EFFECT OF CARBON DIOXIDE ON PULMONARY VASCULAR TONE AT VARIOUS PULMONARY ARTERIAL PRESSURE LEVELS

1
EFFECT OF CARBON DIOXIDE ON PULMONARY VASCULAR
TONE AT VARIOUS PULMONARY ARTERIAL PRESSURE
LEVELS INDUCED BY ENDOTHELIN-1 AND MECHANICAL
STRESS
Ming-Shyan Huang, MD, PhD Yvonne Yis Juang, MS,
RRT Rei-Cheng Yang, MD, PhD Tung-Heng Wang,
MDChin-Ming Chen, MD Tuan-Jung Hsu, BS and
Inn-Wen Chong, MD Kaohsiung Medical University,
Chi-Mei Medical Center, Taiwan R.O.C
3. Methods and Materials
1. Abstract
2. Introduction
The effect of CO2 on pulmonary vascular
tone is controversial with evidence for both
vasoconstrictor and vasodilator. Previous
investigation showed that high CO2 tension with
elevated hydrogen ion concentration in the blood
increases the extracellular Ca2 influx. That is
the main cause of vasoconstriction property of
CO2 in the pulmonary circulation. However CO2
also plays a vasodilator role under the condition
of high vascular tone, and such vasodilatory
effect is related to the concentration of inhaled
CO2, not with the blood pH value. Other line of
evidence has also indicated that CO2 may
attenuate vasoconstriction induced by drug or
hypoxia. The detail mechanism is still need to be
clarify. In the present study, we attempted to
determine whether the vasodilator effect of CO2
was pressure dependent and its possible
mechanism. Isolated perfused rats lung was used.
Two different methods were employed to induced
pulmonary hypertension increase vascular
resistance by graded administration of ET-1 and
increase in perfusion rate . The vasodilator
effects of CO2 during normoxia and hypoxia on
pulmonary hypertension were evaluated. We also
assessed the effect of endogenous NO on the
hypoxia-induced pulmonary vasoconstriction.
There have been contradictory reports that CO2
may constrict, dilates or have no action on the
pulmonary vessels. Permissive hypercapnia has
become a widely adopted ventilatory technique to
avoid ventilator-induced lung injury particularly
in patients with acute respiratory distress
syndrome (ARDS). On the other hand, respiratory
alkalosis (hypocapnia) produced by mechanically
induced hyperventilation, is the mainstay of
treatment for newborn infant with persistent
pulmonary hypertension. It is important to
clarify the vasomotor effect CO2 on pulmonary
circulation in order to better evaluate the
strategies of mechanical ventilation in intensive
care. In the present study, the pulmonary
vascular responses to CO2 were observed in
isolated rats lung under different levels of
pulmonary arterial pressure (PAP) induced by
various doses of ET-1 (endothelin-1) and graded
perfusion flow rate. The purposes of this study
were to investigate (1) the vasodilatory effect
of 5 CO2 in either N2 (hypoxia) or air
(normoxia) at pulmonary arterial pressure (PAP)
levels induced by various dose of endothelin-1
and perfusion flow rates. (2) the role of
endogenous nitric oxide (NO) in pulmonary
hypertension induced by hypoxia. The results
indicate that (1) CO2 produces pulmonary
vasodilatation at high PAP only under ET-1 and
hypoxic vasoconstriction but not under flow
alteration. (2) Vasodilatory effects of CO2 in
different pressure levels varied in accordance
with the levels of PAP the dilatory effect tends
to be more evident at higher PAP. (3) Endogenous
NO attenuates the Hypoxic pulmonary
vasoconstriction but dose not augment the
CO2-induced Vasodilation.

• Animal preparation male SD, 300-350g isolated
  perfused lung
• ?PAP R Q
• Group A (n 19) administration with various
  doses
• (5 p mol, 50 p
  mol, 200 p mol) of ET-1
• A1 (n6) nomoxia, 5 CO2 in Air
• A2 (n8) hypoxia, 5 CO2 in N2
• A3 (n5) hypoxia with pretreatment of
  nitric oxide
• synthesis inhibitor, L-
  NAME(400µM) and
• an ET-1B receptor
  antagonist, BQ 788(1 µM)
• Group B (n 17)
• setting with various perfusion flow rates
  (13, 18, 25 ml/min)
• B1 (n6) nomoxia, 5 CO2 in Air
• B2 (n6) hypoxia, 5 CO2 in N2
• B3 (n5) hypoxia with pretreatment of
  L-NAME(400µM)
• Measurements
• PAP, LAP
• ABGs (pH, PaO2, PaCO2)

6. Conclusion
5. Result
4. Result
Effect of CO2 on ET-1
induced pulmonary vasoconstriction under normoxic
and hypoxic ventilation. In the first series of
experiment, the PAP was elevated by various doses
of ET-1(Fig.1). In Group A1, the
pressure-dependent CO2-induced vasodilatation was
observed in ventilation with 5 CO2 in air
(nomoxia). In Group A2 with challenge of various
dose of ET-1, a direct vasodilatation in response
to hypoxic gas (5 CO2 95 N2) inhalation was
observed and the sustained vasodilatation could
be aborted with pure N2 inhalation. In Group A3,
inhibition of NO synthesis with L-NAME BQ788
evoked a biphasic response with a transient
hypoxic vasoconstriction. The pressure-dependent
CO2-induced vasodilatation was also observed
in ventilation with 5 CO2 95 N2 (hypoxia).
(Fig.2)
Effect of CO2 on
mechanical stress induced pulmonary hypertension
under normoxic and hypoxic ventilation. In the
second series of experiment, the PAP was elevated
by stepwise increase in flow rate alteration
(Fig.3). CO2 only reversed the pulmonary
vasoconstriction caused by hypoxic gas under
various flow rates (Group B2) but not the
elevated PAP induced by higher flow rate
(GroupB1, B2 and B3). In Group B3, pretreatment
with L-NAME (400µM) tends to increase the
pulmonary vasoconstrictory response to hypoxia,
but did not eliminate the vasodilatory effect
of CO2. (Fig.4)
The results indicate that (1) CO2 produced
pulmonary vasodilatation at high PAP only
under ET-1 and hypoxic vasoconstriction but not
under flow alteration. (2) Vasodilatory effects
of CO2 in different pressure levels varied in
accordance with the levels of PAP the dilatory
effect tended to be more evident at higher PAP.
(3) Endogenous NO attenuated the hypoxic
pulmonary vasoconstriction but dose not augment
the CO2induced vasodilatation.
Figure 4
Figure 3
Figure 2
Figure 1
Fig. 1 Increase in pulmonary arterial pressure at
varying dose of ET-1 (5, 50, 200 p mol) in Group
A1, A2 and A3. , Pulmonary arterial
pressure increased significantly in response to
each dose of ET-1. PAP at ET-1 50 p mol compared
with PAP at ET-1 5 p mol PAP at ET-1 200 p mol
compared with PAP at ET-1 50 p mol. Plt0.05
Plt0.01.
Fig. 3 Increase in pulmonary arterial pressure at
varying perfusion flow rate (13ml/min, 18ml/min,
25ml/min) in Group B1, B2 and B3. ,
Pulmonary arterial pressure increased
significantly in response to different speed of
perfusion flow. PAP at perfusion flow 18ml/min
compared with PAP at perfusion flow 13ml/min PAP
at perfusion flow 25ml/min compared with PAP at
perfusion flow 18ml/min. Plt0.05 Plt0.01.
Figure 2. PAP changes in response to 5 CO2 in
air (GroupA1) and in N2 (Group A2, A3) following
various dose of ET-1. Group A3 was pretreated
with L-NAME and BQ 788. Values are means SE
P lt 0.01 CO2 vasodilatation Vs. previous course.
RARoom air.
Figure 4. PAP changes in response to 5 CO2 in
air (Group B1) and in N2 (Groups B2, B3) at
various flow rates. Group B3 was pretreated with
L-NAME. Values are means SE p lt 0.01 CO2
vasodilatation Vs. previous course. RAroom air.