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Vol. 83, Issue 5, 1476-1481, 1997
Department of Pathology and Meakins-Christie Laboratories, McGill University, Montréal, Quebec, Canada H3A 2B4
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Shi, Weibin, David H. Eidelman, and René P. Michel.
Differential relaxant responses of pulmonary arteries and veins in
lung explants of guinea pigs. J. Appl.
Physiol. 83(5): 1476-1481, 1997.
The endothelium
regulates vascular tone through release of relaxing or contracting
factors, with nitric oxide (NO) being a major endothelium-derived
relaxing factor. In the present study, we used a lung explant technique
to determine the differential abilities and mechanisms of pulmonary
arteries and veins of normal guinea pigs to relax after precontraction.
Excised lungs of 15 guinea pigs were filled through the airways with
1% agarose, cut into 1-mm-thick slices, and cultured overnight.
Luminal areas of vascular cross sections were measured with an
image-analysis system. Vessels were precontracted with U-46619, and
responses to histamine, acetylcholine (ACh), sodium nitroprusside, and
papaverine were examined. We also determined the effects of
N
-nitro-L-arginine
and of indomethacin on ACh-induced responses. We found that histamine
relaxed arteries more than veins and that ACh relaxed only arteries.
N-nitro-L-arginine pretreatment
abolished ACh-induced relaxation of arteries and caused ACh-induced
contraction of veins, whereas indomethacin markedly augmented
ACh-induced relaxation of arteries (maximal relaxation: 48.5 ± 4.7 vs. 19.2 ± 5.1% without it) and induced a dose-dependent
relaxation of veins (maximal relaxation: 17.0 ± 4.1%). Sodium
nitroprusside induced a significantly greater relaxation of arteries
than veins, whereas papaverine relaxed them equally. We conclude that
in guinea pigs endothelial NO-mediated relaxation is greater in
pulmonary arteries than in veins and that ACh-induced NO-mediated
relaxation is reduced by the simultaneous production of
cyclooxygenase-derived vasoconstrictors.
endothelium; acetylcholine; histamine; nitric oxide
INTRODUCTION DIFFERENTIAL ABILITIES of pulmonary arteries and veins
to dilate in response to pharmacological agents may influence
perfusion, ventilation-perfusion relationships, and vascular resistance
in the lung, all of which may affect fluid exchange and right
ventricular afterload. The endothelium regulates the tone of the
underlying vascular smooth muscle by synthesizing and releasing
endothelium-derived relaxing and contracting factors (13, 30). Nitric
oxide (NO), a chemically unstable radical, is a major
endothelium-derived relaxing factor synthesized from
L-arginine (13). Acetylcholine (ACh), histamine, bradykinin, and other agents dilate vascular smooth
muscle by stimulating the endothelium to release NO (13, 24). In
contrast, nitrogen-containing vasodilators, such as sodium
nitroprusside (SNP), act on smooth muscle directly by release of NO
(22). In the pulmonary vasculature, the endothelium-derived NO-mediated
relaxation of arteries and veins differs among species. In lambs and
pigs, it plays a larger role in veins than in arteries (4, 11). In
cattle, it modulates pulmonary arterial and venous tone similarly (16).
In ferrets, however, it acts predominantly in arteries (15). These
differences can be related either to the ability of the endothelium to
release NO or to the responsiveness of the vascular smooth muscle to it
(17, 30). In a previous study, Sakuma et al. (24) demonstrated that
histamine and ACh induced endothelium-derived NO-mediated relaxation in
pulmonary arteries of guinea pigs; what happens in pulmonary veins is
not known. Therefore, in the present study, we compared the relaxant responses of intrapulmonary arteries and veins of guinea pigs to
pharmacological agents that activate the different steps of the NO
pathway, i.e., endothelial-dependent and -independent, with those of
papaverine that, like NO, also increases cytosolic guanosine
3 METHODS
,5-cyclic monophosphate content but does so via
inhibition of phosphodiesterase activity (3, 8). To investigate further the differential responses of arteries and veins to these relaxing agents and their mechanisms, we opted for an in vitro lung-explant technique in guinea pigs. The method was previously used to study airway constriction in the rat (9). In this preparation, small airways
and vessels are readily and directly visualized by light microscopy,
and the structural relationships between vessels, airways, and
parenchyma are preserved.
-2-ethanesulfonic acid-buffered culture medium (HCM) (9) and placed on the stage of an
inverted microscope (LH50A, Olympus). Arteries and veins were
identified and imaged with a video camera (CDS; Sony, Nagano, Japan),
and images were recorded with a video disk recorder (TQ2026F; Panasonic, Osaka, Japan). To distinguish arteries from veins, we used
the following criteria: 1) the
arteries usually accompanied airways, whereas veins were at a
distance from them, and 2) arterial walls had a thick media and their inner lining was
slightly wrinkled, whereas veins were thinner and wrinkles were
inconspicuous.
Experimental protocol.
First, in all explants, baseline images of the vessels were generated.
Then they were precontracted with 1 or 3 × 10
6 M
9,11-dideoxy-11
,9-epoxymethanoprostaglandin
F2
(U-46619), the
thromboxane A2 analog, added
directly to the surface of the lung explants. Images were gathered
every 10 s for the first minute, then every minute for another 4 min.
Thereafter they were followed for a further 15 min to ensure stable
contraction, for a total of 20 min. To test the dilator responses of
these precontracted vessels, cumulative dose-response curves were
constructed by adding histamine solution in half-log unit intervals
from 1011 to
107 M and by adding ACh,
SNP, and papaverine solutions in one-log unit intervals from
1011 to
104 M. In addition, to
determine the differential roles of the NO and of the prostaglandin
pathways, some vessels were preincubated with
N-nitro-L-arginine benzyl ester
(L-NNA,
104 M) or with indomethacin
(105 M) for 30 min before
generating dose-response curves to ACh. In addition, as a control, we
tested the effects of the L-NNA and of indomethacin on the vessels in their baseline state without precontraction. In each explant, for the responses over time, we
studied one vessel, whereas for the dose responses, we usually observed
one artery and/or one vein and, in a few instances, two veins.
We studied a total of 75 arteries and 88 veins from 123 explants. The
numbers of animals used in each step of the protocol are indicated in
Figs. 1, 2, 3, 4, 5, 6.
6
M U-46619 of pulmonary arteries (Art) and veins in lung explants;
n, no. of animals. U-46619 constricted arteries and veins, with peak at 20 s, after which only arteries relaxed. After 120 s, both arteries and veins constricted gradually to
reach steady levels at 20 min.
* P < 0.05 vs. arteries.
-nitro-L-arginine
(L-NNA) resulted in further
contraction. * P < 0.05 vs.
ACh only.
8 to
104 M. * P < 0.05 vs.
veins.
Image and data analysis. The stored images were digitized by using an 80386 Intel-based microcomputer equipped with a frame-grabber board (PIP1024B; Matrox, Montreal, QC, Canada). The digitized images were then transferred to a scientific work station (RS6000; IBM, Armonk, NY), and measurements of luminal area were made with Galileo Image Processing Software (Inspiraplex, Montreal, QC, Canada). The contractile responses of arteries or veins to U-46619 were calculated as a percentage of complete vessel closure, using the equation
![Response = [1 − (residual area after drug/baseline area)] × 100](/content/vol83/issue5/fulltext/1476/img001.gif)
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![(baseline area − area before dilator)] × 100](/content/vol83/issue5/fulltext/1476/img003.gif)
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100% indicates a return to baseline state (i.e., before
precontraction) and 0% indicates full persistence of the precontracted state.
From these responses, time course and dose-response curves of arteries
and veins were constructed by plotting the mean values against time and
concentrations, respectively. The 50% effective concentration values were determined from each vessel and
expressed as negative log molar
(pD2) values.
Drugs.
All drugs were purchased from Sigma Chemical, St. Louis, MO. Histamine
(dihydrochloride), ACh (chloride), SNP, papaverine (hydrochloride), and
L-NNA (benzyl ester) were
prepared as stock solutions in HCM from which dilutions were prepared
fresh daily. Indomethacin was dissolved in ethanol and then diluted
with HCM. For U-46619, the stock solution at a concentration of
104 or 3 × 104 M was used directly.
All drugs were added to the explants in the culture wells in 20-µl
volumes, and their concentrations were expressed as values after
dilution of the 20 µl by the 2 ml of medium (i.e., 100-fold).
Statistical analysis.
Data are presented as means ± SE, with
n being the number of animals from
which the vessels were obtained, and with which all statistical
analyses were done. To compare the curves of the dose responses and of
the responses over time between arteries and veins or between control
and treated groups from the same type of vessels, two-way analysis of
variance was used. If the F-value was
significant, the Tukey test for unpaired observations or Student's
paired t-test for paired observations
was applied to ascertain significance at each concentration or time
point. The comparison of maximal responses or
pD2 values was performed by
two-way block analysis of variance, with Student's paired
t-test or the Tukey test as post hoc
tests. All the analyses were performed by using proprietary software
(Systat, Evanston, IL). Differences were considered statistically
significant at P < 0.05.
RESULTS
6 M U-46619. The veins
contracted rapidly and attained a plateau at 20 s that lasted
~120 s, followed by a slowly increasing contraction. The arteries reached their peak of contraction at the same time as the
veins. However, the artery responses waned substantially up to 120 s
and thereafter slowly increased their contraction.
Overall, the veins constricted to a greater degree than the arteries
(P < 0.01). By 20 min, both arteries
and veins reached a plateau of contraction, greater in the latter
(P < 0.05).
Responses to histamine.
In the arteries, after precontraction with U-46619, histamine
(1011 to
107 M) produced
dose-dependent relaxation in arteries and veins, significantly greater
in the arteries (Fig. 2). At
107 M, histamine started to
contract the arteries and veins.
Responses to ACh and effects of
L-NNA and indomethacin.
In precontracted arteries, ACh caused a dose-dependent relaxation (Fig.
3), with maximal responses of 19.2 ± 5.1% and
pD2 values of 8.1 ± 0.7 (Table
1). In the arteries pretreated with L-NNA, ACh caused further
constriction instead of relaxation. Indomethacin, however, markedly
augmented ACh-induced relaxation (Fig. 3 and Table 1). In precontracted
veins, ACh had no significant effect
(P > 0.05), although it caused a
slight contraction at 105
and 104 M
(Fig. 4). In veins pretreated with
L-NNA, however, ACh induced constriction, whereas after indomethacin, it produced a dose-dependent relaxation, with a maximal relaxation response of 17.0 ± 4.1% (Fig. 4 and Table 1).
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1.6 ± 0.6 and 3.4 ± 0.8%, respectively) or of veins
(1.3 ± 1.0 and 1.9 ± 0.5%, respectively).
Responses to SNP and papaverine.
SNP produced dose-dependent relaxation in both arteries and veins,
significantly greater (P < 0.05) in
the arteries between 108 and
104 M (Fig.
5).
The pD2 values were also
significantly greater (P < 0.05) for
arteries than veins (Table 1). Papaverine also caused relaxation of
both arteries and veins, the extent of which did not differ
significantly between either vessel types for the whole curves or in
the maximal relaxation responses (P > 0.05; Table 1, Fig. 6).
DISCUSSION
In the present study, we examined the differential responses of intrapulmonary arteries and veins to ACh, histamine, SNP, and papaverine after precontraction with U-46619. We found that 1) ACh relaxed arteries but had no significant effects on veins, and the effect in the former was mediated by NO, not by dilator prostaglandins; 2) histamine and SNP relaxed arteries more than veins; and 3) papaverine relaxed arteries and veins equally.
The lung explant technique has been successfully used to study constriction of the airways in rats (9). Like the airways, the pulmonary arteries and veins in this preparation have a nearly circular cross section within the framework of an intact and supporting parenchyma, just as they do in vivo. The reasons the pulmonary vessels remain open and nearly circular despite the absence of intraluminal pressure are most likely their low baseline tone and the preload provided by the stretch from the surrounding parenchyma filled through the airways with agarose. In preliminary experiments in rats, we also perfused the vessels with agarose to increase their preload and, although we found an increased contractile response to 5-hydroxytryptamine, qualitative differences between arteries and veins were unchanged. Thus, in the present study, we opted not to perfuse the vessels with agarose because of the possibility that we might impair drug access to the endothelium or that we might damage the endothelium.
In the pulmonary vessels of adult guinea pigs, we found that neither
L-NNA nor indomethacin had much
effect on baseline vascular areas. This indicates that neither NO nor
prostacyclin modulates its baseline vascular tone significantly. In
rats and dogs, NO synthase inhibitors have also been found to be
without significant effects on pulmonary vascular tone under baseline
conditions (12, 20). In mammalian systemic resistance vessels and in
adult ovine pulmonary veins, however, inhibition of basal NO production
does induce contraction (4, 29). Satoh and Inui (26) first reported that histamine induced endothelium-dependent relaxation in guinea pig
pulmonary arteries. Abacioglu et al. (1) found that
H2 receptors on smooth muscle
contributed to histamine-induced relaxation, even though their effect
was much weaker than that produced by H1 receptors on the endothelium. A
subsequent study indicated that NO was the mediator responsible for
histamine-induced endothelium-dependent relaxation and that it was
unaffected by indomethacin (24). Our results extend these studies by
showing that histamine also relaxed pulmonary veins, although
significantly less than arteries. In a separate study in lung explants,
we found that L-NNA, but not
indomethacin, potentiated the contractile responses of pulmonary arteries and veins to histamine (27). Thus the histamine-induced relaxation in guinea pig pulmonary veins was probably also primarily mediated by NO, not by prostaglandin
I2. Moreover, in the present study, we found that at higher concentrations
(>107 M), histamine
contracted pulmonary arteries and veins (Fig. 2). This observation is
in accordance with the findings of Abacioglu et al. (1) in main
pulmonary artery strips of guinea pigs.
It has been suggested that ACh produces endothelium-dependent
relaxation of pulmonary arteries in newborn and adult guinea pigs (10,
24, 25). The mediators involved in this relaxation, however, have not
been completely elucidated. Sakuma et al. (24) reported that the NO
synthase inhibitor
N-monomethylarginine
antagonized only 64% of ACh-induced relaxation. In the present study,
however, we found that it was completely abolished by the
NO inhibitor L-NNA. One
explanation for the discrepancy between the data of Sakuma et
al. and ours is that the different analogs of
L-arginine could affect
endothelium-dependent relaxation differentially (6). Another
explanation may be that we used a higher concentration of this
inhibitor and/or that responses of smaller intrapulmonary
arteries differ from those of larger ones. Our findings that
indomethacin potentiated the relaxation of arteries and caused
relaxation of the veins with ACh were unexpected, and these results
suggest that the relative contribution of vasoconstrictor cyclooxygenase products was greater than that of vasodilator
cyclooxygenase products during the response. This
contrasts with the results in dogs reported by Miller and Vanhoutte
(21), who found that arachidonic acid relaxed pulmonary arteries but
contracted veins and that these effects were abolished by inhibitors of
the cyclooxygenase pathway and by denudation of the endothelium.
Although ACh is a classic agonist of endothelium-dependent relaxation
in most blood vessels, it fails to produce relaxation in some blood
vessels [for example, in bovine pulmonary veins (16) and in
newborn ovine pulmonary arteries (14)], even causing
endothelium-dependent constriction. Contraction has also been reported
in the pulmonary vessels of rabbits (2) and in coronary arteries of
most species (18). Thromboxane
A2 is the putative mediator,
because constriction could be prevented by cyclooxygenase inhibitors,
thromboxane A2 synthase
inhibitors, and thromboxane A2
antagonists (2). In addition, our findings seem to exclude an important
role for prostacyclin, another endothelium-derived relaxing factor, in
the ACh-induced relaxation of guinea pig pulmonary arteries.
Compared with the arteries in the present study, the pulmonary veins of
guinea pigs showed a weaker relaxation to ACh, and the relaxation
occurred only after inhibition of the cyclooxygenase pathway with
indomethacin. This relaxation was probably also mediated by NO, because
prostacyclin had been inhibited with indomethacin during the response
and the NO synthase inhibitor
L-NNA enhanced ACh-induced
contraction in these veins. The weaker relaxant response of the veins
could also be explained by the lower reactivity of their smooth muscle
to NO or by a reduced ability of the endothelium to produce NO. We
investigated this by using SNP, which acts like exogenous NO (22), and
indeed found that the veins responded less to SNP than did the
arteries. This finding is in agreement with previous findings in
isolated perfused lungs of rats and pigs (7, 23), as well as in
systemic vessels (17). The smaller relaxant response of the veins could
be due in part to the greater precontraction to U-46619 (28). However,
this is unlikely because papaverine, which increases cytosolic
guanosine 3,5-cyclic monophosphate content by inhibiting
the activity of phosphodiesterase independent of the endothelium and
the NO pathway (3, 19), relaxed arteries and veins equally. Thus, after
inhibition of the cyclooxygenase pathway, the differences between arteries and veins in response to ACh lie in the reduced responsiveness of the venous smooth muscle to NO, with a component of
the reduced ability of the venous endothelium to release NO.
In conclusion, our data demonstrate that in guinea pigs, endothelial NO-mediated relaxation is greater in pulmonary arteries than in veins and that ACh-induced relaxation was reduced in the arteries and masked in the veins by constricting factors from the cyclooxygenase pathway. Differences in NO-mediated relaxation of pulmonary arteries and veins may also contribute to their differential contractile responses. Indeed, the data of Bradley et al. (5) in isolated perfused lungs and our own findings in lung explants (27) reveal that, in guinea pigs, pulmonary veins constrict more than arteries in response to histamine and serotonin. Because histamine and 5-hydroxytryptamine stimulate the release of endothelial NO, in addition to contracting vascular smooth muscle (13), the reduced release of NO by the venous endothelium and the diminished responsiveness of the venous smooth muscle to NO may produce a smaller relaxant effect to antagonize the vasoconstriction. Furthermore, the present study, together with others (21, 30), has indicated that endothelium-derived contracting factors contribute to the differential relaxant responses of arteries and veins. Because pulmonary veins are the major site of action of several vasoconstrictors (5, 15, 31), if NO-mediated relaxation in them is decreased and/or if they produce more contracting substances, an exaggerated increase in microvascular pressure could result, potentially contributing, for example, to the formation of pulmonary edema under pathological conditions.
ACKNOWLEDGEMENTS
This work was supported by Medical Research Council of Canada Grants MT-7727 and MT-11330 and by the J. T. Costello Memorial Fund. W. Shi is the recipient of a studentship from the Royal Victoria Hospital Research Institute. D. Eidelman is the recipient of a Chercheur-Boursier award from the Fonds de Recherche en Santé du Québec.
FOOTNOTES
Address for reprint requests: R. P. Michel, Dept. of Pathology, McGill Univ., 3775 University St., Rm. B15, Montréal, QC, Canada H3A 2B4 (E-mail: michel{at}pathology.lan.mcgill.ca).
Received 12 February 1997; accepted in final form 2 July 1997.
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X. Ding and P. A. Murray Regulation of pulmonary venous tone in response to muscarinic receptor activation Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L131 - L140. [Abstract] [Full Text] [PDF]
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W. Shi, F. Hu, W. Kassouf, and R. P. Michel Altered reactivity of pulmonary vessels in postobstructive pulmonary vasculopathy J Appl Physiol, January 1, 2000; 88(1): 17 - 25. [Abstract] [Full Text] [PDF]
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