European Journal of Pharmacology, 50 (1978) 275--278
275
© Elsevier/North-Holland Biomedical Press
Short communication BARORECEPTOR-INDUCED DECREASE IN MUSCLE BLOOD FLOW UPON PROPRANOLOL ADMINISTRATION BJORN LISANDER and HOLGER NILSSON
Department o f Physiology, University o f G~teborg, 400 33 G~teborg, Sweden Received 31 May 1978, accepted 7 June 1978
B. LISANDER and H. NILSSON, Baroreceptor-induced decrease in muscle blood flow upon propranolol administration, European J. Pharmacol. 50 (1978) 275--278. The acute effects of propranolol, 1 mg/kg i.v., were studied in chloralosed, vagotomized cats. The vascularly isolated but innervated calf muscles were perfuscd from another animal. In one group of experiments, the carotid baroreceptors were exposed to ambient arterial pressure. Here, propranolol caused a fall in heart rate and an increase in resistance of the isolated muscle bed. In other experiments, the carotid sinuses were perfused at a constant pressure. In these animals, no increase in muscle flow resistance was observed after the drug. It is concluded that the increase in total peripheral resistance, seen initially upon propranolol administration, may be reflexly induced via the baroreceptors. Propranolol
Muscle blood flow
Baroceptor reflexes
1. Introduction The ~-adrenergic blocking agent propranolol is extensively used in the treatment of disorders such as hypertension and angina pectoris. The drug initially lowers cardiac output and increases peripheral resistance. In long term treatment, the latter variable returns towards its initial value and arterial pressure falls. The reason for the temporary increase in resistance is not known (Conway, 1975). Several mechanisms leading to the increased peripheral resistance can be envisaged. The blocking agent may remove a peripheral ~adrenergic influence, e.g. by eliminating the effects of circulating catecholamines (Johnson, 1975). Alternatively, the resistance increase can be reflexly induced, secondarily, to the hemodynamic changes due to the antiadrenergic effects on the heart. A third possibility is that the drug alters the sensitivity of cardiovascular proprioceptive reflexes by an action on the nervous system. Such an effect may, a priori, be exerted on the periph-
Cats
era] proprioceptive receptors, on peripheral nerve fibres involved in the reflexes or/and on the corresponding central neuron pools. Indeed, there is increasing evidence that ~adrenergic receptor blocking drugs exert central effects (Lewis, 1976). The present experiments were performed to further analyse the mechanisms behind the increase in peripheral resistance induced by propranolol. Interest has been focused on the resistance changes of a cross-circulated, innervated muscle region.
2. Materials and methods Cats of either sex, weighing 2.1--5.0 kg, were utilized in cross-circulation experiments. They were anesthetized with chloralose 50 rag/ kg i.v., following induction with ether. Tracheal cannulae were inserted. The carotids of the recipient were freed and placed on ligatures so that they could be occluded in the course of the experiment. Instead of this, in
276 s o m e e x p e r i m e n t s t h e c a r o t i d sinus regions were dissected free bilaterally and p e r f u s e d f r o m t h e f e m o r a l a r t e r y b y a t u b e and a Sigma m o t o r p u m p . T h e e x t e r n a l c a r o t i d arteries were c a n n u l a t e d and d r a i n e d into t h e right e x t e r n a l jugular vein. T h e c a n n u l a was supplied with an adjustable resistance so t h a t m e a n sinus pressure c o u l d be varied. T h e sinus pressure was m e a s u r e d via a side b r a n c h o f this t u b e b y a S t a t h a m P23 AC t r a n s d u c e r writing o n a Grass p o l y g r a p h . T h e recipient's vagi were cut in t h e n e c k in all e x p e r i m e n t s . T h e recipient's h i n d leg was skinned and t h e calf muscles were isolated b y division o f t h e muscles a b o v e t h e k n e e joint. A h o l e was drilled in t h e f e m u r and t h e b o n e m a r r o w plugged with c o t t o n s o a k e d in silicone grease. T h e paw was e x c l u d e d b y a tight ligature at t h e anke. T h e n , t h e f e m o r a l arteries and veins o f t h e t w o animals were c o n n e c t e d in such a way t h a t t h e d o n o r supplied t h e c i r c u l a t i o n o f t h e isolated calf p r e p a r a t i o n and t h u s the sciatic nerve f o r m e d t h e o n l y i n t a c t connect i o n b e t w e e n t h e calf and t h e recipient. T h e arterial pressure o f t h e d o n o r was m e a s u r e d f r o m a side b r a n c h o f t h e arterial t u b e b y a S t a t h a m P23 AC t r a n s d u c e r writing o n t h e p o l y g r a p h . V e n o u s o u t f l o w f r o m t h e calf was f o l l o w e d b y a d r o p r e c o r d e r c o u p l e d in series with t h e v e n o u s t u b i n g c o n n e c t i n g t h e calf with d o n o r . T h e closed optical d r o p r e c o r d e r device o p e r a t e d an o r d i n a t e writer, writing on t h e p o l y g r a p h . T h e weight o f t h e calf muscles was e s t i m a t e d t o 1.7% o f t h e b o d y w e i g h t (Kjellmer, 1 9 6 4 ) . R e c i p i e n t arterial pressure was m e a s u r e d in the brachial a r t e r y t h r o u g h a c a t h e t e r , conn e c t e d t o a S t a t h a m P23 AC t r a n s d u c e r . T h e electrically d a m p e n e d pressure, r e p r e s e n t i n g m e a n arterial b l o o d pressure, was r e c o r d e d o n a n o t h e r channel. H e a r t rate was o b t a i n e d b y a t a c h o g r a p h unit, triggered b y t h e arterial pulse. P r o p r a n o l o l ( c h l o r i d e 0.51mg/ml, ICI), c l o n i d i n e ( h y d r o c h l o r i d e 1 5 0 / z g / m l , Boehringet, Ingelheim), h e x a m e t h o n i u m (chloride 1 m g / m l ) were all dissolved in 0.9% saline and t h e doses are e x p r e s s e d in t e r m s o f t h e salts.
B. LISANDER, H. NILSSON T h e variables b e f o r e p r o p r a n o l o l and 15 min a f t e r t h e drug were c o m p a r e d b y a paired ttest.
3. R e s u l t s
In all e x p e r i m e n t s t h e calf muscles o f t h e r e c i p i e n t were cross-perfused f r o m a n o t h e r cat. T h e p a t e n c y o f t h e v a s o c o n s t r i c t o r fibre c o n n e c t i o n s was c h e c k e d t h r o u g h o u t , e i t h e r b y bilateral c o m m o n c a r o t i d occlusion or, in animals w i t h a sinus p r e p a r a t i o n , b y b a r y i n g t h e intrasinusoidal pressure. In 6 e x p e r i m e n t s t h e c a r o t i d sinuses were e x p o s e d t o t h e a m b i e n t arterial pressure. F o l l o w i n g p r o p r a n o l o l , 1 m g / k g i.v. t o t h e
TABLE 1 The cardiovascular variables in the control situation and 15 min after propranolol, 1 mg/kg, given i.v. to the recipient. BP = mean arterial pressure; HR = heart rate; AP=arterial pressure in the isolated calf muscles; MBFR = muscle blood flow resistance. Mean +_SD is given. No significant difference = n.s. Control
After drug
P-level
Carotid sinuses exposed to ambient arterial pressure
Recipient BP (mm Hg) Recipient HR (beats/rain) AP (ram Hg) MBFR (PRU100)
115 +_4.9 208 +_24.6 122.5 +_19.4 25.7 +3.9
100.8 +_34.0 161.7 +_20.2 128.3 _+24.8 29.5 +4.8
n.s. d0.01 n.s. ~0.05
Carotid sinuses artificially perfused
Recipient BP
(~Hg) Recipient HR (beats/rain) AP (ram Hg) MBFR (PRU100 ) Carotid sinus pressure (ram Hg)
110 +16.7 214.3 _+32.7 122.5 +18.1 22.9 +_5.2 114.2 +_34.4
92.5 +12.1 158.8 _+15.8 123.3 +_18.3 22.7 _+6.6 110.8 +_35.8
n.s. 0.90) n.s.
PROPRANOLOL, BAROREFLEXESAND MUSCLE BLOOD FLOW recipient, there was a decrease in recipient heart rate by about 47 beats/rain (P 0.90) (table 1). At the end of 8 experiments, clonidine, 10~g/kg i.v. was given to the recipient, causing a marked dilatation of the crossperfused bed. In 4 experiments hexamethonium (5 mg/kg, i.v.) was given instead, first to the donor and then to the recipient. In the latter, but n o t in the former case, the crossperfused vascular bed dilated markedly which indicates that the ganglia of the vasoconstrictor fibres to this region are not peripherally located.
4. Discussion Flow resistance in the skeletal muscle vascular bed is of great importance for the overall hemodynamics. At rest, this vascular bed, comprising 40--50% of total body mass, may receive about 15% of the cardiac output. It is the major effector organ for the baroreceptor reflexes and contains an easily mobilizable pool of interstitial fluid (Folkow and Neil, 1971). In some of the present experiments, the carotid baroreceptor stations of the recipient were exposed to the ambient arterial pressure. When propranolol 1 mg/kg i.v. was given to these animals, the flow resistance of the isolated, cross-perfused muscle vascular bed increased regularly; because of the cross-
277
circulation arrangement, this increase must have been entirely neurogenicalIy mediated. In this context, it should be noted that increased total peripheral resistance had been observed not only with propranolol but also during treatment with other ~-adrenergic blockers, such as the ~l-selective blocker metroprolol, with minimal antiadrenergic effects in the peripheral vasculature (Stenberg et al., 1975). As the vagi were cut in all recipients, the carotid sinus regions contained the only intact cardiovascular proprioceptors. In some cats, the latter were exposed to a constant transmural pressure during propranolol administration. In this situation, no change in muscle flow resistance was observed. This finding excludes that a change in the sensitivity of the carotid sinus baroreceptor reflex was the cause of the resistance increase in the cats where sinus pressure was not held constant. On the other hand, Sleight et al. (1971) have suggested that propranolol caused an enhancement of the reflex bradycardia response to an arterial pressure increase. It should be emphasized, however, that in the latter experiments, the reflex responses were in all likelihood induced from a multitude of receptor stations in the vessels and the heart. Furthermore, the reflex effector organs, the heart and the vessels, were also exposed to the drug and hence peripheral effects of the drug may have caused the observed changes in the reflex responses. Not all sympathetic fibres are accessible to baroreceptor control (Taylor and Gebber, 1973). Therefore, it is a priori conceivable that the drug may alter sympathetic tone by a central nervous point of action, without influencing the sensitivity of the baroreceptor reflex. There is increasing evidence that ~adrenergic blocking agents may change the activity of central "cardiovascular" neurons (Lewis, 1976). In both cats and rabbits the blood pressure response to intracerebroventricular propranolol is biphasic, with an initial transient rise before a long-lasting blood pressure fall (Lewis, 1976). Therefore, a central
278
nervous effect of propranolol must also be considered with respect to the initial increase in peripheral resistance observed in the present experiments. However, the absence of this latter p h e n o m e n o n in the cats where carotid sinus pressure was kept constant seems to rule o u t this possibility. The present data indicate that an altered activation of the carotid baroreceptors was the cause of the observed increase in muscle flow resistance. It may be assumed that the slightly lowered mean arterial pressure (n.s.), the reduced heart rate (P < 0.01) and, possibly, decreased cardiac inotropy, may together cause a decreased activation of the baroreceptors. Neurophysiological studies of impulse activity in baroreceptor afferents show a burst of impulses during the rapid systolic rise of arterial b l o o d pressure. This activity ceases more or less completely during diastole, provided the mean arterial pressure is not very high. The number of impulses in each systolic burst is dependent on the magnitude and the rate of blood pressure change which in turn is determined b y stroke volume and inotropy (Kirchheim, 1976). Therefore, the total number of inhibitory impulses reaching the vasomotor centre from the baroreceptors is a function of mean arterial pressure as well as of pulse rate, pulsation amplitude and rate of rise in pulse pressure. Extrapolation of the present data from anesthetized, vagotomized cats to the clinical situation in humans should be made with caution. However, following i.v. propranolol in man, there is an unchanged mean arterial pressure and a decreased heart rate, stroke volume and cardiac inotropy (Robin et al., 1967). These changes seem sufficient to cause a parallel, baroreceptor-mediated, increase in total peripheral resistance and in muscle flow resistance. It also deserves mention that during long term treatment the peripheral
B. LISANDER, H. NILSSON
vascular beds have been postulated to gradually "autoregulate" their resistance in accordance with the metabolic demands o f the tissues in the face of an unchanged cardiac o u t p u t and thereby to cause a secondary decrease in mean arterial pressure (cf. Lewis, 1976).
Acknowledgement This work was supported by a grant from the Swedish Medical Research Council (14X-4249).
References Conway, J., 1975,/3-Adrenergic blockade and hypertension, in: Modern Trends in Cardiology, Vol. 3, ed. M.F. Oliver (Butterworth's, London, Boston) p. 376. Folkow, B. and E. Nell, 1971, Circulation (Oxford University Press, New York, London, Toronto). Johnson, G., 1975, Influence of metoprolol and propranolol on hemodynamic effects induced by adrenaline and physical work, Acta Pharmacol. Toxicol. 36, Suppl. V, 59. Kirchheim, H.R., 1976, Systemic arterial baroreceptor reflexes, Physiol. Rev. 56, 100. Kjellmer, I., 1964, The effect of exercise on the vascular bed of skeletal muscle, Acta Physiol. Scand. 62, 18. Lewis, P., 1976, The essential action of propranolol in hypertension, Amer. J. Med. 60, 837. Robin, E., C. Cowan, P. Purl, S. Ganguly, E. De Boyrie, M. Martinez, T. Stock and R.J. Bing, 1967, A comparative study of nitroglycerin and propranolol, Circulation 36, 175. Sleight, P., B. Gribbin and T.G. Pickering, 1971, Baroreflex sensitivity in normal and hypertensive man: the effect of beta adrenergic blockade on reflex sensitivity, Postgrad. Med. J. 32, 79. Stenberg, J., H. Wasir, A. Amery, R. Sannerstedt and L. WerkS, 1975, Comparative hemodynamic studies in man of adrenergic ~l-receptor agents without (H 93/26 = metroprolol) or with (H 87/ 07) intrinsic sympathomimetic activity, Acta Pharmacol. Toxicol. 36, Suppl. V, 76. Taylor, D.G. and G.L. Gebber, 1973, Sympathetic unit responses to stimulation of cat medulla, Amer. J. Physiol. 225, 1138.
275
© Elsevier/North-Holland Biomedical Press
Short communication BARORECEPTOR-INDUCED DECREASE IN MUSCLE BLOOD FLOW UPON PROPRANOLOL ADMINISTRATION BJORN LISANDER and HOLGER NILSSON
Department o f Physiology, University o f G~teborg, 400 33 G~teborg, Sweden Received 31 May 1978, accepted 7 June 1978
B. LISANDER and H. NILSSON, Baroreceptor-induced decrease in muscle blood flow upon propranolol administration, European J. Pharmacol. 50 (1978) 275--278. The acute effects of propranolol, 1 mg/kg i.v., were studied in chloralosed, vagotomized cats. The vascularly isolated but innervated calf muscles were perfuscd from another animal. In one group of experiments, the carotid baroreceptors were exposed to ambient arterial pressure. Here, propranolol caused a fall in heart rate and an increase in resistance of the isolated muscle bed. In other experiments, the carotid sinuses were perfused at a constant pressure. In these animals, no increase in muscle flow resistance was observed after the drug. It is concluded that the increase in total peripheral resistance, seen initially upon propranolol administration, may be reflexly induced via the baroreceptors. Propranolol
Muscle blood flow
Baroceptor reflexes
1. Introduction The ~-adrenergic blocking agent propranolol is extensively used in the treatment of disorders such as hypertension and angina pectoris. The drug initially lowers cardiac output and increases peripheral resistance. In long term treatment, the latter variable returns towards its initial value and arterial pressure falls. The reason for the temporary increase in resistance is not known (Conway, 1975). Several mechanisms leading to the increased peripheral resistance can be envisaged. The blocking agent may remove a peripheral ~adrenergic influence, e.g. by eliminating the effects of circulating catecholamines (Johnson, 1975). Alternatively, the resistance increase can be reflexly induced, secondarily, to the hemodynamic changes due to the antiadrenergic effects on the heart. A third possibility is that the drug alters the sensitivity of cardiovascular proprioceptive reflexes by an action on the nervous system. Such an effect may, a priori, be exerted on the periph-
Cats
era] proprioceptive receptors, on peripheral nerve fibres involved in the reflexes or/and on the corresponding central neuron pools. Indeed, there is increasing evidence that ~adrenergic receptor blocking drugs exert central effects (Lewis, 1976). The present experiments were performed to further analyse the mechanisms behind the increase in peripheral resistance induced by propranolol. Interest has been focused on the resistance changes of a cross-circulated, innervated muscle region.
2. Materials and methods Cats of either sex, weighing 2.1--5.0 kg, were utilized in cross-circulation experiments. They were anesthetized with chloralose 50 rag/ kg i.v., following induction with ether. Tracheal cannulae were inserted. The carotids of the recipient were freed and placed on ligatures so that they could be occluded in the course of the experiment. Instead of this, in
276 s o m e e x p e r i m e n t s t h e c a r o t i d sinus regions were dissected free bilaterally and p e r f u s e d f r o m t h e f e m o r a l a r t e r y b y a t u b e and a Sigma m o t o r p u m p . T h e e x t e r n a l c a r o t i d arteries were c a n n u l a t e d and d r a i n e d into t h e right e x t e r n a l jugular vein. T h e c a n n u l a was supplied with an adjustable resistance so t h a t m e a n sinus pressure c o u l d be varied. T h e sinus pressure was m e a s u r e d via a side b r a n c h o f this t u b e b y a S t a t h a m P23 AC t r a n s d u c e r writing o n a Grass p o l y g r a p h . T h e recipient's vagi were cut in t h e n e c k in all e x p e r i m e n t s . T h e recipient's h i n d leg was skinned and t h e calf muscles were isolated b y division o f t h e muscles a b o v e t h e k n e e joint. A h o l e was drilled in t h e f e m u r and t h e b o n e m a r r o w plugged with c o t t o n s o a k e d in silicone grease. T h e paw was e x c l u d e d b y a tight ligature at t h e anke. T h e n , t h e f e m o r a l arteries and veins o f t h e t w o animals were c o n n e c t e d in such a way t h a t t h e d o n o r supplied t h e c i r c u l a t i o n o f t h e isolated calf p r e p a r a t i o n and t h u s the sciatic nerve f o r m e d t h e o n l y i n t a c t connect i o n b e t w e e n t h e calf and t h e recipient. T h e arterial pressure o f t h e d o n o r was m e a s u r e d f r o m a side b r a n c h o f t h e arterial t u b e b y a S t a t h a m P23 AC t r a n s d u c e r writing o n t h e p o l y g r a p h . V e n o u s o u t f l o w f r o m t h e calf was f o l l o w e d b y a d r o p r e c o r d e r c o u p l e d in series with t h e v e n o u s t u b i n g c o n n e c t i n g t h e calf with d o n o r . T h e closed optical d r o p r e c o r d e r device o p e r a t e d an o r d i n a t e writer, writing on t h e p o l y g r a p h . T h e weight o f t h e calf muscles was e s t i m a t e d t o 1.7% o f t h e b o d y w e i g h t (Kjellmer, 1 9 6 4 ) . R e c i p i e n t arterial pressure was m e a s u r e d in the brachial a r t e r y t h r o u g h a c a t h e t e r , conn e c t e d t o a S t a t h a m P23 AC t r a n s d u c e r . T h e electrically d a m p e n e d pressure, r e p r e s e n t i n g m e a n arterial b l o o d pressure, was r e c o r d e d o n a n o t h e r channel. H e a r t rate was o b t a i n e d b y a t a c h o g r a p h unit, triggered b y t h e arterial pulse. P r o p r a n o l o l ( c h l o r i d e 0.51mg/ml, ICI), c l o n i d i n e ( h y d r o c h l o r i d e 1 5 0 / z g / m l , Boehringet, Ingelheim), h e x a m e t h o n i u m (chloride 1 m g / m l ) were all dissolved in 0.9% saline and t h e doses are e x p r e s s e d in t e r m s o f t h e salts.
B. LISANDER, H. NILSSON T h e variables b e f o r e p r o p r a n o l o l and 15 min a f t e r t h e drug were c o m p a r e d b y a paired ttest.
3. R e s u l t s
In all e x p e r i m e n t s t h e calf muscles o f t h e r e c i p i e n t were cross-perfused f r o m a n o t h e r cat. T h e p a t e n c y o f t h e v a s o c o n s t r i c t o r fibre c o n n e c t i o n s was c h e c k e d t h r o u g h o u t , e i t h e r b y bilateral c o m m o n c a r o t i d occlusion or, in animals w i t h a sinus p r e p a r a t i o n , b y b a r y i n g t h e intrasinusoidal pressure. In 6 e x p e r i m e n t s t h e c a r o t i d sinuses were e x p o s e d t o t h e a m b i e n t arterial pressure. F o l l o w i n g p r o p r a n o l o l , 1 m g / k g i.v. t o t h e
TABLE 1 The cardiovascular variables in the control situation and 15 min after propranolol, 1 mg/kg, given i.v. to the recipient. BP = mean arterial pressure; HR = heart rate; AP=arterial pressure in the isolated calf muscles; MBFR = muscle blood flow resistance. Mean +_SD is given. No significant difference = n.s. Control
After drug
P-level
Carotid sinuses exposed to ambient arterial pressure
Recipient BP (mm Hg) Recipient HR (beats/rain) AP (ram Hg) MBFR (PRU100)
115 +_4.9 208 +_24.6 122.5 +_19.4 25.7 +3.9
100.8 +_34.0 161.7 +_20.2 128.3 _+24.8 29.5 +4.8
n.s. d0.01 n.s. ~0.05
Carotid sinuses artificially perfused
Recipient BP
(~Hg) Recipient HR (beats/rain) AP (ram Hg) MBFR (PRU100 ) Carotid sinus pressure (ram Hg)
110 +16.7 214.3 _+32.7 122.5 +18.1 22.9 +_5.2 114.2 +_34.4
92.5 +12.1 158.8 _+15.8 123.3 +_18.3 22.7 _+6.6 110.8 +_35.8
n.s. 0.90) n.s.
PROPRANOLOL, BAROREFLEXESAND MUSCLE BLOOD FLOW recipient, there was a decrease in recipient heart rate by about 47 beats/rain (P 0.90) (table 1). At the end of 8 experiments, clonidine, 10~g/kg i.v. was given to the recipient, causing a marked dilatation of the crossperfused bed. In 4 experiments hexamethonium (5 mg/kg, i.v.) was given instead, first to the donor and then to the recipient. In the latter, but n o t in the former case, the crossperfused vascular bed dilated markedly which indicates that the ganglia of the vasoconstrictor fibres to this region are not peripherally located.
4. Discussion Flow resistance in the skeletal muscle vascular bed is of great importance for the overall hemodynamics. At rest, this vascular bed, comprising 40--50% of total body mass, may receive about 15% of the cardiac output. It is the major effector organ for the baroreceptor reflexes and contains an easily mobilizable pool of interstitial fluid (Folkow and Neil, 1971). In some of the present experiments, the carotid baroreceptor stations of the recipient were exposed to the ambient arterial pressure. When propranolol 1 mg/kg i.v. was given to these animals, the flow resistance of the isolated, cross-perfused muscle vascular bed increased regularly; because of the cross-
277
circulation arrangement, this increase must have been entirely neurogenicalIy mediated. In this context, it should be noted that increased total peripheral resistance had been observed not only with propranolol but also during treatment with other ~-adrenergic blockers, such as the ~l-selective blocker metroprolol, with minimal antiadrenergic effects in the peripheral vasculature (Stenberg et al., 1975). As the vagi were cut in all recipients, the carotid sinus regions contained the only intact cardiovascular proprioceptors. In some cats, the latter were exposed to a constant transmural pressure during propranolol administration. In this situation, no change in muscle flow resistance was observed. This finding excludes that a change in the sensitivity of the carotid sinus baroreceptor reflex was the cause of the resistance increase in the cats where sinus pressure was not held constant. On the other hand, Sleight et al. (1971) have suggested that propranolol caused an enhancement of the reflex bradycardia response to an arterial pressure increase. It should be emphasized, however, that in the latter experiments, the reflex responses were in all likelihood induced from a multitude of receptor stations in the vessels and the heart. Furthermore, the reflex effector organs, the heart and the vessels, were also exposed to the drug and hence peripheral effects of the drug may have caused the observed changes in the reflex responses. Not all sympathetic fibres are accessible to baroreceptor control (Taylor and Gebber, 1973). Therefore, it is a priori conceivable that the drug may alter sympathetic tone by a central nervous point of action, without influencing the sensitivity of the baroreceptor reflex. There is increasing evidence that ~adrenergic blocking agents may change the activity of central "cardiovascular" neurons (Lewis, 1976). In both cats and rabbits the blood pressure response to intracerebroventricular propranolol is biphasic, with an initial transient rise before a long-lasting blood pressure fall (Lewis, 1976). Therefore, a central
278
nervous effect of propranolol must also be considered with respect to the initial increase in peripheral resistance observed in the present experiments. However, the absence of this latter p h e n o m e n o n in the cats where carotid sinus pressure was kept constant seems to rule o u t this possibility. The present data indicate that an altered activation of the carotid baroreceptors was the cause of the observed increase in muscle flow resistance. It may be assumed that the slightly lowered mean arterial pressure (n.s.), the reduced heart rate (P < 0.01) and, possibly, decreased cardiac inotropy, may together cause a decreased activation of the baroreceptors. Neurophysiological studies of impulse activity in baroreceptor afferents show a burst of impulses during the rapid systolic rise of arterial b l o o d pressure. This activity ceases more or less completely during diastole, provided the mean arterial pressure is not very high. The number of impulses in each systolic burst is dependent on the magnitude and the rate of blood pressure change which in turn is determined b y stroke volume and inotropy (Kirchheim, 1976). Therefore, the total number of inhibitory impulses reaching the vasomotor centre from the baroreceptors is a function of mean arterial pressure as well as of pulse rate, pulsation amplitude and rate of rise in pulse pressure. Extrapolation of the present data from anesthetized, vagotomized cats to the clinical situation in humans should be made with caution. However, following i.v. propranolol in man, there is an unchanged mean arterial pressure and a decreased heart rate, stroke volume and cardiac inotropy (Robin et al., 1967). These changes seem sufficient to cause a parallel, baroreceptor-mediated, increase in total peripheral resistance and in muscle flow resistance. It also deserves mention that during long term treatment the peripheral
B. LISANDER, H. NILSSON
vascular beds have been postulated to gradually "autoregulate" their resistance in accordance with the metabolic demands o f the tissues in the face of an unchanged cardiac o u t p u t and thereby to cause a secondary decrease in mean arterial pressure (cf. Lewis, 1976).
Acknowledgement This work was supported by a grant from the Swedish Medical Research Council (14X-4249).
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