(12 cats in 28 experiments) and diminished movement. A rise in mean blood pressure (1030% of the initial 70-90 mm Hg) was observed for 3-6 min immediately after the injection. This rise was followed by a decrease in blood pressure accompanied by bradycardia and a decrease of cardiac output. The regression coefficient values, reflecting baroreceptor reflex activity, were increased (table 1). The effect of a-methyldopa (10 cats, 20 experiments) was estimated after a period of 1.5-2 h following the injection. At 10 or 20 mg/kg doses, a-methyldopa slightly decreased emotional behaviour. The effect increased with 40 or 50 mg/kg doses. At 20 mg/kg dose, a-methyldopa lowered the blood pressure and increased baroreceptor reflexes as well as caused bradycardia; the regression coefficient and the bradycardia were increased by the drug in the 40 mg/kg dose (table 1). One h after reserpine injection (7 cats, 14 experiments), no change in behaviour was observed but the other parameters were altered (table 2). After 4-6 h the sedative effect of the drug was more pronounced and was n o t restored in 24 h. After a period of 5-7 days following the operation in which the sino-carotic and aortic nerves were cut, the blood pressure was 60-
2. 3. Statistical analysis Student's t-test was used to find whether or not the pulse intervals were dependent on blood pressure values. A control set of experiments showed that the regression coefficient in the cat at rest did not change when the blood pressure varied by 50-70 mm Hg. Average values of h e m o d y n a m i c reactions and baroreceptor reflexes were calculated on the basis of 3 series of measurements taken both during rest and under emotional tension. Data were analysed by Student's t-test; the paired t-test was used for paired comparisons. All differences were considered significant at P 0.05.
3. Results 3.1. The action o f drugs on mean blood pressure, heart rate, cardiac o u t p u t and baroreceptor reflexes in the resting state Within 15-20 min of its injections, clonidine 0.001 or 0.003 mg/kg evoked a sedative effect
TABLE 1 T h e a c t i o n o f c l o n i d i n e a n d a - m e t h y l d o p a o n h e m o d y n a m i c p a r a m e t e r s a n d regression c o e f f i c i e n t in conscious cats. Drug dose (mg/kg)
Parameters M e a n arterial pressure ( m m Hg)
Pulse interval (msec)
Cardiac o u t p u t (ml/min)
Control Clonidine 0.001 0.003
78_+1
442+11
570+15
74+11 65-+1 1
476-+ 520_+
Control ¢~-Methyldopa 20 40
75+1
465_+12
520+18
7.8
71_+1 1 89-+21
493-+ 535-+
510-+17 508-+14
9.2 11.1
I p < 0.05.
5 1 7 I
8 1 7 1
528-+ 485_+
Regression c o e f f i c i e n t ( m s e c / m m Hg) 8.5
41 61
+0.6
9.27_+0.51 11.3 -+0.6 1 -+0.5 -+0.3 1 _+0.5 I
78
V.A. TSYRLIN, M.F. BRAVKOV
TABLE 2 The effect of reserpine on hemodynamic parameters and regression coefficient in conscious cats. Parameters
Control
Reserpine (0.1 mg/kg) in l h
Mean arterial pressure (mmHg)
in6h
in 2 4 h
75
-+ 1
87
-+ 2 1
63
-+ 1 1
68
-+ 1 1
Pulse interval (msec)
473
-+ 12
541
-+ 14 I
535
-+ 14 l
540
-+ 13 1
Cardiac output (ml/min)
450
-+ 18
410
-+ 11 1
525
-+ 14 1
458
-+ 11 1
Regression coefficient (msec/mm Hg)
9.58 -+ 0.63
7.86 -+ 0.71 1
13.03 -+ 0.66 1
11.21 + 0.59 1
1 p < 0.05. 100 mm Hg while the pulse interval was 300350 msec. In this case, clonidine caused a s i g n i f i c a n t d e c r e a s e in b l o o d p r e s s u r e a n d heart rate, whereas a-methyldopa caused insignificant hypotension without bradycardia, and reserpine reduced blood pressure rapidly - - w i t h i n 1 h o f t h e i n j e c t i o n ( t a b l e 3).
3.2. Effects o f the drugs on cardiovascular alterations caused by emotional tension Tachycardia (pulse interval decreased to 350-250msec) developed in the cat confronting a dog, and there was a two-phase b l o o d p r e s s u r e r e a c t i o n , i.e. s m a l l i n i t i a l h y p o t e n s i o n ( b y 1 0 - 1 5 m m Hg) f o l l o w e d b y a rise in b l o o d p r e s s u r e . D u r i n g h y p e r t e n s i o n , the baroreceptor reflexes were suppressed (the regression coefficient went down to 0 - 1 . 7 -+ 0 . 4 m s e c / m m H g ) . Clonidine decreased significantly the emotional stress reaction caused by the presence o f a d o g in t h e e x p e r i m e n t a l r o o m . T h e sedative effect was accompanied by a decrease in t h e h y p e r t e n s i v e r e a c t i o n a n d i n c r e a s e o f b a r o r e c e p t o r r e f l e x e s (fig. 1, t a b l e 4). a - M e t h y l d o p a in d o s e s o f 1 0 o r 2 0 m g / k g did not affect the emotional reactions, pulse i n t e r v a l a n d r e g r e s s i o n c o e f f i c i e n t ; 4 0 o r 50 mg/kg doses suppressed emotional reactions, diminished the pressor reactions, tachycardia and increased the baroreceptor reflexes ( t a b l e 4).
Similarly to clonidine and a-methyldopa, reserpine was found to suppress emotional tension and hypertensive reactions after a period of 1-24 h following the injections ( t a b l e 4).
3.3. Effects of the drugs on cardiovascular alterations caused by hypothalamic stimulation Tachycardia developed and the blood pressure increased when the hypothalamic ven-
TABLE 3 The action of the drugs on circulation in conscious cats with sinocarotid and aortic nerves cut. Drug dose (mg/kg)
Blood pressure (mm Hg)
Pulse interval (msec)
Control Clonidine 0.001 0.003
90 + 3
300 -+ 5
85 -+ 3 72 + 4 1
325 + 7 355 + 9 1
Control (~-Methyldopa 20
82 _+4
280 _+6
78 _+3
284 _+5
Control Reserpine 0.1 in l h in6h in 2 4 h
92 + 5
300 _+5
77 + 4 I 77 + 5 I 80-+6
375_+4 1 410-+5 1 440-+61
1 p < 0.05.
0~-ADRENOCEPTOR STIMULATING DRUGS ON B A R O R E F L E X E S - "":
_----
.
.
---
.
.
:-~'~'''"~--"%
79 A
I
'
_......._.,,...,%.:.-.------"~'y "---..
B
Fig. 1. The effect of clonidine (0.001 mg/kg, i.v.) on change of pulse interval, arterial blood pressure and baroreceptor reflexes in the conscious cat confronted by a barking dog. (A) Before injections; (B) after injection. From top to b o t t o m : pulse interval, arterial blood pressure and duration of confrontation. Vertical arrow marks the time of phenylephrine injection. Horizontal arrows between vertical lines mark the duration of the arterial blood pressure increase after injection of phenylephrine.
tromedial nucleus was stimulated electrically and emotional behaviour reactions of the 'rage-to-escape' t y p e were induced. The blood pressure increased by 40-50 mm Hg. The baroreceptor reflexes were sharply suppressed during hypertension (the regression coefficient decreased to 0-1.5 + 0.3 msec/mm Hg). Even when injected in doses of 0.003 mg/ kg, clonidine did not affect the emotional or vegetative aspects of the behavioural reactions to hypothalamic stimulation (fig. 2). Similarly, when injected in doses of 20 mg/kg, a-methyldopa caused a slight but significant decrease solely in the hypertensive reactions (table 4).
With a higher dose (40 mg/kg) the inhibitory effect was increased but no changes were observed in baroreceptor reflexes (table 4).
4. Discussion The present study shows that administration of all 3 drugs used activated baroreceptor reflexes and, simultaneously, decreased arterial blood pressure. A number of causes appear to be responsible for the increase of baroreceptor reflexes: (1) activation of baroreceptors located in the wall of the carotid sinus and
80
V.A. TSYRLIN, M.F. BRAVKOV 1
[ ~00 msec
.....~'-"-'--'--
I_ IllLIllll.
[ 40 mm
,,
.
-
. -
--
#4g P,
,
10 sec
Fig. 2. The effect of clonidine (0.003 mg/kg, i.v.) on change of pulse interval, arterial blood pressure and baroreceptor reflexes in a conscious cat with hypothalamic stimul~ion. (A) Before injection; (B) after injection. The other symbols as in fig. 1.
aortic arc; (2) activation of the central neurones mediating baroreceptor reflexes; (3) suppression of processes involved in the hypothalamic inhibition of baroreceptor reflexes; (4) suppression of processes providing for activation of the hypothalamic 'defence area' under emotional tension. Clonidine and a-methyldopa are b o t h k n o w n to activate the peripheral as well as the central a-adrenoceptors (Day and Rand, 1964; Hodge and Robinson, 1972). During the first few hours after reserpine injection, norepinephrine is released from the fibre endings of both central and peripheral adrenergic neurones (Maxwell et al., 1957; Rozanov, 1971). Contraction of the smooth muscles in the walls of the carotid sinus and aortic arec intensifies
baroreceptor reflexes and diminishes blood pressure and heart rate (Kezdi and Hilker, 1955; Bolter and Ledsome, 1976). At the same time our experiments show that the hypotensive effect and bradycardia induced by clonidine, a-methyldopa or reserpine were retained when the animals had their sinocarotid and aortic nerves cut. Analysis of the action exerted by the drugs on the hypothalamic modulation of the baroreceptor reflexes has shown that the suppression of baroreflexes due to electrical stimulation of the hypothalamus was not influenced by c o m p o u n d s with an a-adrenoceptor stimulating effect. Thus, our experiments serve to support the data of Zandberg and De Jong (1977) i.e. the idea that activation of a-
a-ADRENOCEPTOR STIMULATING DRUGS ON BAROREFLEXES
81
TABLE 4 The effect of the drugs on hemodynamic reactions caused by a natural stress situation and hypothalamic stimulation. Drug dose (mg/kg)
Modification (as percent of control) Pressor reaction
Pulse interval
Regression coefficient
Clonidine 0.001 0.003
18 +3 1 ~ 47-+7 I $
15_+21 1" 35_+4 1 t
45_+2 1 f" 92+31 t
a-Methyldopa 20 40
21 -+ 5 1 $ 52+7 I 4
0 16_+3 t t
0 68_+5 1 t
Reserpine 0.1inlh in6h in24h
23_+3 1 ~ 57_+5 1 4 83-+8 I 4
30_+4 1 1" 48_+5 1 1" 29-+4 1 1"
16_+4 1 t 62-+4 1 1' 64-+3 1 1"
N a t u r a l stress s i t u a t i o n
Hypothalamic stimulation
Clonidine 0.003 c~-Methyldopa 20 40
0 11 _+3 1 $ 19+3 1 ~
0 0 12-+2 l ~"
0 0 0
i p < 0.05; 1' increase; $ decrease; 0 without effect.
a d r e n o c e p t o r n e u r o n e s in t h e n u c l e u s t r a c t u s solitarii w h i c h are r e s p o n s i b l e f o r t h e t o n i c i n h i b i t o r y c o n t r o l a n d reflex r e g u l a t i o n o f t h e c a r d i o v a s c u l a r s y s t e m is o n e o f t h e m e c h a nisms i n t e n s i f y i n g b a r o r e c e p t o r r e f l e x e s a f t e r the administration of a drug which stimulates c e n t r a l a - a d r e n o c e p t o r s . O u r d a t a indicate, h o w e v e r , t h a t a c t i v a t i o n of n e u r o n e s w h i c h m o d u l a t e b a r o r e c e p t o r r e f l e x e d d i r e c t l y cann o t h a v e b e e n t h e single cause o f t h e intensification o f b a r o r e f l e x e s a f t e r i n j e c t i o n o f o n e o f t h e drugs u n d e r s t u d y . T h e experim e n t s i n d i c a t e t h a t t h e drugs r e d u c e d t h e hypertensive reactions and increased the regression c o e f f i c i e n t u n d e r a n a t u r a l e m o tional stress. T h e n e u r o c h e m i c a l m e c h a n i s m o f t h e e f f e c t is n o t y e t clear. Earlier observations (Bravkov and Tsyrlin, 1978) s h o w e d t h a t a similar a c t i o n was p r o d u c e d b y general a n e s t h e t i c s (such as s o d i u m p e n t o barbital) w h e n i n j e c t e d in small doses (1-3
m g / k g ) a n d also b y s o m e tranquillizers. Clonidine, a - m e t h y l d o p a a n d r e s e r p i n e m a y be able t o k e e p u n d e r c o n t r o l t h e a c t i v a t i o n o f the hypothalamic 'defence area' under natural e m o t i o n a l stress a n d t h u s r e d u c e t h e e x t e n t o f b e h a v i o u r a l r e a c t i o n s and, t h e r e f o r e , t h e h i n d e r t h e s u p p r e s s i o n o f b a r o r e c e p t o r reflexes a n d d e v e l o p m e n t o f h y p e r t e n s i v e reactions. All t h r e e drugs a p p e a r t o h a v e a p r o n o u n c e d sedative effect. Since t h e s u p r a b u l b a r structures o f t h e brain are able to s u p p r e s s baror e c e p t o r r e f l e x e s t o n i c a l l y ( K o r n e r et al., 1 9 7 2 ) , t h e r e d u c t i o n in f u n c t i o n a l a c t i v i t y o f t h e h y p o t h a l a m i c n e u r o n e s in c o n s c i o u s animals m a y be c o n s i d e r e d o n e o f t h e f a c t o r s r e s p o n s i b l e f o r an i n t e n s i f i c a t i o n o f baror e c e p t o r r e f l e x e s d u r i n g rest. This d o e s n o t contradict our observations indicating that t h e b a r o r e f l e x e s d o n o t u n d e r g o a n y alterat i o n s w h e n t h e brain is s t i m u l a t e d , since electrical s t i m u l a t i o n o f n e r v e tissue p r o m o t e s
82 activation of a great number of passing nerve f i b r e s as well as o f t h e n e r v e cells ( R a n c k , 1975).
References Antonaccio, M.J., R.D. Robson and R. Burrell, 1975, Effect of clonidine on baroreceptor function in anesthetized dogs, European J. Pharmacol. 30, 6. Bloom, F.E., 1970, The fine structural localization of biogenic monoamines in nervous tissue, Int. Rev. Neurobiol. 13, 27. Bolter, C.P. and J.R. Ledsome, 1976, Effect of cervical sympathetic nerve stimulation on canine carotid sinus reflex, Am. J. Physiol. 230, 1026. Bravkov, M.F. and V.A. Tsyrlin, 1978, Pharmacological correction of the changes of homeostatic mechanisms of hemodynamic regulation under the conditions of emotional stress in freely moving animals, in: Neuropharmacological aspects of the emotional stress and drug dependence, ed. A.V. Valdman (Leningrad) p. 134 (in Russian). Chalmers, J.P., S.W. White, J.B. Geffen and R. Rush, 1977, The role of central catecholamines in the control of blood pressure through the baroreceptor reflex and the nasopharyngeal reflex in the rabbit, in: Hypertension and brain mechanisms, Prog. Brain Res., Vol. 47, eds. W. De Jong, A.P. Proroost and A.P. Shapiro (Elsevier/North-Holland Biomedical Press) p. 85. Chiba, T. and N. Doba, 1976, Catecholaminergic axoaxonic synapses in the nucleus of the tractus solitarius (pars commissuralis) of the cat: possible relation to presynaptic regulation of baroreceptor reflexes, Brain Res. 102, 255. Coote, S.H., S.M. Hilton and J.F. Perez-Gonzalez, 1979, Inhibition of the baroreceptor reflex on stimulation in the brain stem defence centre. J. Physiol. (London) 288,549. Day, M.D. and M.J. Rand, 1964, Some observations on the pharmacology of methyldopa, Br. J. Pharmacol. 22, 7. Hilton, S.M., 1963, Inhibition of baroreceptor reflexes on hypothalamic stimulation, J. Physiol. 165, 56. Hodge, R.L. and S.M. Robinson, 1972, The action of clonidine on isolated arterial preparations, Aust. J. Exp. Biol. Med. Sci. 50, 517. De Jong, W., 1974, Noradrenaline; central inhibitory control of blood pressure and heart rate, European J. Pharmacoh 29,179. De Jong, W. and E.P. Nijkamp, 1976, Centrally induced hypotension and bradycardia after administration of (~-methylnoradrenaline into the area of the nucleus tractus solitarii of the rat, Br. J. Pharmacol. 58,593.
V.A. TSYRLIN, M.F. BRAVKOV Kezdi, P. and R.R. Hilker, 1955, Local application of epinephrine to carotid sinus: lowering of blood pressure and modification ofhyperreactor response in hypertensive patients, Arch. Int. Med. 9 5 , 7 2 0 . Korner, P.I,, J. Shaw, M.J. West and J.R. Oliver, 1972, Central nervous system control of baroreceptor reflexes in the rabbit, Circ. Res. 31,637. Lipski, J., J. Przybylski and E. Solnicka, 1976, Reduced hypotensive effect of clonidine after lesions of the nucleus tractus solitarii in rats, European J. Pharmacol. 38, 19. Maxwell, R., S. Ross, A. Plummer and E. Sigg, 1957, A peripheral action of reserpine, J. Pharmacoh Exp. Ther. 119, 69. Medvedev, O.S., 1974, A chronic measurement of the blood pressure in the cat, Sechenov Physiol. J. U.S.S.R. 60, 1473 (in Russian). Ranck, J.B., 1975, Which elements are excited in electrical stimulation of mammalian central nervous system: a review, Brain Res. 98,417. Rozanov, J.B., 1971, The reserpine action on central mechanisms of the blood pressure regulation, in: The pharmacology of the monoaminergic processes, eds. V.V. Zacusov and N.V. Kaverina (Medicina, Moscow) p. 78 (in Russian). Saper, C.B., A.D. Loewy, L.W. Swanson and W.M. Cowan, 1976, Direct hypothalamo-autonomic connections. Brain Res. 117,305. Schmitt, H., H. Schmitt and S. F~nard, 1971, Evidence for an (~-sympathomimetic component in the effect of catapresan on vasomotor centres. Antagonism by piperoxane, European J. Pharmacol. 14, 98. Skolnic, P. and J. Daly, 1976, Interaction of clonidine with pre- and post-synaptic adrenergic receptors of rat brain: effects on cyclic AMP-generating systems, European J. Pharmacoh 39, 11. Sleight, P. and M.J. West, 1975, The effect of clonidine on the baroreflex arc in man, in: Central action drugs blood pressure regulation, Proc. Intern. Syrup. Tunbridge Wells, p. 291. Smyth, H.S., P. Sleight and G.W. Pickering, 1969, Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity, Circ. Res. 24,109. Snyder, S.H., M.I. Kuhar, A.I. Green, I.T., Coyle and E.G. Shaskan, 1970, Uptake and subcellular localization of neurotransmitters in the brain, Int. Rev. Neurobioh 13,127. Starke, K. and K.P. Altman, 1973, Inhibition of adrenergic neutrotransmission by clonidine: an action on prejunctional a-receptors, Neuropharmacol. 12,339. Tsyrlin, V.A., M.F. Bravkov and B.G. Bershadsky, 1978, Baroreceptor reflexes during emotional tension in alert animals, Sechenov Physiol. J. U.S.S.R. 6 4 , 6 2 6 .
a-ADRENOCEPTOR STIMULATING DRUGS ON BAROREFLEXES Tsyrlin, V.A. and E.N. Yekimov, 1976,Baroreflectory regulation of blood pressure and local blood flow during emotional tension, Sechenov Physiol. J. U.S.S.R. 62, 1466 (in Russian). Van Zwieten, P.A., 1973, The central action of antihypertensive drugs, mediated via central a-receptors, J. Pharm. Pharmacol. 25, 89.
83
Vogt, M., 1959, Catecholamines in brain, Pharmacol. Rev. 11,483. Zandberg, P. and W. De Jong, 1977, a-Methylnoradrenaline-induced hypotension in the nucleus tractus solitarii of the rat: a localization study, Neuropharmacol. 16,219.
75
© Elsevier/North-Holland Biomedical Press
EFFECTS OF a-ADRENOCEPTOR-STIMULATING REFLEXES IN CONSCIOUS CATS
DRUGS ON BARORECEPTOR
VITALIY A. TSYRLIN and MICHAIL F. BRAVKOV Division o f Pharmacology, The Central Scientific Research Laboratory, I.P. Pavlov 1st Medical Institute, 197089 Leningrad, U.S.S.R.
Received 25 March 1980, revised MS received 8 July 1980, accepted 17 July 1980
V.A. TSYRLIN and M.F. BRAVKOV, Effects o f o~-adrenoceptor-stirnulating drugs on baroreceptor reflexes in conscious cats, European J. Pharmacol. 67 (1980) 75--83. The action of some ~-adrenoceptor stimulating drugs with a central effect (clonidine, ~-methyldopa, reserpine) on baroreceptor reflexes was studied in conscious cats (both in the resting condition and when influenced by emotional tension or electrical stimulation of the hypothalamus). The sedative effect of these drugs was observed simultaneously with bradycardia and the increase of baroreceptor reflexes. Clonidine and reserpine (in 6-24 h after injection) lowered blood pressure while ~-methyldopa (40 mg/kg) increased it. Confrontation with a dog or electrical hypothalamic stimulation produced hypertensive reactions and diminished the baroreflexes. All drugs reduced the emotional and hypertensive reactions caused by natural stress situations and restored baroreceptor reflexes. On the other hand, neither clonidine nor ¢t-methyldopa changed the decrease of baroreceptor reflexes caused by electrical hypothalamic stimulation. It is supposed that central ~-adrenoceptor stimulating drugs do not influence processes of hypothalamic modulation of baroreceptor reflexes. The increase in baroreflex activity after clonidine, (~-methyldopa and reserpine appears to be due to a direct effect of the drugs on the central neurones mediating baroreceptor reflexes and to the tranquillizing action of these drugs. ~-Adrenoceptor-stimulating drugs
Baroreceptor reflexes
1. I n t r o d u c t i o n Administration of noradrenaline and a-methylnoradrenaline into the area of the nucleus t r a c t u s solitarii was s h o w n t o i n d u c e h y p o t e n sion a n d b r a d y c a r d i a in a n e s t h e t i z e d a n i m a l s (De J o n g , 1 9 7 4 ; De J o n g a n d N i j k a m p , 1976). C l o n i d i n e , d u e t o its c e n t r a l a - a d r e n o c e p t o r s t i m u l a t i n g e f f e c t ( S c h m i t t et al., 1 9 7 1 ; V a n Zwieten, 1973; Starke and Altman, 1973; S k o l n i k a n d D a l y , 1 9 7 6 ) , increases b a r o r e c e p t o r r e f l e x e s ( A n t o n a c c i o et al., 1 9 7 5 ; Sleight a n d West, 1 9 7 5 ) . T h e s a m e e f f e c t is s u p p o s e d to b e r e s p o n s i b l e f o r t h e h y p o t e n s i v e a c t i o n o f c l o n i d i n e , since n o r e d u c t i o n o f arterial b l o o d p r e s s u r e was o b s e r v e d w h e n t h e d r u g was a d m i n i s t e r e d to a n i m a l s w h o s e n u c l e u s
Blood pressure
Emotional tension
t r a c t u s solitarii h a d b e e n d e s t r o y e d (Lipski et al., 1976). T h e a b o v e p a p e r s p r o v i d e i n s u f f i c i e n t data, h o w e v e r , as t o t h e i m m e d i a t e cause o f baror e c e p t o r reflex a c t i v a t i o n a f t e r t h e a d m i n i s t r a t i o n o f clonidine. T h e a c t i v a t i o n m a y b e d u e t o a c h a n g e in t h e r e g u l a t i o n o f b a r o r e c e p t o r r e f l e x e s b y t h e u p p e r s t r u c t u r e s o f t h e brain, as well as t o t h e i m m e d i a t e a c t i v a t i o n o f neurones which mediate the h y p o t e n s i o n and bradycardia resulting from the stimulation of b a r o r e c e p t o r s . T h e c e n t r a l links o f t h e b a r o r e c e p t o r r e f l e x arc s i t u a t e d in t h e brain s t e m are k n o w n to be i n h i b i t e d t o n i c a l l y b y h y p o t h a l a m i c s t r u c t u r e s ( K o r n e r et al., 1972). Stimulation of the hypothalamic 'defence area' enhances the hypothalamic inhibition of
76 baroreceptor reflexes (Hilton, 1963; Coote et al., 1979), a factor in the production of hypertensive reactions to emotional stress (Tsyrlin et al., 1978). Direct connections were described between the hypothalamic structures containing a large number of adrenergic neurones (Vogt, 1959; Bloom, 1970; Snyder et al., 1970) and the neurones of the nucleus tractus solitarii (Saper et al., 1976). Histochemical data indicate that noradrenaline is not released from the ending of the primary afferent fibers in the IX-X pairs of cranialis nerves converging on the neurones of the nucleus tractus solitarii (Chiba and Doba, 1976). This allows the suggestion (Chalmers et al., 1977) t h a t the activation of barorecept o t reflexes induced by clonidine may be due to the effect of the drug on the processes of hypothalamic modulation of baroreceptor reflexes, rather than to the direct action on the central link of the baroreceptor reflex arc. There are no adequate studies on the regulation of these processes or on the manner in which drugs with a central aadrenoceptor stimulating effect affect the character of baroreceptor reflexes when the hypothalamus is stimulated. It should be noted that the problem can hardly be solved by experimenting with anesthetised animals as general anesthetics add to the disturbances in the processes of hypothalamic modulation of baroreceptor reflexes (Tsyrlin and Yekimov, 1976). The purpose of the present experiments was to use conscious animals in a s t u d y of the effects produced by clonidine, a - m e t h y l d o p a and reserpine u p o n baroreceptor reflexes under both resting conditions and emotional tension caused by either electrical stimulation of the h y p o t h a l a m u s or a natural stress.
2. Materials and methods
V.A. TSYRLIN, M.F. BRAVKOV mg/kg i.p.) and two blood vessels were cannulated under sterile conditions: the aorta (via the c o m m o n carotid artery) and the jugular vein. Steel electrodes (150-200 pm in diameter) were inserted stereotaxically in the hypothalamic ventromedial nucleus and their localization was later found histologically. After 6-8 days following the operation, each cat was placed in a chamber (150 × 65 × 50 cm) divided by a partition, and its movements there were only limited by two light thin catheters connecting a system fixed to the cat's head with the Statham transducer for measuring blood pressure and the syringe for injecting the drugs. This system (Medvedev, 1974) was connected with distal ends of the vessel catheters. After the main part of each experiment, some cats were operated anew; this time the animals either had their aortic and synocarotid nerves cut or had an electromagnetic flow transducer ('Nihon Kodem') fixed to the ascending aorta. After a few days following the operation the cat was placed into the experimental chamber a second time. Blood pressure, pulse interval and cardiac o u t p u t were recorded (by a photowriting polygraph) and baroreceptor reflexes tested. Measurements were made with the animals either at rest or under emotional tension caused by a a dog barking in the same chamber or by electrical stimulation (50-100 pA, 100 Hz, I msec, 15-30 sec) of the hypothalamus. Baroreflexes were evaluated quantitatively by a m e t h o d described by Smyth et al. (1969). The linear regression coefficient was calculated as a ratio of the rates at which changes occurred in the pulse intervals and blood pressure values. A rise in blood pressure was induced by intravenous (i.v.) injection of phenylephrine (0.03-0.04 mg/kg).
2.2. Drugs
2.1. General Male mongrel cats weighing 3-4 kg were anesthetized with sodium pentobarbital (30
The following drugs were used in the study: clonidine, ~-methyldopa and reserpine. The e f f e c t of clonidine and ~-methyldopa were
a - A D R E N O C E P T O R S T I M U L A T I N G D R U G S ON B A R O R E F L E X E S
estimated for 6 h after injection and the effect of reserpine for 24 h.
77
(12 cats in 28 experiments) and diminished movement. A rise in mean blood pressure (1030% of the initial 70-90 mm Hg) was observed for 3-6 min immediately after the injection. This rise was followed by a decrease in blood pressure accompanied by bradycardia and a decrease of cardiac output. The regression coefficient values, reflecting baroreceptor reflex activity, were increased (table 1). The effect of a-methyldopa (10 cats, 20 experiments) was estimated after a period of 1.5-2 h following the injection. At 10 or 20 mg/kg doses, a-methyldopa slightly decreased emotional behaviour. The effect increased with 40 or 50 mg/kg doses. At 20 mg/kg dose, a-methyldopa lowered the blood pressure and increased baroreceptor reflexes as well as caused bradycardia; the regression coefficient and the bradycardia were increased by the drug in the 40 mg/kg dose (table 1). One h after reserpine injection (7 cats, 14 experiments), no change in behaviour was observed but the other parameters were altered (table 2). After 4-6 h the sedative effect of the drug was more pronounced and was n o t restored in 24 h. After a period of 5-7 days following the operation in which the sino-carotic and aortic nerves were cut, the blood pressure was 60-
2. 3. Statistical analysis Student's t-test was used to find whether or not the pulse intervals were dependent on blood pressure values. A control set of experiments showed that the regression coefficient in the cat at rest did not change when the blood pressure varied by 50-70 mm Hg. Average values of h e m o d y n a m i c reactions and baroreceptor reflexes were calculated on the basis of 3 series of measurements taken both during rest and under emotional tension. Data were analysed by Student's t-test; the paired t-test was used for paired comparisons. All differences were considered significant at P 0.05.
3. Results 3.1. The action o f drugs on mean blood pressure, heart rate, cardiac o u t p u t and baroreceptor reflexes in the resting state Within 15-20 min of its injections, clonidine 0.001 or 0.003 mg/kg evoked a sedative effect
TABLE 1 T h e a c t i o n o f c l o n i d i n e a n d a - m e t h y l d o p a o n h e m o d y n a m i c p a r a m e t e r s a n d regression c o e f f i c i e n t in conscious cats. Drug dose (mg/kg)
Parameters M e a n arterial pressure ( m m Hg)
Pulse interval (msec)
Cardiac o u t p u t (ml/min)
Control Clonidine 0.001 0.003
78_+1
442+11
570+15
74+11 65-+1 1
476-+ 520_+
Control ¢~-Methyldopa 20 40
75+1
465_+12
520+18
7.8
71_+1 1 89-+21
493-+ 535-+
510-+17 508-+14
9.2 11.1
I p < 0.05.
5 1 7 I
8 1 7 1
528-+ 485_+
Regression c o e f f i c i e n t ( m s e c / m m Hg) 8.5
41 61
+0.6
9.27_+0.51 11.3 -+0.6 1 -+0.5 -+0.3 1 _+0.5 I
78
V.A. TSYRLIN, M.F. BRAVKOV
TABLE 2 The effect of reserpine on hemodynamic parameters and regression coefficient in conscious cats. Parameters
Control
Reserpine (0.1 mg/kg) in l h
Mean arterial pressure (mmHg)
in6h
in 2 4 h
75
-+ 1
87
-+ 2 1
63
-+ 1 1
68
-+ 1 1
Pulse interval (msec)
473
-+ 12
541
-+ 14 I
535
-+ 14 l
540
-+ 13 1
Cardiac output (ml/min)
450
-+ 18
410
-+ 11 1
525
-+ 14 1
458
-+ 11 1
Regression coefficient (msec/mm Hg)
9.58 -+ 0.63
7.86 -+ 0.71 1
13.03 -+ 0.66 1
11.21 + 0.59 1
1 p < 0.05. 100 mm Hg while the pulse interval was 300350 msec. In this case, clonidine caused a s i g n i f i c a n t d e c r e a s e in b l o o d p r e s s u r e a n d heart rate, whereas a-methyldopa caused insignificant hypotension without bradycardia, and reserpine reduced blood pressure rapidly - - w i t h i n 1 h o f t h e i n j e c t i o n ( t a b l e 3).
3.2. Effects o f the drugs on cardiovascular alterations caused by emotional tension Tachycardia (pulse interval decreased to 350-250msec) developed in the cat confronting a dog, and there was a two-phase b l o o d p r e s s u r e r e a c t i o n , i.e. s m a l l i n i t i a l h y p o t e n s i o n ( b y 1 0 - 1 5 m m Hg) f o l l o w e d b y a rise in b l o o d p r e s s u r e . D u r i n g h y p e r t e n s i o n , the baroreceptor reflexes were suppressed (the regression coefficient went down to 0 - 1 . 7 -+ 0 . 4 m s e c / m m H g ) . Clonidine decreased significantly the emotional stress reaction caused by the presence o f a d o g in t h e e x p e r i m e n t a l r o o m . T h e sedative effect was accompanied by a decrease in t h e h y p e r t e n s i v e r e a c t i o n a n d i n c r e a s e o f b a r o r e c e p t o r r e f l e x e s (fig. 1, t a b l e 4). a - M e t h y l d o p a in d o s e s o f 1 0 o r 2 0 m g / k g did not affect the emotional reactions, pulse i n t e r v a l a n d r e g r e s s i o n c o e f f i c i e n t ; 4 0 o r 50 mg/kg doses suppressed emotional reactions, diminished the pressor reactions, tachycardia and increased the baroreceptor reflexes ( t a b l e 4).
Similarly to clonidine and a-methyldopa, reserpine was found to suppress emotional tension and hypertensive reactions after a period of 1-24 h following the injections ( t a b l e 4).
3.3. Effects of the drugs on cardiovascular alterations caused by hypothalamic stimulation Tachycardia developed and the blood pressure increased when the hypothalamic ven-
TABLE 3 The action of the drugs on circulation in conscious cats with sinocarotid and aortic nerves cut. Drug dose (mg/kg)
Blood pressure (mm Hg)
Pulse interval (msec)
Control Clonidine 0.001 0.003
90 + 3
300 -+ 5
85 -+ 3 72 + 4 1
325 + 7 355 + 9 1
Control (~-Methyldopa 20
82 _+4
280 _+6
78 _+3
284 _+5
Control Reserpine 0.1 in l h in6h in 2 4 h
92 + 5
300 _+5
77 + 4 I 77 + 5 I 80-+6
375_+4 1 410-+5 1 440-+61
1 p < 0.05.
0~-ADRENOCEPTOR STIMULATING DRUGS ON B A R O R E F L E X E S - "":
_----
.
.
---
.
.
:-~'~'''"~--"%
79 A
I
'
_......._.,,...,%.:.-.------"~'y "---..
B
Fig. 1. The effect of clonidine (0.001 mg/kg, i.v.) on change of pulse interval, arterial blood pressure and baroreceptor reflexes in the conscious cat confronted by a barking dog. (A) Before injections; (B) after injection. From top to b o t t o m : pulse interval, arterial blood pressure and duration of confrontation. Vertical arrow marks the time of phenylephrine injection. Horizontal arrows between vertical lines mark the duration of the arterial blood pressure increase after injection of phenylephrine.
tromedial nucleus was stimulated electrically and emotional behaviour reactions of the 'rage-to-escape' t y p e were induced. The blood pressure increased by 40-50 mm Hg. The baroreceptor reflexes were sharply suppressed during hypertension (the regression coefficient decreased to 0-1.5 + 0.3 msec/mm Hg). Even when injected in doses of 0.003 mg/ kg, clonidine did not affect the emotional or vegetative aspects of the behavioural reactions to hypothalamic stimulation (fig. 2). Similarly, when injected in doses of 20 mg/kg, a-methyldopa caused a slight but significant decrease solely in the hypertensive reactions (table 4).
With a higher dose (40 mg/kg) the inhibitory effect was increased but no changes were observed in baroreceptor reflexes (table 4).
4. Discussion The present study shows that administration of all 3 drugs used activated baroreceptor reflexes and, simultaneously, decreased arterial blood pressure. A number of causes appear to be responsible for the increase of baroreceptor reflexes: (1) activation of baroreceptors located in the wall of the carotid sinus and
80
V.A. TSYRLIN, M.F. BRAVKOV 1
[ ~00 msec
.....~'-"-'--'--
I_ IllLIllll.
[ 40 mm
,,
.
-
. -
--
#4g P,
,
10 sec
Fig. 2. The effect of clonidine (0.003 mg/kg, i.v.) on change of pulse interval, arterial blood pressure and baroreceptor reflexes in a conscious cat with hypothalamic stimul~ion. (A) Before injection; (B) after injection. The other symbols as in fig. 1.
aortic arc; (2) activation of the central neurones mediating baroreceptor reflexes; (3) suppression of processes involved in the hypothalamic inhibition of baroreceptor reflexes; (4) suppression of processes providing for activation of the hypothalamic 'defence area' under emotional tension. Clonidine and a-methyldopa are b o t h k n o w n to activate the peripheral as well as the central a-adrenoceptors (Day and Rand, 1964; Hodge and Robinson, 1972). During the first few hours after reserpine injection, norepinephrine is released from the fibre endings of both central and peripheral adrenergic neurones (Maxwell et al., 1957; Rozanov, 1971). Contraction of the smooth muscles in the walls of the carotid sinus and aortic arec intensifies
baroreceptor reflexes and diminishes blood pressure and heart rate (Kezdi and Hilker, 1955; Bolter and Ledsome, 1976). At the same time our experiments show that the hypotensive effect and bradycardia induced by clonidine, a-methyldopa or reserpine were retained when the animals had their sinocarotid and aortic nerves cut. Analysis of the action exerted by the drugs on the hypothalamic modulation of the baroreceptor reflexes has shown that the suppression of baroreflexes due to electrical stimulation of the hypothalamus was not influenced by c o m p o u n d s with an a-adrenoceptor stimulating effect. Thus, our experiments serve to support the data of Zandberg and De Jong (1977) i.e. the idea that activation of a-
a-ADRENOCEPTOR STIMULATING DRUGS ON BAROREFLEXES
81
TABLE 4 The effect of the drugs on hemodynamic reactions caused by a natural stress situation and hypothalamic stimulation. Drug dose (mg/kg)
Modification (as percent of control) Pressor reaction
Pulse interval
Regression coefficient
Clonidine 0.001 0.003
18 +3 1 ~ 47-+7 I $
15_+21 1" 35_+4 1 t
45_+2 1 f" 92+31 t
a-Methyldopa 20 40
21 -+ 5 1 $ 52+7 I 4
0 16_+3 t t
0 68_+5 1 t
Reserpine 0.1inlh in6h in24h
23_+3 1 ~ 57_+5 1 4 83-+8 I 4
30_+4 1 1" 48_+5 1 1" 29-+4 1 1"
16_+4 1 t 62-+4 1 1' 64-+3 1 1"
N a t u r a l stress s i t u a t i o n
Hypothalamic stimulation
Clonidine 0.003 c~-Methyldopa 20 40
0 11 _+3 1 $ 19+3 1 ~
0 0 12-+2 l ~"
0 0 0
i p < 0.05; 1' increase; $ decrease; 0 without effect.
a d r e n o c e p t o r n e u r o n e s in t h e n u c l e u s t r a c t u s solitarii w h i c h are r e s p o n s i b l e f o r t h e t o n i c i n h i b i t o r y c o n t r o l a n d reflex r e g u l a t i o n o f t h e c a r d i o v a s c u l a r s y s t e m is o n e o f t h e m e c h a nisms i n t e n s i f y i n g b a r o r e c e p t o r r e f l e x e s a f t e r the administration of a drug which stimulates c e n t r a l a - a d r e n o c e p t o r s . O u r d a t a indicate, h o w e v e r , t h a t a c t i v a t i o n of n e u r o n e s w h i c h m o d u l a t e b a r o r e c e p t o r r e f l e x e d d i r e c t l y cann o t h a v e b e e n t h e single cause o f t h e intensification o f b a r o r e f l e x e s a f t e r i n j e c t i o n o f o n e o f t h e drugs u n d e r s t u d y . T h e experim e n t s i n d i c a t e t h a t t h e drugs r e d u c e d t h e hypertensive reactions and increased the regression c o e f f i c i e n t u n d e r a n a t u r a l e m o tional stress. T h e n e u r o c h e m i c a l m e c h a n i s m o f t h e e f f e c t is n o t y e t clear. Earlier observations (Bravkov and Tsyrlin, 1978) s h o w e d t h a t a similar a c t i o n was p r o d u c e d b y general a n e s t h e t i c s (such as s o d i u m p e n t o barbital) w h e n i n j e c t e d in small doses (1-3
m g / k g ) a n d also b y s o m e tranquillizers. Clonidine, a - m e t h y l d o p a a n d r e s e r p i n e m a y be able t o k e e p u n d e r c o n t r o l t h e a c t i v a t i o n o f the hypothalamic 'defence area' under natural e m o t i o n a l stress a n d t h u s r e d u c e t h e e x t e n t o f b e h a v i o u r a l r e a c t i o n s and, t h e r e f o r e , t h e h i n d e r t h e s u p p r e s s i o n o f b a r o r e c e p t o r reflexes a n d d e v e l o p m e n t o f h y p e r t e n s i v e reactions. All t h r e e drugs a p p e a r t o h a v e a p r o n o u n c e d sedative effect. Since t h e s u p r a b u l b a r structures o f t h e brain are able to s u p p r e s s baror e c e p t o r r e f l e x e s t o n i c a l l y ( K o r n e r et al., 1 9 7 2 ) , t h e r e d u c t i o n in f u n c t i o n a l a c t i v i t y o f t h e h y p o t h a l a m i c n e u r o n e s in c o n s c i o u s animals m a y be c o n s i d e r e d o n e o f t h e f a c t o r s r e s p o n s i b l e f o r an i n t e n s i f i c a t i o n o f baror e c e p t o r r e f l e x e s d u r i n g rest. This d o e s n o t contradict our observations indicating that t h e b a r o r e f l e x e s d o n o t u n d e r g o a n y alterat i o n s w h e n t h e brain is s t i m u l a t e d , since electrical s t i m u l a t i o n o f n e r v e tissue p r o m o t e s
82 activation of a great number of passing nerve f i b r e s as well as o f t h e n e r v e cells ( R a n c k , 1975).
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