1 Section of Pediatric Critical
Care Medicine, We hypothesized
that capillary recruitment may not be solely dependent on
extracapillary factors. To test this hypothesis, rabbits were
anesthetized and placed on total cardiac bypass at a constant,
physiological pulmonary blood flow. Vascular occlusion techniques were
combined with measurement of the transpulmonary metabolism of an
angiotensin-converting enzyme substrate, allowing the concomitant
assessment of changes in segmental resistances and dynamically perfused
capillary surface area. Intra-arterial serotonin infusion increased
upstream pulmonary vascular resistances without affecting dynamically
perfused capillary surface area. Intra-arterial isoproterenol infusion
diminished serotonin-induced increased upstream resistances, also
without affecting capillary surface area. These findings
support the hypothesis that pulmonary capillary recruitment may not be
solely dependent on extracapillary factors.
isoproterenol; serotonin; capillary recruitment; pulmonary
circulation; pulmonary hypertension; rabbit
PULMONARY CAPILLARY RECRUITMENT has been thought to be
modulated by pressures in the extracapillary vessels and alveoli. West et al. (32) demonstrated that distribution of blood flow within the
lung could be related to the relationship among alveolar, arterial, and
venous pressures. Wagner and Latham (30) showed a strong
correlation between pulmonary arterial pressure and capillary recruitment during hypoxia. These and other similar studies suggested that segmental capillary blood flow may depend solely on external forces, leading to the conclusion that capillaries open or close passively. This understanding was further supported by histological evidence (8) where only extracapillary vessels were shown to contain
smooth muscle and autonomic innervation. Moreover, an early study (14)
demonstrated that the sympathetic nervous system contributed to the
pulmonary pressor response to hypoxia, suggesting that only
extracapillary vessels possessed the apparatus needed to change vessel
tone and resistance and that capillary segments served as "passive
conduits" for blood flow.
More recently, there has been mounting evidence supporting a component
of pulmonary capillary recruitment intrinsic to the capillary bed.
Warrell et al. (31) examined rapidly frozen lung sections and found
that patterns of capillary filling were not correlating purely with
arteriolar distribution. They concluded that there was heterogeneous
recruitment of capillary segments fed by the same arteriole. An
electrical-mapping model by West et al. (33) lent further support to
the concept of intrinsic recruitment. Very similar patterns were
demonstrated by Okada et al. (18) using capillary video mapping of
blood flow within individual alveolar walls. They found reproducible
patterns of recruitment, concluding that individual capillary segments
possessed properties affecting their recruitment.
To date, the nature of intrinsic factors affecting capillary
recruitment remains unclear. These intrinsic factors could be characterized as either fixed or variable. Fixed factors would be those
related to the spatial arrangement of each capillary segment within its
surrounding tissue. Variable factors could be either external to the
endothelial cell or inherent to the endothelial cell itself. There is
evidence to support both types of variable factors. Kapanci et al. (13)
demonstrated the presence of pulmonary interstitial cells with
contractile elements. These contractile elements were noted to have
anchoring points on both alveolar elements and capillary basement
membranes. These anchoring points might allow transmission of the
cell's contractile force to adjacent capillaries, allowing the Kapanci
cell to be an effector of capillary recruitment.
The endothelial cell itself may actively participate in capillary
recruitment, in contradistinction to previous thinking that the
capillary endothelial cell was a passive cell lining a passive conduit
system. Endothelial cells are metabolically active. Ectoenzymes such as
angiotensin-converting enzyme (ACE), 5'-nucleotidase, carboxypeptidase N, and aminopeptidase P are involved in regulating circulating hormones (25). Via catecholamine uptake (4), endothelial
cells contribute to sympathetic regulation. Endothelium-derived relaxing factor (nitric oxide) is now known to be a modulator of blood
pressure due to its effects on vascular smooth muscle tone (21). In
addition to hormonal regulation, endothelial cells have been shown to
interact with blood elements, including altered expression of white
cell adhesion molecules in response to tumor necrosis factor- The present study begins to test the hypothesis that mechanisms of
pulmonary capillary recruitment are not solely dependent on changes in
the extracapillary vasculature; i.e., there is a component of intrinsic
regulation. To that end, we examined whether changes in extracapillary
vessel tone can occur without affecting capillary
recruitment-derecruitment.
Drug and animal preparation. The
experimental protocol was reviewed and approved by the Institutional
Committee on Animal Research and complied with the guidelines on the
humane treatment of animals of the American Physiological Society. Male
New Zealand White rabbits, mean weight 3.6 kg, were housed in
individual cages and were allowed food and water ad libitum up to the
time of the experiment. After being anesthetized with
urethan-5,5-diallylbarbituric acid (Sigma Chemical, St. Louis, MO)
administered in a marginal ear vein, each animal was placed supine,
tracheostomized, and ventilated with a small-animal ventilator (Harvard
Apparatus, Mills, MA). Airway pressure was continuously measured with a
pressure transducer (Statham Instruments, Hato Riley, PR) connected to the expiratory limb of the ventilator circuit and recorded on a Gould
2400 (Gould Instruments, Columbus, OH) physiograph. After the left
carotid artery was cannulated, 1 mg of pancuronium bromide (Organon, W. Orange, NJ) was administered. The catheter was then connected to a
pressure transducer zeroed to midthorax to continuously monitor and
record systemic arterial pressure. After a median sternotomy was
performed, an anterior pericardiectomy and bilateral anterior
pleurectomies were performed to expose the heart and great vessels. In
preparation for cardiac bypass, silk sutures were loosely tied around
the ascending aorta and the pulmonary artery. Before cardiac bypass,
the animal was then given 1,000 U/kg of heparin (Elkin-Sinn, Cherry
Hill, NJ) to provide anticoagulation and 5 mg/kg of indomethacin (Sigma
Chemical) to inhibit the production and release of cyclooxygenase
pressor products.
Cardiac bypass. The extracorporeal
bypass system consisted of two parallel circuits to provide systemic
and pulmonary blood flows. Each circuit contained a double-jacketed
Plexiglas reservoir with Tygon tubing leading from the base of each
reservoir through a roller pump (P/N 13400, Sarns, Ann Arbor, MI) and
then to a vascular (pulmonary or aortic) cannula. The pulmonary circuit also incorporated a bubble filter and a flow probe (300A, Carolina Medical Electronics, King, NC). The pump was calibrated so that the
systemic and pulmonary flows were equal. The bypass circuit was primed
with a mixture of rabbit blood and Krebs-Henseleit solution.
After a purse-string suture was placed in each ventricular free wall, a
catheter was placed in the right ventricle and advanced through the
tricuspid annulus into the right atrium. The catheter was secured with
the previously placed suture so that systemic venous drainage returned
into the "pulmonary" reservoir. The left atrium was cannulated
similarly to drain all pulmonary venous blood into the "systemic"
reservoir. The ascending aorta was rapidly tied off, and the cannula
was secured with the previously placed ligature. The pulmonary artery
was cannulated immediately above the pulmonary valve, with care being
taken to avoid introduction of air emboli. The mean time of interrupted
circulation was 7.9 min.
After bypass was established, the rabbit was allowed to stabilize (mean
time 32 min). Arterial blood gases were measured (Instrumentation Laboratory 1304, Lexington, MA), and minute ventilation was adjusted to
keep the pH at ~7.40. Pulmonary arterial and left atrial pressures were continuously monitored and recorded from catheters placed within
the appropriate cannulas connected to pressure transducers zeroed at
the midthoracic level. Pulmonary blood flow was continuously measured
with an electromagnetic flowmeter (Cliniflow II, Carolina Medical
Electronics) and was initially adjusted to 100 ml · min Fresh solutions of the vasoactive drugs were prepared in normal saline
for each experiment. Serotonin [5-hydoxytryptamine creatinine
sulfate complex (5-HT); Sigma Chemical] was prepared as a 1 mg/ml
solution and stored and administered in light-shielded containers.
Isoproterenol (Sigma Chemical) was prepared at 0.6 mg · kg Estimation of capillary surface area.
Dynamically perfused capillary surface area was calculated from the
single-pass transpulmonary metabolism of the specific ACE substrate
[3H]benzoyl-phenylalanyl-alanyl-proline
([3H]BPAP;
20 Ci/mmol; Ventrex). For each determination, 2 µCi of [3H]BPAP were injected
into the pulmonary artery, and left atrial outflow was collected in 19 0.6-s samples by a fraction collector (Gilson Escargot, Gilson
Instruments, Lexington, MA). Measurements were obtained during end
expiration. Blood samples were centrifuged at 3,000 revolutions/min for
10 min to separate the plasma. To determine the total
3H radioactivity in each sample, a
0.5-ml plasma aliquot was placed in a 7-ml plastic scintillation vial
(Fisher Scientific, Atlanta, GA) to which 5 ml of Ecoscint A
scintillation cocktail (National Diagnostics, Atlanta, GA) were added.
To determine the radioactivity due to the metabolite of
[3H]BPAP,
[3H]benzoyl-phenylalanine,
a 0.5-ml plasma aliquot from each sample was placed in a 7-ml plastic
scintillation vial (Fisher) to which was added 2.5 ml of 0.12 N HCl and
3 ml of 4 g/l Omnifluor (Dupont, Boston, MA) in toluene (Baxter,
Muskegon, MI). The samples were then capped and inverted 20 times for
thorough mixing and stored in a dark cabinet for 48 h before being
placed in a scintillation spectrometer (LS7000, Beckman Instruments,
Irvine, CA).
Experimental procedures and protocol.
The experimental protocol is shown in Fig.
1. After the stabilization period, baseline measurements were taken. All measurements were obtained at end expiration, with the lungs in zone III conditions. Pulmonary arterial occlusion, simultaneous arterial and venous occlusion, and venous occlusion maneuvers were performed (see Determination
of segmental pressures). An aliquot of
left atrial outflow blood was obtained for blood gas and hematocrit
(Hct) determinations.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
(17).
Along with these metabolic and cell-to-cell activities, endothelial
cells may regulate their own recruitment by virtue of contractile
properties. Elliott et al. (7) showed that changes in the structure of
pulmonary capillaries were quickly reversible. Shasby et al. (26)
suggested that the endothelial cytoskeleton played a role in
endothelial permeability, whereas McDonald (16) found evidence for
endothelial cell motility in tracheal venules. Therefore, there is
evidence to support intrinsic capillary segmental recruitment and that
such recruitment may be influenced by variable elements. These elements
may be external to the endothelium (i.e., Kapanci cells) or may involve
the metabolically active endothelium.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
1 · kg
body weight
1; this flow
produced a stable pulmonary arterial pressure of ~20 mmHg
[normal for rabbit (28)], with a left atrial pressure of 1-2 mmHg. Pulmonary blood flow was thereafter kept constant.
1 · ml
1.
View larger version (7K):
[in a new window]
Fig. 1.
Experimental protocol. Serotonin [5-hydroxytryptamine
(5-HT)] infusion began after baseline measurements and was then
kept constant throughout the experiment. Isoproterenol infusion began
after constricted (5-HT) measurements were made and was increased until
mean pulmonary arterial pressure decreased ~50% toward pre-5-HT
baseline (Iso1). After measurements were made again, infusion was
increased until pulmonary arterial pressure was approximately at
pre-5-HT level (Iso2).
After baseline measurements were made, pulmonary hypertension was
induced by continuously infusing 5-HT into the pulmonary artery with a
syringe pump (242A, Sarns). The infusion was increased until a maximal
pressor response was established (mean infusion rate 91 µg · kg1 · min
1).
The rate of 5-HT infusion remained constant until the end of the
experiment. Pulmonary blood flow was kept constant by adjusting the
pump speed.
An isoproterenol infusion into the pulmonary artery was begun and gradually increased until the mean pulmonary arterial pressure decreased by ~50% toward the pre-5HT baseline (Iso1). All measurements were then repeated, after which the isoproterenol infusion was gradually increased again until the pulmonary arterial pressure was approximately at the pre-5HT baseline (Iso2). A final series of measurements was taken before the experiment was terminated.
Determination of segmental pressures.
Segmental resistances were estimated by vascular occlusion techniques
(10). During pulmonary arterial occlusion, the point of inflection in
the pulmonary arterial occlusion pressure
(Ppao) tracing
corresponds to the arteriolar pressure. During simultaneous arterial
and venous occlusions, the two pressures equilibrate at the
double-occlusion pressure (Pdo),
which closely approximates the capillary pressure. During venous
occlusion, the inflection point in the venous occlusion pressure
(Pvo) tracing is
equivalent to the pulmonary venule pressure (10). With total pulmonary
blood flow
(T) at the
time of occlusion known, the segmental resistances were calculated as
large-artery resistance
(Rla) = (Ppa
Pao)/
T,
small-artery resistance
(Rsa) = (Ppao
Pdo)/
T,
small-vein resistance
(Rsv) = (Pdo
Pvo)/
T, large-vein resistance
(Rlv) = (Pvo
Ppv)/
T,
and total pulmonary resistance = (Ppa
Ppv)/
T,
where Ppa is pulmonary arterial pressure and Ppv is pulmonary
venous pressure.
Calculation of perfused capillary surface
area. ACE is distributed homogeneously over the entire
endothelial luminal surface (25); thus the amounts of ACE reflect the
dynamically perfused capillary surface area (5). Under first-order
reaction conditions, the integrated form of the Henri-Michaelis-Menten
equation can be rearranged to
Amax /Km = p · ln
([S0]/[S]),
where
p is the
pulmonary plasma flow,
[S0] and
[S] are the initial and surviving substrate concentrations,
respectively,
Amax is the
product of enzyme mass and
kcat (turnover
number; a constant), and
Km is the
Michaelis-Menten constant. Changes in perfused capillary surface area
as reflected by changes in enzyme mass are thus indicated by changes in
the quantity
Amax /Km.
Statistical analysis. Statistical analysis of obtained parameters utilized one-way analysis of variance followed by the Newman-Keuls test. A P value < 0.05 was accepted as indicating a significant difference.
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RESULTS |
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Baseline hemodynamic measurements on cardiac bypass were a mean
systemic arterial pressure of 91.5 ± 3.8 mmHg, mean
pulmonary arterial pressure of 20 ± 1.8 mmHg, and left atrial
pressure of 1.9 ± 0.04 mmHg. Mean pulmonary arterial pressure
increased significantly during the infusion of 5-HT
(P < 0.01) and then significantly decreased during the graduated infusions of isoproterenol (Table 1). Small-artery pressures also rose
significantly (from 12.8 ± 0.5 to 14.8 ± 1.3 mmHg;
P < 0.05) with 5-HT, then fell to
12.0 ± 1.1 (P < 0.05) and 11.3 ± 1.2 mmHg (P < 0.01) during
Iso1 and Iso2 infusions, respectively. Neither capillary, small-vein,
nor large-vein pressures were significantly affected by the 5-HT or isoproterenol infusions. 5-HT did not affect mean systemic arterial pressure, but isoproterenol did result in a significant decrease in
mean systemic pressure to 76.7 ± 5.4 mmHg at Iso2. Pulmonary blood
flow remained stable at 106
ml · kg
1 · min
1.
|
The Hct decreased, but stable pH and arterial PO2 values (as shown in Table 1) suggested adequate lung function throughout the protocol.
Despite changes in large- and small-artery pressures, dynamically perfused capillary surface area (as reflected by Amax /Km) did not change in response to 5-HT, Iso1, or Iso2 (Table 1).
Figure 2 shows the time course of total pulmonary vascular resistance and capillary surface area (values expressed as multiples of baseline) during the 5-HT infusion alone (constricted) and with increasing infusions of isoproterenol (Iso1 and Iso2). Capillary surface area did not change significantly. In contrast, total pulmonary resistance first increased significantly and then dropped significantly at Iso1 and Iso2. Large-artery resistance more than doubled during the 5-HT infusion, then significantly decreased at both stages of the isoproterenol infusion (Fig. 3). Resistance in the small arteries was similarly affected (Fig. 3). There were no significant changes in downstream resistances throughout the experiment (Fig. 4).
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DISCUSSION |
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Pressure measurements in the pulmonary artery and left atrium allow assessment of total pulmonary vascular tone and control but do not assess the contributions of the various populations of vessels within the pulmonary vasculature. Bhattacharya et al. (3) measured pressures in 10-µm-diameter vessels with micropipette techniques. Such measurements are technically difficult and restricted to vessels near the pleural surface. Mathematical models equating the vascular tree to an electrical circuit have resulted in techniques that examine small vascular pressures using combinations of large-vessel occlusions. Inflection points in the resultant pressure waveforms are then equated with various segmental pressures (10). Other techniques have been used to assess vascular responsiveness. Intrapulmonary fluid volumes have been measured with techniques such as dye dilution (6) and blood pool scintigraphy (27) to look at volume distributions within the lung, whereas the low-viscosity bolus technique (9) shows the distribution of resistances across the vascular bed without indicating the anatomic location of those resistances.
Although these techniques, singly or in combination, have allowed investigation into the extracapillary vessels, examining the function of the capillary bed has been more difficult. Investigators have analyzed the anatomic morphology of the capillary-alveolar unit. Lung tissue has been quick-frozen (26) or direct observations of the pleural surface have been performed using video mapping (18). Such techniques are useful but difficult to apply to the entire lung. Capillary function has been assessed indirectly by measuring filtration coefficients (2). Investigations into the perfused capillary surface area using gases such as ether (20) depend on ventilation-perfusion matching, thus missing segments of the capillary bed that may be active but associated with nonventilated alveoli. Techniques based on a metabolically active endothelium are therefore attractive, in that they will assess potential changes in the total capillary bed independent of the status of alveolar ventilation. Examples of such methods include 5-HT uptake (23), blue dextran binding (24), and measurement of endothelial ectoenzyme function (28). Assessment of pulmonary capillary surface area via ACE activity has been shown to correlate well with measurements based on carbon monoxide diffusing capacity and postmortem structural assessments (19).
The "passive conduit" concept holds that the pulmonary capillary bed is simply a network of tubes where recruitment of individual segments depends mostly on extracapillary changes in blood pressure and volume. The model has been supported by histological findings that show that the arteries and, to a lesser extent, the veins are the only portions of the pulmonary vasculature that are endowed with smooth muscle; the same segments possess innervation as well (8).
Precapillary factors, primarily the pressure in the small arterioles just upstream from the capillary network, are believed to exert a major influence on capillary recruitment (30). Certainly, precapillary mechanisms have an effect on capillary blood volume. Changes in cardiac output as well as in arterial and arteriolar tone will affect the amount of blood per unit time that the capillary bed must accommodate (11, 29), with the altered blood volume potentially resulting in changes in segmental filling and recruitment.
Postcapillary effects on the capillary bed have also been studied; when venous pressure increases temporarily, alveolar vessel volume increases (6) and pulmonary vascular resistance decreases (1).
Despite these findings, both morphological and pressure-volume studies (15, 31) have suggested that there are changes within the capillary beds that occur independently of changes in the extracapillary beds. It remains unclear whether such effects are due to fixed mechanical properties of the lung (i.e., the structural composition of the lungs) (33) or whether they are due to variable qualities within the capillary bed, e.g., endothelial or interstitial contractile elements.
The concept of variable factors of intrinsic capillary control is supported by the presence of cells with contractile elements [Kapanci cells (13)], which are closely associated with the capillaries. In addition to contractile elements external to the endothelial cell, there is evidence that endothelial cells themselves possess active internal contractile elements (26). Pursuit of the intrinsic variable properties may eventually lead to manipulation of pulmonary capillary vasomodulation and allow therapeutic contributions to clinical conditions such as pulmonary hypertension, pneumonia, pulmonary edema, and adult respiratory distress syndrome.
If pulmonary capillary bed surface area (hence capillary recruitment)
is not solely dependent on extracapillary vessel tone, capillary
responsiveness to vasomodulators could function independently of
extracapillary effects of those modulators. To evaluate this, we
combined techniques to study segmental resistances and perfused capillary surface area. Experiments were performed at constant flow
because blood volume changes could affect capillary recruitment. We
demonstrated that after upstream constriction with a continuous infusion of 5-HT, isoproterenol effectively lowered upstream
resistances. These findings were anticipated because others (12) have
demonstrated this previously in the canine pulmonary macrovasculature,
an area with known -receptors. However, we found that the capillary
surface area remained unchanged. This occurred despite the fact that
pressures in the vessels upstream from the capillary bed were elevated
and then brought back to baseline. This supports the hypothesis that the capillary bed may have modulatory properties that are independent of changes in the upstream vascular tone.
As shown in Table 1, mean arterial pressure (MAP), Hct, and arterial PCO2 decreased significantly during the experiment. The decrease in MAP is not surprising because isoproterenol is known to cause systemic vasodilation, but the MAP did not fall abnormally low. The fall in Hct is not unexpected because ~13 ml of blood are withdrawn for each measurement of transpulmonary metabolism. Although the resultant decrease in viscosity could possibly potentiate the decreases in upstream resistances observed with isoproterenol, Hct value differences at the initial vs. final measurements were of a magnitude unlikely to significantly affect viscosity. The observed drop in arterial PCO2 without a significant change in pH is indicative of a compensated metabolic acidosis, which may be due to a combination of the decreases in MAP and Hct. Because there was no acidemia, ACE function would have remained stable throughout each protocol (22). Even if such changes resulted in upstream pressure drops, there still was no change in the estimated perfused capillary surface area.
In this rabbit constant pulsatile flow cardiac-bypass model, we demonstrated that large- and small-artery resistances in the pulmonary circulation could be altered without any significant change in the perfused capillary surface area. In contrast to earlier thought, there was no decrease in capillary recruitment despite a decrease in the small-artery pressure. This supports the hypothesis that recruitment of the pulmonary capillary circulation is not solely dependent on changes in extracapillary tone.
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ACKNOWLEDGEMENTS |
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We acknowledge the diligent expertise of Jim Parkerson and Dr. Wendell Hoffman.
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FOOTNOTES |
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Address for reprint requests: L. E. Fisher, Jr., 1120 15th St., BIW-6033, Medical College of Georgia, Augusta, GA 30912-3758.
Received 25 March 1996; accepted in final form 29 October 1997.
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