(Stroke. 1997;28:2486-2492.)
© 1997 American Heart Association, Inc.
Articles |
Diameter Dependence of Myogenic Tone of Human Pial Arteries
Possible Relation to Distensibility
From the Totman Laboratory for Human Cerebrovascular Reseach, Department of Pharmacology (N.T.-T., T.B., R.D.B., J.A.B.) and the Division of Neurosurgery (N.H., P.L.P.), University of Vermont, Burlington, Vt and Neurological Surgeons (C.L.W.), Phoenix, Ariz.
Correspondence to John A. Bevan, MD, the Totman Laboratory for Human Cserebrovascular Research, University of Vermont, Given Building, Burlington, VT 05405-0068.
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Abstract |
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Background and Purpose Responses to changes in intraluminal pressure of isolated human pial arteries (200 to 1200 µm i.d.) obtained from patients undergoing neurosurgery were measured.
Methods The vessels were cannulated and pressurized (60 mm Hg); vascular diameter and intraluminal pressure were recorded simultaneously. After spontaneous development of steady state tone, intraluminal pressure was changed to both higher and lower levels in random sequence.
Results Human pial arteries exhibited myogenic responses and maintained their diameter over the pressure range of 20 to 100 mm Hg. The level of myogenic tone observed at 30 mm Hg did not vary significantly with artery diameter. In contrast, at 60 and 90 mm Hg, the extent of myogenic tone increased as the diameter decreased (up to 70% to 80% of maximum in 200-µm i.d. arteries). The arteries contracted to KCl 30 mmol/L, norepinephrine 1µmol/L, and vasopressin 0.1µmol/L and relaxed to acetylcholine 3 µmol/L. The extent of these responses did not vary with the diameter of the artery. Arterial distensibility, represented by the slope of the tangent of the passive pressure-diameter curve at lower pressures (5 to 50 mm Hg), increased as arteries became smaller. This is consistent with the possibility that the level of myogenic tone is related to vessel distensibility. Human omental arteries of comparable size did not develop myogenic tone but contracted to KCl and norepinephrine and relaxed to acetylcholine to an extent similar to pial arteries.
Conclusions There is a specific gradient of myogenic responsiveness in human pial arteries that varies inversely with their diameter. This tone does not develop in all vascular beds. These levels of tone in the pial circulation would be expected to be of profound functional significance by allowing blood flow to vary widely.
Key Words: human cerebral artery • myogenic response • arterial wall distensibility
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Introduction |
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The myogenic response first reported by Bayliss1 refers to the ability of a blood vessel to respond by contraction when intraluminal pressure is increased or by dilation when it is reduced. Myogenic muscle tone contributes to the autoregulation of blood flow,2 underlies the basal tone of small blood vessels, and is thus an important component of vascular resistance. The cerebral circulation autoregulates effectively, and it is generally conceded that myogenic responsiveness is a key element in this mechanism.3
Most of the information concerning the characteristics and cellular mechanisms of myogenic responses in the cerebrovascular system has been derived from the study of animals under both in vivo4 5 6 and in vitro7 8 9 10 conditions. In vitro observations have been made primarily on arteries of 100 to 300 µm (i. d.), and in vivo studies rarely encompass vessels >400 µm (i. d.). However, there is no reason to assume that cerebral myogenic activity in humans should be restricted to vessels of these dimensions. Large pial arteries are known to respond to pharmacological agents,11 12 13 14 15 16 and human pial arteries of >1 mm in diameter obey the principles of optimality in situ.17 This implies active regulation. They therefore might be expected to participate in autoregulative responses. Myogenic tone seems to be a common feature of the mammalian cerebral circulation. It is found in the rat,4 18 rabbit,10 cat,5 6 and dog.19 However, different relations between intraluminal pressure and diameter have been found even in different strains of the same species.18 In a number of vascular systems, myogenic tone was found to vary with diameter,20 21 but whether this is the case for the human cerebral circulation is not known.
We used isolated human pial artery segments obtained from patients undergoing neurological surgery to investigate the myogenic responses of pial arteries to changes in intraluminal pressure. These vessels ranged from 200 to 1200 µm i.d. We found that there is a gradient of myogenic responsiveness that varies inversely with the diameter of the artery that reaches values at 60 mm Hg in arteries of 200 µm i. d. of 70% to 80% of maximum possible contraction. Because we found that the tangential modulus of elasticity increases with decreasing vessel diameter, we propose that the increased level of myogenic activity might be associated, at least in part, with increased wall distensibility.
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Materials and Methods |
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Preparation of Vessels
Human pial arteries (n=29 patients; 20 men, 9 women) were obtained from intact regions of the cortex removed during neurosurgical procedures for access to tumors. The arteries had no macroscopic disease. Age varied between 15 and 69 years for men (45±3 years) and between 15 and 70 years for women (52±7 years).
Segments of omental arteries (n=9 patients; 4 men, 5 women) were removed during abdominal surgery when the lesions were distant from the omental tissue. Age varied between 23 and 85 years for the men (47±14 years) and between 22 and 71 years for the women (41±9 years).
The arteries were brought to the laboratory in cold modified PSS that contained deferoxamine (100 µmol/L), heparin (10 U/ml), penicillin (50 U/ml), and streptomycin (50 µg/ml). PSS has the following composition (mmol/L): NaCl 119, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, NaHCO3 24.9, CaCl2 1.6, EDTA 0.023, and dextrose 5.5. The vessels were studied either in vitro on the same day of removal or held at 4°C in saline solution for no more than 24 hours. We have reported previously that overnight storage does not affect myogenic and vasoactive responses.22 After dissection, each segment 1.5 to 2.5 mm in length was mounted in a pressure-perfusion system arteriograph (Living Instruments).
The study was approved by the University of Vermont Human Use and Ethics Committee.
The arteriograph consists of a 15-mL vessel chamber with inlet and
outlet ports for superfusing saline solution bubbled with a mixture of
10% O2, 85% N2, and 5% CO2 and
an optical window in the base to allow vessel visualization through an
inverted microscope (Leitz). Two glass microcannulae are suspended
within the chamber. After the vessel was mounted on the proximal
microcannula (connected to a servo-syringe system), the pressure was
raised to 5 to 10 mm Hg to flush and clear the vessel of
blood. Then, the distal end of the artery was mounted to the outflow
microcannula (attached to a micrometer to permit
adjustments in axial length). Artery diameter was measured at a
pressure of 5 mm Hg (see below). The outflow cannula was
closed and pressure raised and set to 20 mm Hg with the
pressure-servo system. Potential leaks were revealed by the loss of
pressure; any leaking vessel was rejected. Transmural pressure was then
raised to 60 mm Hg, and the vessel was warmed slowly to
37°C and allowed to equilibrate for 60 to 90 minutes. Sixty
mm Hg was arbitrarily chosen because it represents 
60%
of human mean blood pressure (see "Discussion"). Changes in the
steady-state diameter of the artery were measured under no flow
conditions and in response to step increases or decreases in
intravascular pressure.
Experimental Protocol
Human Pial Arteries
Myogenic tone usually began to appear after 30 to 40 minutes of
equilibration. When the level of pressure (60 mm Hg)-induced
constriction was stable, data for an active pressure-diameter curve was
obtained; transmural pressure was increased or decreased in 20- to
30-mm Hg steps, over the range of 30 to 100 mm Hg in random
sequence. The pressure was maintained at each pressure step for 15 to
20 minutes to allow the vessel to reach a steady state. Effects of
lower or higher pressures were tested only at the end of the protocol.
These pressures induced unstable fluctuations in diameter with eventual
loss of tone. At 60 mm Hg, the contractile responses to KCl
30 mmol/L, NE 1µmol/L, and vasopressin 0.1µmol/L were
measured. The vasoactive function of the endothelium
was assessed by the exposure of an NE-constricted vessel to ACh 1
µmol/L. At the conclusion of the experiment, the suffusion solution
was changed to a solution containing 127 mmol/L KCl to allow the
measurement of the maximum constricted diameter at each pressure step.
Then, the suffusion solution was changed to a Ca2+-free
solution containing ethylene glycol-bis (ß-aminoethyl ether)-N, N,
N',N'-tetraacetic acid (EGTA, 2 mmol/L), which eliminates all
active tone, and a passive pressure-diameter curve was constructed.
Human Omental Arteries
Myogenic tone did not develop in the omental arteries within 2
to 3 hours of setup. At this time, contractile responses to KCl 30
mmol/L and NE 3 µmol/L were measured at 60 mm Hg. ACh
3 µmol/L was tested after the tone had increased on exposure to
NE. Finally, changes in diameter in the presence of 127 mmol/L KCl
and in Ca2+-free solution with incremental changes in
pressure were recorded.
Parameters Measured
Pressure-diameter curves were constructed by the use of absolute
diameter (µm) values (Fig 1A
, 1B, and 1C) (1) in normal PSS (active pressure-diameter curves), (2) in
Ca2+-free solution (passive pressure-diameter curves), and
(3) in a solution containing 127 mmol/L KCl (maximum
pressure-diameter curves).
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) to obtain the maximum
pressure-diameter relations and repeated in the presence of
Ca2+-free solution containing 2 mmol/L EGTA (
) to
obtain the maximum passive diameter at each pressure value. Results are
mean±SEM of n patients; *P<.05 active vs passive
diameter (paired Student's t-test).
To pool pressure-diameter curves from omental arteries varying from 100
to 900 µm i. d., the diameter data were normalized to the
diameter of each vessel obtained in Ca2+-free solution at
100 mm Hg when the passive pressure-diameter curve had
plateaued. The normalized diameter data were averaged to obtain
composite pressure-diameter relations of human omental arteries (Fig 4).
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) were obtained after
normalization of the diameter data for each vessel obtained in
Ca2+-free solution containing 2 mmol/L EGTA at
100 mm Hg (see "Methods" for details). Passive curves
(
) were obtained in Ca2+-free solution containing 2
mmol/L EGTA. Results are mean±SEM of n patients.The level of myogenic tone developed at a given intraluminal pressure was calculated according to the following equation: myogenic tone=100x[(dCa-free-d)/(dCa-free-dKPSS)] where dCa-free is the diameter obtained at a given luminal pressure in Ca2+-free solution, d is the steady state diameter reached by the vessel at a given luminal pressure, and dKPSS is the diameter obtained at a given luminal pressure in KCl 127 mmol/L-solution.
Arterial distensibility was represented by the slope of the tangent of a normalized passive pressure-diameter curve. This is equivalent to the tangential modulus of elasticity. The slope was calculated as follows: passive pressure-diameter curve from each vessel was first normalized to the diameter obtained in calcium-free solution at 100 mm Hg. This normalized passive pressure-diameter curve was then fitted to a 3rd polynomial function because this gave the best fit (r2=0.99, for all arteries). Thirteen data points were collected on each artery that were summarized by the 3rd polynomial. Then, the first derivative of this equation (ie, the slope of the tangent of the curve) was calculated at every data point over the range of 5 to 140 mm Hg.
Criteria were established for an acceptable tissue: (1) there should be no leaks from the segment; (2) it should develop spontaneously maintained tone within 2 hours of setup, the tone should be uniform and should not show significant drift over the time course of the experiment; and (3) it should constrict to KCl and NE and relax to ACh. With the use of such criteria, 29 patients (pial arteries) were selected from 52 patients tested. Nine omental arteries from 9 patients were tested; the vessels did not develop myogenic tone but constricted and relaxed to vasoactive drugs.
Human pial and omental arteries were of similar size (100 to 1000 µm) and were obtained from patients of similar age (20 to 70 years).
Statistics
The data are presented as mean±SEM of n patients.
Differences were considered significant at P<.05 and were
determined by ANOVA followed by a Scheffe test and by paired or
unpaired Student's t test, as appropriate. Because complete
pressure-diameter curves were not always constructed in all arteries
tested, the sample size varies from one figure to the other.
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Results |
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Pressure-Diameter Relations of the Human Pial Arteries
Pressure-diameter relations for human pial arteries are summarized in Fig 1
. The vessels have been divided into three groups: small
(217±23 µm, n=14), medium (618±72 µm, n=4), and large
(984±57 µm, n=2). The ages of the donors were similar in the
three groups (47.3±4.7 years [16 to 69 years], 52.5±8.2 years [37
to 69 years], and 62.5±6.5 years [56 to 69 years], respectively).
In small and medium sized arteries, the active pressure-diameter values
(middle curves) were significantly different from the passive
pressure-diameter values (top curves) over the pressure range of 30 to
90 mm Hg (Fig 1A and 1B). The same trend appeared to be
present in the larger vessels (Fig 1C). The mean diameters remained
constant despite an increase in pressure over 20 to 100 mm
Hg. When the experimental pressure step was positive, the diameter
initially increased, presumably because of passive distention; then,
over the next 1 to 2 minutes, the diameter actively approached original
value (Fig 2). The opposite occurred when
the pressure step was negative (Fig 2). The maintained constancy of
active diameter contrasted with the passive diameter that invariably
increased with increasing pressure. Thus, the maintenance of
the active diameter with a rise in pressure represents a
shortening of the smooth muscle cells and an increase in active stress
development.
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Relations Between Myogenic Tone and Human Pial Artery
Diameter
In Fig 3 are shown the relations
between myogenic tone developed at 30, 60, and 90 mm Hg and
pial artery inner diameter measured at 5 mm Hg. At 60 and
90 mm Hg, the level of myogenic tone increased significantly
as the vessel diameter decreased (y=-0.036x+ 81.014 at 60 mm
Hg and y=-0.026x+75.22 at 90 mm Hg, Fig 3B and 3C). The
regression relations at these two pressures suggest that the maximum
level of tone when the diameter is 1000 µm is 45% of maximum
contraction and that at a diameter of 200 µm it varies between
70% and 80%. Extrapolation suggests that vessels of a diameter
>2000 µm would not develop myogenic tone.
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), (B) 60 mm Hg
(
At 30 mm Hg, responses were more varied and no significant
correlation between myogenic tone and pial artery diameter was found
(y=-0.009x+52.816 at 30 mm Hg, Fig 3A). The mean level of
myogenic tone was approximately one-half of the maximum capacity to
constrict.
The relation between vessel diameter and the amplitude of myogenic responses was not observed with other stimuli. Pial arteries contracted to KCl 30 mmol/L (41.3±13.4% of maximum, n=5), NE 1µmol/L (39.7±7.5% of maximum, n=11), and vasopressin 0.1µmol/L (68.8±12.1% of maximum, n=8) and relaxed to ACh 3µmol/L (54.5±20.1% of NE-induced tone, n=6) and histamine 0.1µmol/L (100.0±0.0% of vasopressin-induced tone, n=4). The size of the responses to KCl, NE, vasopressin, ACh, and histamine was not related to artery diameter (P=.49, P=.58, P=.78, P=.21, and P=.9, respectively). However, vasoactive agents were added to pial arteries that were already myogenically constricted. Because myogenic tone varies with artery size, the absolute change in diameter in response to a vasoactive agent would be expected to vary with the diameter.
Human Omental Arteries
A total of nine technically successful experiments were carried
out on omental artery segments that ranged from 141 to 729 µm
i.d.. Fig 4 shows that no myogenic tone
developed when intraluminal pressure was held at 50, 60, 70, 80, 90, or
100 mm Hg. The mean percentage decrease in diameter with KCl
30 mmol/L was 41.9±10.6% (n=5) and with NE 3µmol/L it was
52.3±16.4% (n=5). The latter level of tone was reduced by
69.2±23.2% by ACh 1µmol/L.
Human Pial Artery Elasticity and Myogenic Tone
One possible explanation of the increase in the level of myogenic
(stretch-induced) tone with a decrease in vessel diameter is that
smaller vessels are more distensible than larger ones. Thus, a standard
intraluminal pressure would stretch the smaller vessel relatively more
than the larger one, and this would result in relatively greater
contraction of the smaller vessel. As myogenic tone is expressed in
relation to the difference between passive and maximally active
diameters at a particular pressure, the myogenic response to the
increased distensibility would be seen as a higher percentage level of
developed tone in the smaller arteries.
In Fig 5, arterial
distensibility is represented by the slope of the tangent
of the normalized passive pressure-diameter curve measured at 5
mm Hg. The slope is significantly greater in smaller vessels
compared with larger vessels (P<.05). A similar relation
was found at other lower pressures (10, 15, 20, 30, and 40 mm
Hg, [P<.01] and 50 mm Hg
[P<.05]). In contrast, at higher pressures (60, 70, 80,
100, 120, and 140 mm Hg) distensibility did not vary with the
diameter. These results suggest that the slope that corresponds to the
tangential modulus of elasticity is significantly greater in smaller
vessels compared with larger vessels.
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Myogenic Tone, Elasticity, and Age
Age of the donors of pial arteries varied between 15 and 70 years.
The level of myogenic tone developed at 30, 60, and 90 mm Hg
was not related to the age of the donor (P=.57,
P=.14, and P=.62, respectively). Similarly, the
vasoactive responses to KCl, NE, vasopressin, ACh, and histamine were
independent of the age of the donor (P=.54,
P=.19, P=.16, P=.93, and
P=.90, respectively).
Distensibility measured at 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 100, 120, and 140 mm Hg was also independent of the age of the donor (P>.05 for each pressure).
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Discussion |
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Our experiments show that human pial arteries develop myogenic tone in response to changes in intravascular pressure between 30 to 90 mm Hg. Diameter was maintained constant over this pressure range. Similar pressure-diameter relations were observed in small (200 µm i.d.), medium (600 µm i.d.), and large (1000 µm i.d.) human pial arteries. The magnitude of the response at 60 and 90 mm Hg increased as artery diameter diminished. This gradient was specific to myogenic responses because it was not observed with pharmacological stimuli. We suggest that myogenic tone is greater in smaller vessels because they are more distensible than larger ones.
This is a study of myogenic tone in a human adult resistance artery. With the use of a similar technique, no myogenic tone developed in arteries from human gluteal biopsies.23 We did not observe tone in human omental arteries or in the human superficial temporal artery (unpublished data, Bevan). With the use of spiral strips and wire-mounted segments, tone has been rarely seen in animal cerebral arteries; for example, see Reference 2424 . Spontaneous tone occurs in the human umbilical artery,25 the human facial vein,26 and the saphenous vein.27
Our experiments were concluded by measuring diameters when the arteries were maximally constricted and then when tone was prevented. By this means, the myogenic response magnitude could be related to the maximum constrictor capacity at each intravascular pressure (see References 7 and 207 20 ). Levels of steady state myogenic tone at 60 and 90 mm Hg varied from 70% to 80% in arterial segments of approximately 200 µm i.d. to 45% in those of 1000 µm i.d.. In the largest pial arteries studied, levels of 20% to 30% were observed. Myogenic tone levels of 30% have been observed in the isolated rat posterior cerebral artery segments.7 The highest reported level of myogenic tone is 60% to 70% in the hamster cheek pouch arteries (50 to 80 µm i.d.).21 Myogenic tone has been observed in cat middle cerebral arteries of 2509 and 350 µm i.d..28
Fein et al29 measured cortical artery and systemic
pressures of patients. When the systemic pressure was 60 mm
Hg, the pressure in cortical arteries (600 to 1600 µm o.d.) was
close to 54 mm Hg. In the cat, when central
arterial pressure was 100 mm Hg, pressure in
arteries of 150 to 225 µm i.d. was 50 to 60 mm
Hg.5 Kontos et al,5 concluded that in the cat
and dog, vessels between the aorta and the Circle of Willis account for
17% of the total peripheral resistance and that the
consecutive arteries, down to those approximately 200 µm i.d.
account for an additional 26%. The gradient in pressure along the
human pial arterial tree is not known.
Relation Between the Level of Myogenic Tone and Diameter
According to a conclusion based on studies restricted to smaller
arteries, the level of myogenic tone increases with a decrease in
arterial diameter in a variety of regional vascular beds
from a number of species.20 Greater responses in the
smaller arteries compared with the larger arteries were found in vivo
in the rabbit30 and the rat.31 These various
studies were undertaken in vivo when there were likely to be a number
of concurrent influences that would modify the primary myogenic
response. These include alterations in intraluminal flow,10
circulating vasoactive substances,32 perivascular nerve
activity,33 and metabolic factors. Previous
studies concluded that vessel myogenic responses were size dependent
and that the autoregulatory adjustments in caliber of some vessels
would modify those of others.6 31 34 In comparison to some
other beds, however, large cerebral arteries play a major role in the
regulation of blood flow and contribute to the total cerebral vascular
resistance.35 Because of the very considerable difference
in the diameter range of human and animal pial arteries, meaningful
comparisons between species are difficult.
Stretch-induced changes in tone have been reported in muscular and elastic arteries other than the cerebral arteries36 ; however, this is not a common finding. Stretch-induced changes in the tone of larger arteries have not been studied in isolated segments under isobaric conditions. Vessels of this size are usually examined in vitro on a wire myograph where stretch-dependent myogenic responses are rare.37 The absence of stretch-induced tone in larger vessels studied on the myograph does not exclude myogenic activity in vivo.
Myogenic Activity and Distensibility
It is interesting to speculate on the basis of the increased
myogenic level with decreasing diameter observed in a number of
regional vascular branching systems. The following are some
possibilities.
Differences in Muscle Mass
We have observed that the size of medial wall thickness relative
to vessel internal diameter (media-lumen ratio) increases with
decreasing diameter in the human pial arteries.38 A similar
relation has been seen in subcutaneous human resistance
arteries.39 Furthermore, the maximum force developed can be
correlated with medial thickness. Thus, the increase in myogenic tone
could reflect the increase in smooth muscle mass relative to the
diameter. In this present study, however, myogenic tone is
expressed in relation to the maximum capacity of that particular
segment to develop tone (ie, responses are normalized to exclude
differences caused by wall thickness or capacity to develop wall
force).
Myogenic Tone Develops to Maintain a Constant Level of Wall Force
at Varying Pressures
This is clearly not the case in these human pial vessels. Pial
artery lumen diameter remained remarkably constant over the middle
pressure range. This could be achieved only by increasing levels of
wall force development with an increase in intraluminal pressure and an
increase in passive diameter with pressure rise.
Magnitude of Response of a Blood Vessel to Vasoactive
Stimuli
Gore40 proposed that the magnitude of the response of
a blood vessel to vasoactive stimuli would vary with the resting length
of the smooth muscle cells. The shape of the active length-tension
curve of smooth muscle cells is well known. Changes in intravascular
pressure would alter smooth muscle length and this would, in turn,
influence the size of the active response to reflect the shape of the
curve. It might be that the level of myogenic tone achieved in isolated
segments reflects optimization of response characteristics.
Differences in Distensibility
To maintain arterial diameter constant over a range of pressure,
the shortening of the smooth muscle cell must vary with pressure and
the cells shorten to a constant length. Thus, the amount of myogenic
tone seen to develop experimentally reflects the difference between
passive and active tone diameters. This concept is consistent
with our observation that as vessels get smaller their distensibility
increases and the extent of myogenic contraction also increases (Fig 4). Thus, at a given intraluminal pressure, smaller vessels are
distended more than larger ones, and this results in a relatively
greater myogenic contraction of the smaller arteries to achieve a
particular diameter goal. The slope of the passive diameter pressure
curve at 60 mm Hg suggests that the distensibility of a
200-µm i.d. artery is 1.8 times that of a 1000-µm i.d. vessel.
Myogenic tone levels at 60 mm Hg in the smallest arteries are
approximately twice what they are in the largest arteries. At 50
mm Hg, mean distensibility is 2.3 times greater in the smallest
vessels compared with that in the largest vessels.
This argument, however, is diminished by observations that in some vessels from other vascular beds (see above) the myogenically assumed diameter decreases with increasing pressure. Osol and Halpern18 found that pial diameter decreased in response to increasing intravascular pressure in normotensive rats, but in spontaneously hypertensive rats diameter was maintained constant. Diameter decrease with increasing pressure was observed in the rat mesenteric artery,41 the hamster cheek pouch arteriole,21 and the rabbit skeletal muscle arteriole.42 The reasons for these differences are unknown.
Physiological Significance
In summary, human pial arteries of 1 mm i.d. and less were
found to develop increasing levels of myogenic tone as they became
smaller. This gradient was specific for the response to changes in
intravascular pressure. Myogenic tone in situ would possibly be
modified by a variety of other concurrent influences that include
flow,10 43 44 metabolic factors, and
neurogenically released and circulating vasoactive substances.
The human cerebral vasculature, as a whole, effectively autoregulates but also has the innate capacity to alter blood flow to local areas of the brain in relation to the need. To permit this, the more distal pial arteries must have the capacity to both decrease and increase their diameters, with the latter being achieved by dilating from the constricted state. To achieve this economically, as the human pial arteries become smaller, they exhibit increasing levels of intrinsic stretch-induced tone and also an increase in the wall thickness–to-lumen ratio. This design results in considerable power and flexibility of vascular responsiveness.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Totman Medical Research Fund and USPHS HL 32985. The authors thank Alynn Gentry for her technical assistance.
Received March 27, 1997; revision received September 26, 1997; accepted September 26, 1997.
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