oxygen supply and demand: a means by which to integrate the of muscle systems russell s. richardson,...
TRANSCRIPT
OXYGEN SUPPLY AND DEMAND: A MEANS BY WHICH TO INTEGRATE THE OF MUSCLE SYSTEMS
Russell S. Richardson, Ph.D. Department of Medicine,University of California, San Diego
OUTLINE:
• Cardiovascular system or skeletal muscle, who is the “boss”?
• Human whole body exercise
• The “middle man”, smooth muscle
• Summary and conclusions
• Understanding the determinants of maximal exercise model
• Canine P50 data
• Human small muscle mass exercise, intracellular and dilator studies
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
HEART
MUSCLE
SKELETAL
“THE MIDDLE MAN”: BLOOD VESSELS
sGCi sGCa
GTPcGMP
RELAXATION
NO
Vascular smoothmuscle cell
Endothelium
NOSL-Arginine
ENDOTHELIUM / SMOOTH MUSLCE INTERACTION
Red blood cellO2
ATPNO
Heart and lungs Skeletal muscle
O2
HUMAN SINGLE LEG KNEE-EXTENSOR MODEL
Blood flow = Qs (Tb2 - Ts) / (Tb1-Tb2)
.
O2 CO2
100% 11%
On-line gas analysis
CO administration
CO2
absorption
30, 54, 63, 72 W, 60 rpm, 3 min
EXERCISE AND ACUTE REDUCTION IN HbO2
BLOOD FLOW AND ACUTE REDUCTION IN HbO2:
0 20 40 60 80
MU
SC
LE B
LOO
D F
LOW
(ml/m
in)
0
1000
2000
3000
4000
5000
6000
7000
SEDENTARY +COSEDENTARY NORMOXIAACTIVE NORMOXIAACTIVE +CO
WORK RATE (WATTS)
VASOREACTIVITY AND EXERCISE TRAINING
OLD PRE TRAINING
WORK RATE (WATTS)
0 5 10 15 20 25 30
20
40
60
80
100
120
YOUNG PRE TRAINING
LE
G V
AS
CU
LA
R R
ES
IST
AN
CE
(m
mH
g.m
in/m
L)
20
40
60
80
100
120
140
OLD POST TRAINING
WORK RATE (WATTS)
5 10 15 20 25 30 35 40
Room AirCO
YOUNG POST TRAINING
LE
G V
AS
CU
LA
R R
ES
IST
AN
CE
(m
mH
g.m
in/m
L)
QUOTE FROM A RECENT MANUSCRIPT REVIEW:
“The authors also need to be wary of giving the “supplier”
(cardiac output) priority over the “consumer” (muscle)
since the consumer must drive supply not the other way
around (i.e. increasing supply does not increase demand,
but surely increasing demand requires an increased supply).”
Paper now published: Poole et al., Am. J. Physiol. 284: H1251-H1259, 2003
What is VO2max?.
VO2max = Q (CaO2 –CvO2)
VO2max = Ve (FiO2 –FeO2)
VO
2 (l/
min
)
Work rate (Watts)
Ve
or Q
(l/
min
)
Work rate (Watts)
Ve
Q
VO2 = Q (CaO2 – CvO2) VO2 = DO2 (CapPO2 – CellPO2)
DETERMINANTS OF VO2MAX
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE
VO
2max
(l/
min
) FICK LAW LINE
FICK PRINCIPLELINE
VO2max
1000
5.0
3.0
40
UNDERSTANDING THE MODEL
VO2 = Q (CaO2 – CvO2) VO2 = DO2 * K * PvO2
MUSCLE VENOUS PO2 (mmHg)
MU
SCL
E V
O2m
ax (
l/m
in)
VO2max
1000
5.0
UNDERSTANDING THE MODEL
CONVECTION
DIFFUSION
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE
VO
2max
(l/
min
) FICK LAW LINE
FICK PRINCIPLELINE
VO2max
1000
5.0
3.0
40
UNDERSTANDING THE MODEL
MUSCLE VENOUS PO2 (mmHg)
MU
SCL
E V
O2m
ax (
l/m
in) VO2max
1000
5.0
UNDERSTANDING THE MODEL
O2 DELIVERYQ * CaO2
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE
VO
2max
(l/
min
) FICK LAW LINE
FICK PRINCIPLELINE
VO2max
1000
5.0
3.0
40
UNDERSTANDING THE MODEL
MUSCLE - DIFFUSION LIMITATION?
LUNG
MUSCLE
DEMONSTRATING DIFFUSION LIMITATION
CANINE GASTROCNEMIUS PREPARTION
CANINE DATA, MANIPULATING P50
Hogan et al. J. Appl. Phys. 1991 Richardson et al. J. Appl. Phys. 1998
RSR treatedFall in p50
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE
VO
2max
(l/
min
) FICK LAW LINE
FICK PRINCIPLELINE
VO2max
1000
5.0
3.0
40
UNDERSTANDING THE MODEL
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE V
O2m
ax (
l/min
)
8.0
5.0
2.5VO2max
10040 160
ALTERATIONS IN CONVECTION (DECREASED)
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE V
O2m
ax (
l/min
)
8.0
5.0
2.5
VO2max
10040 160
ALTERATIONS IN CONVECTION (INCREASED)
MUSCLE VENOUS PO2 (mmHg)
MU
SC
LE V
O2m
ax (
l/min
)
8.0
5.0
2.5
VO2max
10040 160
VO2max
Heart Failure
Athlete
CHANGES IN BOTH CONVECTION AND DIFFUSION
MUSCLE VENOUS PO2
MU
SC
LE V
O2m
ax
(nor
mal
ized
for
mus
cle
mas
s)
FICK LAW LINE
FICK PRINCIPLELINES
Untrained Subjects
FIO2:.12
.211.0
VENOUS PO2 (mmHg)
0 20 40 60 80
SK
ELE
TA
L M
US
CLE
VO
2MA
X (
ml/m
in/1
00g)
0
10
20
30
40
50
FIO2:
.12
.21
1.0
TRAINED SUBJECTS
BICYLCE EXERCISE
Cardus et al. Med. Sci. Sports Ex. 1998Richardson et al. J. Appl. Phys. 1999
BICYCLE Vs KNEE-EXTENSOR EXERCISE
MIT
OC
HO
ND
RIA
L O
2 U
TIL
IZA
TIO
N (
ml/m
in/c
m3
)
0
2
4
6
8
10
12
CYCLE EXERCISE
(TWO LEGS)
KNEE-EXTENSOREXERCISE
(ONE QUADRICEPS)
TRAINED
MIT
OC
HO
ND
RIA
L O
2 U
TIL
IZA
TIO
N (
ml/m
in/c
m3
)
0
2
4
6
8
10
12
CYCLE EXERCISE
(TWO LEGS)
KNEE-EXTENSOREXERCISE
(ONE QUADRICEPS)
UNTRAINED
Richardson et al. J. Appl. Phys. 1999
KNEE-EXTENSOR EXERCISE IN THE MRI
Richardson et al. J. Clin. Invest. 1995
SIG
NA
L M
AG
NIT
UD
ES
IGN
AL
MA
GN
ITU
DE
SIG
NA
L M
AG
NIT
UD
E
SIGNALDEOXY-Mb
REST
5060708090100
CHEMICAL SHIFT (ppm)
5060708090100
5060708090100
1
2
3
DEOXY-MbSIGNAL
MAXIMAL EXERCISE
CUFF ISCHEMIA(10 MINUTE)
MYOGLOBIN MAGNETIC RESONANCE SPECTROSCOPY
Richardson et al. J. Clin. Invest. 1995
INTRACELLULAR PO2 (mmHg)
0 2 4 6 8 10 12 14
SK
ELE
TA
L M
US
CLE
VO
2MA
X (
l/min
)
0.0
0.2
0.4
0.6
0.8
1.0
UNTRAINED
TRAINED
.12
.21
1.0
.12
.211.0
*
VO2 SIGNIFICANTLY REDUCED*
INTRACELLULAR PO2 (mmHg)
0 2 4 6 8 10 12 14
SK
ELE
TA
L M
US
CLE
VO
2MA
X (
l/min
)
0.0
0.2
0.4
0.6
0.8
1.0
UNTRAINED.12
.211.0
FIO2:n= 5
INTRACELLULAR PO2 (mmHg)
0 2 4 6
SK
ELE
TA
L M
US
CLE
VO
2MA
X (
l/min
)
0.0
0.4
0.8
1.2
1.6
FIO2:1.0
.21
.12
n=5
TRAINED
KNEE-EXTENSOR EXERCISE AND PO2
Richardson et al. J. Appl. Phys. 1999
Untrained
Trained
III
50 m
Richardson et al. Am. J. Phys. 1999
3.0 3.5 4.0 4.5 5.0
MA
XIM
AL
O2
CO
ND
UC
TA
NC
E
(ml/m
in/m
mH
g)
15
17
19
21
3.0 3.5 4.0 4.5 5.0
QU
AD
RIC
EP
S V
O2
MA
X (
l/min
)
0.4
0.5
0.6
0.7
0.8
NUMBER OF CAPILLARIES/FIBER
3.0 3.5 4.0 4.5 5.0
MA
XIM
AL
O2
EX
TR
AC
TIO
N (
%)
50
55
60
65
70
75
80
NUMBER OF CAPILLARIES/FIBER
3.0 3.5 4.0 4.5 5.0
VE
GF
/18S
RE
SP
ON
SE
T
O E
XE
RC
ISE
(ar
bitr
ary
units
)
0
5
10
15
20
25
*
**
*
TRAINED
UNTRAINED
TRAINED
TRAINED
TRAINED
UNTRAINED
UNTRAINED
UNTRAINED
Richardson et al. Am. J. Phys. 1999
MEAN CAPILLARY PO2 (l/min)
0 10 20 30 40 50 60Q
UA
DR
ICE
PS
VO
2max
(l/m
in)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
hyperoxia + adenosine
hyperoxia
hypoxia
SINKGLE LEG KNEE-EXTENSOR WORK RATE (Watts)
0 10 20 30 40 50 60 70 80
OX
YG
EN
DE
LIV
ER
Y (
l/min
)
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Hyperoxia Hyperoxia + adensoine
Intra-arterialadenosine infusion
EXOGENOUS DILATION AT MAXIMAL EXERICSE
SUMMARY AND CONCLUSIONS
• HIGHLY dependent upon the scenario!
O2 supply limited
O2 demand limited
Low capillary density
High mitochondrial density
Large muscle mass relative to central components
Small/unresponsive cardiovascular systemrelative to peripheral components
Co-workers:
Peter Wagner, M.D.Tim Gavin, Ph.D.Odile Mathieu-Costello, Ph.D.Robert Henry, M.D.Fabio Esposito, M.D.Harrieth WagnerElizabeth Noyszewski, Ph.D.Bryan Leek, M.D.Kuldeep Tagore, M.D.Sean NewcomerLuke Haseler, Ph.D.Lawrence Frank, Ph.D.John Leigh, Ph.D.Eileen Quintela, B.S.Sundar Mudaliar, M.D.
Funding:American Lung AssociationParker B. Francis FoundationNational Institute of Health
