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Urinary excretion of 3-methoxy-4-hydroxymandelic acid during dreaming sleep in man
Life Sciences Vol . 5, pp " 169-1~3, 1966 . Printed in Great ßritsin .
Per~amon Frees Ltd.
URINARY ERCRETION OF 3-METHOXY-4-HYDROXYMANDELIC ACID DURING DREAMING SLEEP IN MAN Arnold J . Mandell, Peter L . Brill, Mary P . Mandell, Jack Rodnick, Robert T. Rubin, Robert Sheff, Benjamin Chaffey Biochemical Correlates Laboratory, The Neuropsychiatric Institute, University of California Center for the Health Sciences Los Angeles, California 90024
(Received 14 October 1965 ; in final form lô November 1965) A number of studies of rapid eye movement sleep (REMS) in man (1) have
shown that these periods are associated with marked changes in cardiovascular function .
In cats there is a marked fall in both diastolic and systolic
pressure, whereas in man the changes are more variable .
A recent study (2)
in cats has indicated that these changes are even more marked following deafferentiation of the carotid sinus and aortic body, suggesting a primary central origin of these changes in their uncompensated form .
In an attempt to
discern whether catecholaminea were being released as either part of the primary or compensatory group of autonomic events, 3-methoxy-4-hydroxymandelic acid
(VMA) was studied in serial urinea throughout the night in four catheter-
ized urology patients .
Although the excretion of this non-specific catechol-
amine metabolite gives no information about whether epinephrine or norepinephrine is the predominant precursor, the changes in VMA excretion following REM epochs add another biochemical correlate to the growing list of physiological variables associated with the REM state . tion of night time angina pectoris with REMS
The recent report of the asaociain some patients with coronary
artery disease (3) makes this finding of potential clinical significance .
In
addition, another hormonal correlate of REMS is added to those we have reported previously (4, 5) . Methods Four urinary catheter-adapted, male urology patients, ages 45-74, with normal renal function tests, were studied for one night each ~~~i
(following a
U1~IPiARY EXCßETION OF
1~0
VI~~4
Vol .
;,
lio .
2
laboratory adaptation night) using conventional E7 :' "' ., LMG, and F :OG recordings in a sound-attenuated, darkened room (6) .
Th~~ uri : ; .~ry cathe.tei " ~,ac:r~_
l.ed
from the room into a volume-regulated fraction collector which permitte continuous collection of urine samples of :uniform vohune, t}~e vc itunes nc" :.r ::: measured accurar~~ly followin{ collection . scored for REMS without kr, ::.~i.e :ig~ of the criteria of Dement
~7) .
T} :e
The electrical recorc: :ngs a:~r~
the data from the ,cri .ne studies, usia~
time of onset and l~agth of ti:e~ rapi :
movement periods were csr:~ .ully determines .
`ï ire üfling of each t.ubc
c . :~ . in the
fraction collector was time lucked to the electrophysiological dat:c by aTc event recorder
fed into an amplifier of one- channel : f tl -~e electroencs~~ : ;~!.~_-
graph . VMA was determined by the method of Pisano et al (8) .
Optical density
at 360 m~ was linearly related to concentration of vanillici within the range measured and recoveries of known VMA, and urine plus known lR"k1, were consist ently above 90% .
Urinary creatinine was determined by the method of Jaffe .
The osmolality of the urine was determined by freezing point depression using an Advanced Osmometer . Results Twelve REMS epochs were studied in four subjects .
Mean and standard
deviation values of VMA for REM and non-REM sleep states are listed in Figure
1.
Note that there is a consistently higher value for the RIAIS epochs .
Since the peaks of urinary VMA concentration coincided with the hypotonic, diuretic phase of
the biphasic change in ~ :rine volume and osmolality associ :~-
ted with REMS which we have reported previocaly (4, 5), it appears t}iat urine volume changes cannot account for the increases in VAfA concentration .
Since
creatinine concentration changes are inverse to urine volume changes a,sociated with REMS
(4, 5), the micrograms of VAfA per milligram of creatinine is
partially volume corrected .
Changes in VMA per milliosmol of c:rinc were
similar to tl~e creatinine c".quivalent c}ianges .
voi . 5, rlo . 2
17i
tr~zrraRY Exc~.TZOrr o~ vrra
Mean yg . of VMA/cc
Subject
REM
NON-REM
~kl
4 .61+ .53
2 .17+ .61
~2
2 .56+ .37
1 .83+ .33
~3
1 .11+ .16
0 .81+ .18
~~4
4 .22+ .31
3 .67+ .27
Figure 1 A comparison of REM and non-REM VMA excretion values .
VMA EXCRETION IN RELATION TO REMS
133/3 166/3 200 233/3 2P6=/3 300 Minuten Aiter Lylnq Down
F igure 2
333 y3
366sî3
1~2
URINARY E$CRETION OF VL-IA
Vol .
5, ho .
2
Figure 2 demonstrates a typical night's sleep with four REM epochs, with the low base line VMA excretion and marked elevations following each epoch .
The determination of the exact time sequence of this phenomenon is
difficult .
In addition to the time required for the CNS-induced adrenal
medullary and nerve ending release of catecholamines, and the time for metabolism to VMA and excretion by the kidney, there was a time lag associated with catheter dead space .
It is thus not possible to speculate on the temporal
aspects of the VMA increases beyond the quite definite shift from the early evening baseline and the regularity of the peaks following each REMS epoch . Discussion Using isotopic norepinephrine and epinephrine,
and simultaneous determina-
tion of the multiple alternative metabolic pathways of these amines, Kopin (9) among others has shown that VMA is a major excreted metabolite .
Under
physiological states thus far studied, VMA is believed to be derived predominantly from norepinephrine through 0-methylation aad oxidative deamination (10) .
If the VMA rises reported here are for the most part from norepinephrine,
they may be a primary response to activation of the limbic-hypothalamicsympathetic nervous system during REMS, or a secondary compensatory response to the cardiovascular changes .
If the increased catecholamine release follow-
ing REMS epochs is ~oatly epinephrine, it may explain the frequent termination of these epochs by arousals, in that epinephrine has been shown to produce reticular activation (11) .
In addition, epinephrine release might explain the
increase in plasma free fatty acids (12) associated with REMS reported by Scott (13) .
Currently the question is being studied using the same experimen-
tal arrangement but with the direct determinations of these different amines . The potential cardiov»scular effects of these amines and the significant incidence of night time cardiovascular symptoms makes this question of clinical importance . Acknowledgements This work was supported by grants from N .A .S .A .
(NsG 237-62) and
Vol .
5,
I:o .
U .S .P .H .S .
2
(2-T2-MH-5996-11) .
173
LTßIPdA.~Y ~CCILTIGN GF Vt.'iA
Appreciation is expressed to the Brentwood
Veterans Administration Hospital for the use of their EEG Laboratory . References 1.
F, SNYDER, J, A. HOBSON, D,'R . MORRISON, F . GOLDFRANR, J . Appl . Physiol . ~9 , 417 (1964) .
2.
M. GUAZZI and A. ZANCHETTI, Science , 148, 397 (1965) .
3.
J . B, NOWLIN, W, G . TROYER, W . S . COLLINS, G . SILVERMAN, C, R, NICHOLS, H, D, MCINTOSH, E, H, ESTES, and M, D . BOGDONOFF, Clin . Res . 13, 216 (1965) .
4.
A. J. MANDELL and M . P . MANDELL, Am . J . Psychiat .,
5.
A,
6.
A. JACOBSON, A. KALES, J. R. ZWEIZIG, and J. KALES, Am . J . EEG Technol . 5, 5 (1965) . e
7.
W . DEMENT, The PhysioloQV of Dreaming 1958 .
8.
J . L . PISANO, J . R. CROUT and D. ABRAHAM, Clin . Chien . Acta 7 , 285 (1962) .
9.
I . J . KOPIN, Meth . Biochem . Anal . _, 247 (1963) .
122, 391 (1965) .
J. MANDELL, B, CHAFFEY, P. BRILL, M. P. MANDELL, J . RODNICK, R. T. RUBIN, and R, SHEFF, Science . In preparation .
(Ph .D . Thesis), Univ . of Chicago,
10 .
J . A%ELROD, In The Clinical Chemistry of Monoamines , H Gowenlock (Eds .) Elsevier, Amsterdam (1963) .
Varley and A . H .
11 .
M. BONVALLET, P . DELL, and G . HIEKEL, EEG Clin . Neuro~hysiol . 6, (1954) .
12 .
V. P . DOLE, J . Clin . Invest . ~, 150,(1956),
13 .
J. SCOTT, Fourth and Fifth Annual Pitgs . APSS . Washington, D . C . (1964 and 1965) .
119
Palo Alto, California ;
Per~amon Frees Ltd.
URINARY ERCRETION OF 3-METHOXY-4-HYDROXYMANDELIC ACID DURING DREAMING SLEEP IN MAN Arnold J . Mandell, Peter L . Brill, Mary P . Mandell, Jack Rodnick, Robert T. Rubin, Robert Sheff, Benjamin Chaffey Biochemical Correlates Laboratory, The Neuropsychiatric Institute, University of California Center for the Health Sciences Los Angeles, California 90024
(Received 14 October 1965 ; in final form lô November 1965) A number of studies of rapid eye movement sleep (REMS) in man (1) have
shown that these periods are associated with marked changes in cardiovascular function .
In cats there is a marked fall in both diastolic and systolic
pressure, whereas in man the changes are more variable .
A recent study (2)
in cats has indicated that these changes are even more marked following deafferentiation of the carotid sinus and aortic body, suggesting a primary central origin of these changes in their uncompensated form .
In an attempt to
discern whether catecholaminea were being released as either part of the primary or compensatory group of autonomic events, 3-methoxy-4-hydroxymandelic acid
(VMA) was studied in serial urinea throughout the night in four catheter-
ized urology patients .
Although the excretion of this non-specific catechol-
amine metabolite gives no information about whether epinephrine or norepinephrine is the predominant precursor, the changes in VMA excretion following REM epochs add another biochemical correlate to the growing list of physiological variables associated with the REM state . tion of night time angina pectoris with REMS
The recent report of the asaociain some patients with coronary
artery disease (3) makes this finding of potential clinical significance .
In
addition, another hormonal correlate of REMS is added to those we have reported previously (4, 5) . Methods Four urinary catheter-adapted, male urology patients, ages 45-74, with normal renal function tests, were studied for one night each ~~~i
(following a
U1~IPiARY EXCßETION OF
1~0
VI~~4
Vol .
;,
lio .
2
laboratory adaptation night) using conventional E7 :' "' ., LMG, and F :OG recordings in a sound-attenuated, darkened room (6) .
Th~~ uri : ; .~ry cathe.tei " ~,ac:r~_
l.ed
from the room into a volume-regulated fraction collector which permitte continuous collection of urine samples of :uniform vohune, t}~e vc itunes nc" :.r ::: measured accurar~~ly followin{ collection . scored for REMS without kr, ::.~i.e :ig~ of the criteria of Dement
~7) .
T} :e
The electrical recorc: :ngs a:~r~
the data from the ,cri .ne studies, usia~
time of onset and l~agth of ti:e~ rapi :
movement periods were csr:~ .ully determines .
`ï ire üfling of each t.ubc
c . :~ . in the
fraction collector was time lucked to the electrophysiological dat:c by aTc event recorder
fed into an amplifier of one- channel : f tl -~e electroencs~~ : ;~!.~_-
graph . VMA was determined by the method of Pisano et al (8) .
Optical density
at 360 m~ was linearly related to concentration of vanillici within the range measured and recoveries of known VMA, and urine plus known lR"k1, were consist ently above 90% .
Urinary creatinine was determined by the method of Jaffe .
The osmolality of the urine was determined by freezing point depression using an Advanced Osmometer . Results Twelve REMS epochs were studied in four subjects .
Mean and standard
deviation values of VMA for REM and non-REM sleep states are listed in Figure
1.
Note that there is a consistently higher value for the RIAIS epochs .
Since the peaks of urinary VMA concentration coincided with the hypotonic, diuretic phase of
the biphasic change in ~ :rine volume and osmolality associ :~-
ted with REMS which we have reported previocaly (4, 5), it appears t}iat urine volume changes cannot account for the increases in VAfA concentration .
Since
creatinine concentration changes are inverse to urine volume changes a,sociated with REMS
(4, 5), the micrograms of VAfA per milligram of creatinine is
partially volume corrected .
Changes in VMA per milliosmol of c:rinc were
similar to tl~e creatinine c".quivalent c}ianges .
voi . 5, rlo . 2
17i
tr~zrraRY Exc~.TZOrr o~ vrra
Mean yg . of VMA/cc
Subject
REM
NON-REM
~kl
4 .61+ .53
2 .17+ .61
~2
2 .56+ .37
1 .83+ .33
~3
1 .11+ .16
0 .81+ .18
~~4
4 .22+ .31
3 .67+ .27
Figure 1 A comparison of REM and non-REM VMA excretion values .
VMA EXCRETION IN RELATION TO REMS
133/3 166/3 200 233/3 2P6=/3 300 Minuten Aiter Lylnq Down
F igure 2
333 y3
366sî3
1~2
URINARY E$CRETION OF VL-IA
Vol .
5, ho .
2
Figure 2 demonstrates a typical night's sleep with four REM epochs, with the low base line VMA excretion and marked elevations following each epoch .
The determination of the exact time sequence of this phenomenon is
difficult .
In addition to the time required for the CNS-induced adrenal
medullary and nerve ending release of catecholamines, and the time for metabolism to VMA and excretion by the kidney, there was a time lag associated with catheter dead space .
It is thus not possible to speculate on the temporal
aspects of the VMA increases beyond the quite definite shift from the early evening baseline and the regularity of the peaks following each REMS epoch . Discussion Using isotopic norepinephrine and epinephrine,
and simultaneous determina-
tion of the multiple alternative metabolic pathways of these amines, Kopin (9) among others has shown that VMA is a major excreted metabolite .
Under
physiological states thus far studied, VMA is believed to be derived predominantly from norepinephrine through 0-methylation aad oxidative deamination (10) .
If the VMA rises reported here are for the most part from norepinephrine,
they may be a primary response to activation of the limbic-hypothalamicsympathetic nervous system during REMS, or a secondary compensatory response to the cardiovascular changes .
If the increased catecholamine release follow-
ing REMS epochs is ~oatly epinephrine, it may explain the frequent termination of these epochs by arousals, in that epinephrine has been shown to produce reticular activation (11) .
In addition, epinephrine release might explain the
increase in plasma free fatty acids (12) associated with REMS reported by Scott (13) .
Currently the question is being studied using the same experimen-
tal arrangement but with the direct determinations of these different amines . The potential cardiov»scular effects of these amines and the significant incidence of night time cardiovascular symptoms makes this question of clinical importance . Acknowledgements This work was supported by grants from N .A .S .A .
(NsG 237-62) and
Vol .
5,
I:o .
U .S .P .H .S .
2
(2-T2-MH-5996-11) .
173
LTßIPdA.~Y ~CCILTIGN GF Vt.'iA
Appreciation is expressed to the Brentwood
Veterans Administration Hospital for the use of their EEG Laboratory . References 1.
F, SNYDER, J, A. HOBSON, D,'R . MORRISON, F . GOLDFRANR, J . Appl . Physiol . ~9 , 417 (1964) .
2.
M. GUAZZI and A. ZANCHETTI, Science , 148, 397 (1965) .
3.
J . B, NOWLIN, W, G . TROYER, W . S . COLLINS, G . SILVERMAN, C, R, NICHOLS, H, D, MCINTOSH, E, H, ESTES, and M, D . BOGDONOFF, Clin . Res . 13, 216 (1965) .
4.
A. J. MANDELL and M . P . MANDELL, Am . J . Psychiat .,
5.
A,
6.
A. JACOBSON, A. KALES, J. R. ZWEIZIG, and J. KALES, Am . J . EEG Technol . 5, 5 (1965) . e
7.
W . DEMENT, The PhysioloQV of Dreaming 1958 .
8.
J . L . PISANO, J . R. CROUT and D. ABRAHAM, Clin . Chien . Acta 7 , 285 (1962) .
9.
I . J . KOPIN, Meth . Biochem . Anal . _, 247 (1963) .
122, 391 (1965) .
J. MANDELL, B, CHAFFEY, P. BRILL, M. P. MANDELL, J . RODNICK, R. T. RUBIN, and R, SHEFF, Science . In preparation .
(Ph .D . Thesis), Univ . of Chicago,
10 .
J . A%ELROD, In The Clinical Chemistry of Monoamines , H Gowenlock (Eds .) Elsevier, Amsterdam (1963) .
Varley and A . H .
11 .
M. BONVALLET, P . DELL, and G . HIEKEL, EEG Clin . Neuro~hysiol . 6, (1954) .
12 .
V. P . DOLE, J . Clin . Invest . ~, 150,(1956),
13 .
J. SCOTT, Fourth and Fifth Annual Pitgs . APSS . Washington, D . C . (1964 and 1965) .
119
Palo Alto, California ;