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Naloxone effects on the blood pressure response induced by thin-fiber muscular afferents
452
Brain Research, 205 (1981)452 456 i~! Elsevier/North-Holland Biomedical Press
Naloxone effects on the blood pressure response induced by thin-fiber muscular afferents
T. KUMAZAWA, E. TADAKI and K. KIM
Department of Physiology, Nagoya University School o]'Medicine, Showa-ku, Nagoya 466 (Japan) (Accepted September 4th, 1980)
Key words: muscular afferent A~ fiber - - C fiber opiates naloxone
blood pressure response - - endogenous
Naloxone effects on the blood pressure level and on the blood pressure responses induced by thin-fiber muscular afferent stimulation were studied in anesthetized, bilaterally vagotomized and carotid sinus nerve-denervated dogs under artificial ventilation. Repetitive pulses of 8 Hz with various intensities were applied to the gastrocnemius nerve for 1 rain while monitoring the compound action potentials. The mean arterial pressure significantly (P - 0.001) rose by 10.95 ~ 1.78 mmHg (mean ~: S.E.) about 5 rain after a naloxone injection. Compared with the reflexive response in the control period, the depressor effect significantly decreased by 3.80 :~:: 1.06 mmHg, and the pressor effect significantly increased by 3.63 _+ 0.73 mmHg for 30 rain after the injection of naloxone. No correlation was found between naloxone effects on the blood pressure level and on the reflex response, indicating an involvement of different mechanisms with these naloxone effects. We suggest that endogenous opiates might participate in the regulation of the blood pressure level, as well as of the blood pressure responses caused by thin-fiber muscular afferents. Cardiovascular reflexes caused by afferents from excercising muscles have been reported in m a n and in the experimental animaU,:3,1v,'~°. Thin-fiber muscular afferents are most likely responsible for these cardiovascular reflexes as well as simultaneously occurring respiratory responsesg,11,17,19, "°. Our previous observations d e m o n s t r a t e d that the majority of thin-fiber muscular afferents originated from the polymodal receptor12,13. C o m p a r i s o n of the effects of chemical stimulation of the muscle on the unitary discharges of muscular polymodal receptors and those on reflexive respiratory responses to the same stimulus, highly suggested that the polymodal receptor played a role in the respiratory responses caused by muscular afferents 18. Recently, it has been proved that endogenous opiates participate in the reflexive respiratory responses caused by thin-fiber muscular afferents 15. The present paper reports the effects of naloxone on the blood pressure responses caused by thin-fiber muscular afferents. The experiments were performed on 15 mongrel dogs, anesthetized initially with chloralose (35 mg/kg) and urethane (250 mg/kg). Subsequent doses were added to m a i n t a i n the state of anesthesia without active movements, and after paralysing the animal, the same doses were continuously infused. The mean arterial pressure was recorded from the left c o m m o n carotid artery. The right carotid sinus nerve and both
453
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-30
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50 /xmmHg
Control
Fig. 1. Naloxone effects on blood pressure responses induced by thin-fiber muscular afferents. Means of 'min' (©) and 'max' (O) (see insets) following naloxone (ordinate) in each experimental series are plotted against those of the control (abscissa). Note the great majority of the plots lie above the 45° line. vagi were cut. The trachea was cannulated and end-tidal COz and 02 were monitored by a gas analyzer (San-ei Sokki). The mean end-tidal COz was 5.0 ~ , and in one experimental series, fluctuation of the end-tidal CO2 was kept within 0.1 ~ by adjusting the ventilation volume. The esophageal temperature was monitored and its fluctuation was kept within 0.2 °C. The right gastrocnemius nerve was isolated and cut close to the muscle. The distal end of the nerve was stimulated, while compound action potentials were monitored at the proximal part of the nerve in an oil pool. The strength of electrical stimulation was set at multiples of the threshold (T) of the nerve. In one experimental series, the stimulation with intensities of 20, 50, 100, 200 and 400 (T) and with the repetition rate of 8 Hz was applied for 1 rain two or three times with an interval of 10 min before (control) as well as 30 min following naloxone administration. Since the same stimulus caused a marked change in respiration la, the animal was paralyzed and artificially ventilated before stimulation started to avoid effects secondary to the respiratory changes. Naloxone (0.1-2.0 mg/kg) was injected i.v. The mean arterial pressure rose consistently and showed a peak value at about 5 rain after naloxone injection. Since neither the effects of naloxone on the blood pressure level nor those on the reflexive response were dose-dependent, the data with different doses of naloxone were treated together in the following statistical analysis. The mean of rise in blood pressure level 5 min after
454 naloxone injection was 10.95 ± 1.78 mmHg (mean i S.E.), being statistically significant (P < 0.001). Stimulation of muscular afferents above A-b fiber threshold usually caused an initial depressor effect, followed by a pressor effect of various degrees depending on both the intensity and frequency of the stimulus and the state of the animal 14. The minimum and maximum mean arterial pressure during the stimulation period were measured, and as shown in the inset of Fig. 1 the difference between each value thus measured and the prestimulus mean arterial pressure was used as a tentative indication of the depressor and pressor effect respectively. Compared with the responses in the control, the average of the depressor effect significantly (P < 0.005) decreased by 3.80 -q- 1.06 mmHg and that of the pressor effect significantly (P < 0.005) increased by 3.63 ± 0.73 mm Hg (mean ~ S.E.) during 30 min after naloxone. In Fig. 1 the means of the depressor and pressor effects during 30 min after naloxone are plotted against those in the control period of each experimental series. The great majority of these plots are found above the 45 ° line of the figure, indicating a deviation of the response to pressor effect following naloxone. zxmmHg
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Fig. 2. No correlation between naloxone effects on the blood pressure level and on the reflex response. The differences of the mean of 'min' and 'max' values between after naloxone and in the control are plotted against the change of blood pressure 5 rain after naloxone in each experimental series. No correlation was found between them (r: 0.067 shown in the bottom).
455 Thus, naloxone caused a significant rise o f blood pressure level as well as a significant deviation o f pressor effect in the reflexive blood pressure response. However, as shown in Fig. 2, no correlation was found between the former and the latter. Different mechanisms are presumed for the naloxone effects on the regulation of the blood pressure level and on the blood pressure response caused by muscular afferents. Depressant actions o f morphine on respiration and circulation have been well known. Recently it has been reported that externally applied endorphins and their derivatives cause cardiovascular changes which are reversed by naloxone 2,~,7,m, indicating that opioid peptides can play a role in central cardiovascular control. The present findings that naloxone causes a significant rise of blood pressure level and a significant shift o f pressor effect in reflexive blood pressure response elicited by thin-fiber muscular afferents, further confirm an involvement o f endogenous opiates in cardiovascular control. D a s h w o o d and Feldberg 4 reported that a pressor response to naloxone was obtained only when afferent visceral inputs were reduced by bilateral v a g o t o m y and other procedures, and they threw doubts on the release o f endogenous opiates by afferent stimulation. Alternatively, their results may be interpreted reversely by presuming that the larger a m o u n t of endogenous opiates is released following the more invasive procedures used for deafferentation. The latter explanation might be conceivable in taking account o f the facts that an acute stress, like experimental bone fracture, causes a simultaneous increase in plasma levels o f fl-endorphin and A C T H 8 and that naloxone antagonizes hypotension in shock statesS, lo. We are grateful to E n d o Laboratories for a gift ofnaloxone. This work was partly supported by The Naito Research G r a n t for 1979.
1 Alam, M. and Smirk, F. H., Observation in man upon a blood pressure raising reflex arising from the voluntary muscle, J. Physiol. (Lond.), 89 (1937) 372-383. 2 Bolme, P., Fuxe, K., Agnati, L. F., Bradley, R. and Smythies, J., Cardiovascular effects of morphine and opioid peptides following intracisternal administration in chloralose-anesthetized rats, Europ. J. Pharmacol., 48 (1978) 319-324. 3 Coote, J. H., Hilton, S. M. and Perez-Gonzalez, J. F., The reflex nature of the pressor response to muscular excercise, J. Physiol. (Lond.), 215 (1971) 789-804. 4 Dashwood, M. R. and Feldberg, W., A pressor response to naloxone. Evidence for release of endogenous opioid peptides, J. Physiol. (Lond.), 281 (1978) 30-31 p. 5 Faden, A. I. and Holaday, J. W., Opiate antagonists: a role in the treatment of hypovolemic shock, Science, 205 (1979) 317-318 p. 6 Feldberg, W. and Wei, E., Central cardiovascular effects of enkephalins and C-fragment of lipotropin, J. Physiol. (Lond.), 280 (1978) 18. 7 Fl6rez, J. and Mediavilla, A., Respiratory and cardiovascular effects of Met-enkephalin applied to the ventral surface of the brain stem, Brain Research, 138 (1977) 585-590. 8 Guillemin, R., Vargo, T., Rossier, J., Minick, S., Ling, N., Rivier, C., Vale, W. and Bloom, F., fl-endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland, Science, 197 (1977) 1367-1369. 9 Hodgson, H. J.F. and Matthews, P. B. C., The ineffectiveness of excitation of the primary endings of the muscle spindle by vibration as a respiratory stimulant in the decerebrate cat, J. Physiol. (Lond.,), 194 (1968) 555-563. 10 Holaday, J. W. and Faden, A. I., Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock, Nature (Lond.), 275 (1978) 450-451.
456 11 Kalia, M., Senapati, J. M., Parida, B. and Panda, A., Reflex increase in ventilation by muscle receptors with non-medullated fibers (C fibers), J. appl. Physiol., 32 (1972) 189-193. 12 Kumazawa, T. and Mizumura, K., The polymodal C-fiber receptor in the muscle of the dog, Brain Research, 101 (1976) 589-593. 13 Kumazawa, T. and Mizumura, K., Thin-fibre receptors responding to mechanical, chemical, and thermal stimulation in the skeletal muscle of the dog, J. Physiol. (Lond.), 273 (1977) 179-194. 14 Kumazawa, T., Mizumura, K., Tadaki, E. and Kim, K., Depressor and pressor responses produced by the muscular thin-fiber afferents. In M. lto (Ed.), Integrative Control Functions of the Brain, Kodansha, Tokyo, 1978, pp. 242-243. 15 Kumazawa, T., Tadaki, E. and Kim, K., A possible participation of endogenous opiates in respiratory reflexes induced by thin-fiber muscular afferents, Brain Research, 199 (1980) 244-248. 16 Laubie, M., Schmitt, H., Vincent, M. and Remond, G., Central cardiovascular effects of morphinomimetic peptides in dogs, Europ. J. Pharmacol., 46 (1977) 67-71. 17 McCloskey, D. I. and Mitchell, J. H., Reflex cardiovascular and respiratory responses originating in excercising muscle, J. Physiol. (Lond.), 224 (1972) 173-186. 18 Mizumura, K. and Kumazawa, T., Reflex respiratory response induced by chemical stimulation of muscle afferents, Brain Research, 109 (1976) 402406. 19 Perez-Gonzalez, J. F. and Coote, J. H., Activity of muscle afferents and reflex circulatory responses to exercise, Amer. J. Physiol., 223 (1972) 138-143. 20 Tibes, U., Reflex inputs to cardiovascular and respiratory centers from dynamically working canine muscles: some evidence for involvement of group 1II or IV nerve fibers, Circulat. Res., 41 (1977) 332-341.
Brain Research, 205 (1981)452 456 i~! Elsevier/North-Holland Biomedical Press
Naloxone effects on the blood pressure response induced by thin-fiber muscular afferents
T. KUMAZAWA, E. TADAKI and K. KIM
Department of Physiology, Nagoya University School o]'Medicine, Showa-ku, Nagoya 466 (Japan) (Accepted September 4th, 1980)
Key words: muscular afferent A~ fiber - - C fiber opiates naloxone
blood pressure response - - endogenous
Naloxone effects on the blood pressure level and on the blood pressure responses induced by thin-fiber muscular afferent stimulation were studied in anesthetized, bilaterally vagotomized and carotid sinus nerve-denervated dogs under artificial ventilation. Repetitive pulses of 8 Hz with various intensities were applied to the gastrocnemius nerve for 1 rain while monitoring the compound action potentials. The mean arterial pressure significantly (P - 0.001) rose by 10.95 ~ 1.78 mmHg (mean ~: S.E.) about 5 rain after a naloxone injection. Compared with the reflexive response in the control period, the depressor effect significantly decreased by 3.80 :~:: 1.06 mmHg, and the pressor effect significantly increased by 3.63 _+ 0.73 mmHg for 30 rain after the injection of naloxone. No correlation was found between naloxone effects on the blood pressure level and on the reflex response, indicating an involvement of different mechanisms with these naloxone effects. We suggest that endogenous opiates might participate in the regulation of the blood pressure level, as well as of the blood pressure responses caused by thin-fiber muscular afferents. Cardiovascular reflexes caused by afferents from excercising muscles have been reported in m a n and in the experimental animaU,:3,1v,'~°. Thin-fiber muscular afferents are most likely responsible for these cardiovascular reflexes as well as simultaneously occurring respiratory responsesg,11,17,19, "°. Our previous observations d e m o n s t r a t e d that the majority of thin-fiber muscular afferents originated from the polymodal receptor12,13. C o m p a r i s o n of the effects of chemical stimulation of the muscle on the unitary discharges of muscular polymodal receptors and those on reflexive respiratory responses to the same stimulus, highly suggested that the polymodal receptor played a role in the respiratory responses caused by muscular afferents 18. Recently, it has been proved that endogenous opiates participate in the reflexive respiratory responses caused by thin-fiber muscular afferents 15. The present paper reports the effects of naloxone on the blood pressure responses caused by thin-fiber muscular afferents. The experiments were performed on 15 mongrel dogs, anesthetized initially with chloralose (35 mg/kg) and urethane (250 mg/kg). Subsequent doses were added to m a i n t a i n the state of anesthesia without active movements, and after paralysing the animal, the same doses were continuously infused. The mean arterial pressure was recorded from the left c o m m o n carotid artery. The right carotid sinus nerve and both
453
Q
AmmHg I
• •
30
20
I0
•
000 j
o~ o
°
Z -I0
-20
o
s2"
-30
/
I -40
-30
-20
-I0
0
tO
gO
:50
40
50 /xmmHg
Control
Fig. 1. Naloxone effects on blood pressure responses induced by thin-fiber muscular afferents. Means of 'min' (©) and 'max' (O) (see insets) following naloxone (ordinate) in each experimental series are plotted against those of the control (abscissa). Note the great majority of the plots lie above the 45° line. vagi were cut. The trachea was cannulated and end-tidal COz and 02 were monitored by a gas analyzer (San-ei Sokki). The mean end-tidal COz was 5.0 ~ , and in one experimental series, fluctuation of the end-tidal CO2 was kept within 0.1 ~ by adjusting the ventilation volume. The esophageal temperature was monitored and its fluctuation was kept within 0.2 °C. The right gastrocnemius nerve was isolated and cut close to the muscle. The distal end of the nerve was stimulated, while compound action potentials were monitored at the proximal part of the nerve in an oil pool. The strength of electrical stimulation was set at multiples of the threshold (T) of the nerve. In one experimental series, the stimulation with intensities of 20, 50, 100, 200 and 400 (T) and with the repetition rate of 8 Hz was applied for 1 rain two or three times with an interval of 10 min before (control) as well as 30 min following naloxone administration. Since the same stimulus caused a marked change in respiration la, the animal was paralyzed and artificially ventilated before stimulation started to avoid effects secondary to the respiratory changes. Naloxone (0.1-2.0 mg/kg) was injected i.v. The mean arterial pressure rose consistently and showed a peak value at about 5 rain after naloxone injection. Since neither the effects of naloxone on the blood pressure level nor those on the reflexive response were dose-dependent, the data with different doses of naloxone were treated together in the following statistical analysis. The mean of rise in blood pressure level 5 min after
454 naloxone injection was 10.95 ± 1.78 mmHg (mean i S.E.), being statistically significant (P < 0.001). Stimulation of muscular afferents above A-b fiber threshold usually caused an initial depressor effect, followed by a pressor effect of various degrees depending on both the intensity and frequency of the stimulus and the state of the animal 14. The minimum and maximum mean arterial pressure during the stimulation period were measured, and as shown in the inset of Fig. 1 the difference between each value thus measured and the prestimulus mean arterial pressure was used as a tentative indication of the depressor and pressor effect respectively. Compared with the responses in the control, the average of the depressor effect significantly (P < 0.005) decreased by 3.80 -q- 1.06 mmHg and that of the pressor effect significantly (P < 0.005) increased by 3.63 ± 0.73 mm Hg (mean ~ S.E.) during 30 min after naloxone. In Fig. 1 the means of the depressor and pressor effects during 30 min after naloxone are plotted against those in the control period of each experimental series. The great majority of these plots are found above the 45 ° line of the figure, indicating a deviation of the response to pressor effect following naloxone. zxmmHg
0 . , . nlin
0"" INGX +20
+10
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OQ
0
0
•
•
•
0
•
o
o Q
-I0 r - 0.067 Y-O.O417x +
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3.2832
+20
+30
,ammHG
Fig. 2. No correlation between naloxone effects on the blood pressure level and on the reflex response. The differences of the mean of 'min' and 'max' values between after naloxone and in the control are plotted against the change of blood pressure 5 rain after naloxone in each experimental series. No correlation was found between them (r: 0.067 shown in the bottom).
455 Thus, naloxone caused a significant rise o f blood pressure level as well as a significant deviation o f pressor effect in the reflexive blood pressure response. However, as shown in Fig. 2, no correlation was found between the former and the latter. Different mechanisms are presumed for the naloxone effects on the regulation of the blood pressure level and on the blood pressure response caused by muscular afferents. Depressant actions o f morphine on respiration and circulation have been well known. Recently it has been reported that externally applied endorphins and their derivatives cause cardiovascular changes which are reversed by naloxone 2,~,7,m, indicating that opioid peptides can play a role in central cardiovascular control. The present findings that naloxone causes a significant rise of blood pressure level and a significant shift o f pressor effect in reflexive blood pressure response elicited by thin-fiber muscular afferents, further confirm an involvement o f endogenous opiates in cardiovascular control. D a s h w o o d and Feldberg 4 reported that a pressor response to naloxone was obtained only when afferent visceral inputs were reduced by bilateral v a g o t o m y and other procedures, and they threw doubts on the release o f endogenous opiates by afferent stimulation. Alternatively, their results may be interpreted reversely by presuming that the larger a m o u n t of endogenous opiates is released following the more invasive procedures used for deafferentation. The latter explanation might be conceivable in taking account o f the facts that an acute stress, like experimental bone fracture, causes a simultaneous increase in plasma levels o f fl-endorphin and A C T H 8 and that naloxone antagonizes hypotension in shock statesS, lo. We are grateful to E n d o Laboratories for a gift ofnaloxone. This work was partly supported by The Naito Research G r a n t for 1979.
1 Alam, M. and Smirk, F. H., Observation in man upon a blood pressure raising reflex arising from the voluntary muscle, J. Physiol. (Lond.), 89 (1937) 372-383. 2 Bolme, P., Fuxe, K., Agnati, L. F., Bradley, R. and Smythies, J., Cardiovascular effects of morphine and opioid peptides following intracisternal administration in chloralose-anesthetized rats, Europ. J. Pharmacol., 48 (1978) 319-324. 3 Coote, J. H., Hilton, S. M. and Perez-Gonzalez, J. F., The reflex nature of the pressor response to muscular excercise, J. Physiol. (Lond.), 215 (1971) 789-804. 4 Dashwood, M. R. and Feldberg, W., A pressor response to naloxone. Evidence for release of endogenous opioid peptides, J. Physiol. (Lond.), 281 (1978) 30-31 p. 5 Faden, A. I. and Holaday, J. W., Opiate antagonists: a role in the treatment of hypovolemic shock, Science, 205 (1979) 317-318 p. 6 Feldberg, W. and Wei, E., Central cardiovascular effects of enkephalins and C-fragment of lipotropin, J. Physiol. (Lond.), 280 (1978) 18. 7 Fl6rez, J. and Mediavilla, A., Respiratory and cardiovascular effects of Met-enkephalin applied to the ventral surface of the brain stem, Brain Research, 138 (1977) 585-590. 8 Guillemin, R., Vargo, T., Rossier, J., Minick, S., Ling, N., Rivier, C., Vale, W. and Bloom, F., fl-endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland, Science, 197 (1977) 1367-1369. 9 Hodgson, H. J.F. and Matthews, P. B. C., The ineffectiveness of excitation of the primary endings of the muscle spindle by vibration as a respiratory stimulant in the decerebrate cat, J. Physiol. (Lond.,), 194 (1968) 555-563. 10 Holaday, J. W. and Faden, A. I., Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock, Nature (Lond.), 275 (1978) 450-451.
456 11 Kalia, M., Senapati, J. M., Parida, B. and Panda, A., Reflex increase in ventilation by muscle receptors with non-medullated fibers (C fibers), J. appl. Physiol., 32 (1972) 189-193. 12 Kumazawa, T. and Mizumura, K., The polymodal C-fiber receptor in the muscle of the dog, Brain Research, 101 (1976) 589-593. 13 Kumazawa, T. and Mizumura, K., Thin-fibre receptors responding to mechanical, chemical, and thermal stimulation in the skeletal muscle of the dog, J. Physiol. (Lond.), 273 (1977) 179-194. 14 Kumazawa, T., Mizumura, K., Tadaki, E. and Kim, K., Depressor and pressor responses produced by the muscular thin-fiber afferents. In M. lto (Ed.), Integrative Control Functions of the Brain, Kodansha, Tokyo, 1978, pp. 242-243. 15 Kumazawa, T., Tadaki, E. and Kim, K., A possible participation of endogenous opiates in respiratory reflexes induced by thin-fiber muscular afferents, Brain Research, 199 (1980) 244-248. 16 Laubie, M., Schmitt, H., Vincent, M. and Remond, G., Central cardiovascular effects of morphinomimetic peptides in dogs, Europ. J. Pharmacol., 46 (1977) 67-71. 17 McCloskey, D. I. and Mitchell, J. H., Reflex cardiovascular and respiratory responses originating in excercising muscle, J. Physiol. (Lond.), 224 (1972) 173-186. 18 Mizumura, K. and Kumazawa, T., Reflex respiratory response induced by chemical stimulation of muscle afferents, Brain Research, 109 (1976) 402406. 19 Perez-Gonzalez, J. F. and Coote, J. H., Activity of muscle afferents and reflex circulatory responses to exercise, Amer. J. Physiol., 223 (1972) 138-143. 20 Tibes, U., Reflex inputs to cardiovascular and respiratory centers from dynamically working canine muscles: some evidence for involvement of group 1II or IV nerve fibers, Circulat. Res., 41 (1977) 332-341.