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1 Institut für Anatomie und Zellbiologie, Justus-Liebig-Universität Giessen, D-35385 Giessen, Germany; and 2 Physiologisches Institut, Tierärztliche Hochschule, D-30173 Hannover, Germany
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Haberberger, Rainer, Michael Schemann, Holger Sann, and
Wolfgang Kummer. Innervation pattern of guinea pig pulmonary vasculature depends on vascular diameter. J. Appl.
Physiol. 82(2): 426-434, 1997.
The pulmonary
vasculature is supplied by various neurochemically distinct types of
nerve fibers, including sensory substance P-containing and autonomic
noradrenergic, nitrergic, and cholinergic axons.
Pharmacological experiments have suggested that various segments of the
pulmonary vascular tree respond differently to the respective
neuromediators. We, therefore, aimed to determine histochemically and
immunohistochemically for each of these neurochemically distinct
perivascular axons their quantitative distribution along the vascular
tree from the extrapulmonary trunks to the smallest intraparenchymal
ramifications in control guinea pigs
(n = 5). Generally, arterial
innervation was more developed than that of veins. Along the arterial
tree, noradrenergic and substance P-containing axons were ubiquitous
from the pulmonary trunk to smallest intraparenchymal vessels, whereas
nitrergic axons were practically restricted to large (>700-µm)
extrapulmonary arteries. Cholinergic axons were regularly present at
arteries down to 100 µm in diameter and innervated two-thirds of
small arteries (50-100 µm). The results demonstrate that
the noradrenergic vasoconstrictor innervation extends throughout the
pulmonary vascular system whereas the innervation pattern with various
types of vasodilator fibers changes with vascular diameter, parallel to
known pharmacological differences in cholinergic and nitrergic
vasodilator effects.
pulmonary artery; acetylcholine; choline acetyltransferase; nitric
oxide; nitric oxide synthase; substance P; tyrosine hydroxylase; autonomic innervation; sensory innervation; immunohistochemistry
INTRODUCTION ALTHOUGH MANY STUDIES describe cholinergic regulation
of the pulmonary vasculature, the presence of a cholinergic innervation is morphologically not well documented because of the absence of
effective antibodies against the acetylcholine-synthesizing enzyme
choline acetyltransferase (ChAT). Up until now,
morphological investigations of cholinergic innervation have employed
detection of acetylcholinesterase despite it being a less reliable
marker than ChAT (2, 9). The recent development of a polyclonal antiserum raised to a peptide, corresponding to a domain of ChAT, has
provided a new tool for histochemical analysis of peripheral cholinergic nerve fibers (31). We describe here the use of this antibody to perform a systematic study of the distribution of cholinergic nerve fibers in guinea pig pulmonary vasculature. In
addition, the pulmonary vasculature is innervated by noradrenergic postganglionic sympathetic nerve fibers, nitrergic axons of presumably parasympathetic origin, and sensory C fibers containing substance P
(SP) (4, 5, 12, 14, 28, 29, 30). There is only little information on
the contribution of these fibers to the innervation of the various
segments of the pulmonary vascular tree. Therefore, we have extended
our immunohistochemical studies to include these fiber types, and the
results are reported here. Noradrenergic fibers were demonstrated by an
antibody against the rate-limiting enzyme of catecholamine synthesis,
tyrosine hydroxylase (TH). Nitrergic axons were demonstrated by an
antiserum against the nitric oxide (NO)-generating enzyme, NO synthase
(NOS). In addition, catalytic activity of NOS was visualized by means of NADPH diaphorase (NADPHd) activity (7, 32). Pulmonary arteries and
veins were each classified into four groups according to their luminal,
i.e., internal, diameter. In each group, the percentage of vascular
section profiles with axon terminals attached to it was determined for
each of the neurochemically defined classes of perivascular nerve
fibers. This procedure allowed the determination of how far
perivascular axons extended into the lung parenchyma and revealed
drastic differences between the neurochemically distinct fiber
types that are discussed in view of their known pharmacological effects
on pulmonary vascular tone.
MATERIALS AND METHODS Specimens
30°C
until required for immunostaining. They were serially sectioned at a
thickness of 12-14 µm with a cryostat (model HM 500, Microm,
Heidelberg, Germany).
Immunohistochemistry
The sections were first covered for 1 h with a blocking medium consisting of 10% normal swine serum, 0.1% bovine serum albumin, and 0.5% Tween 20 in 0.1 M phosphate-buffered saline (PBS). Primary antibodies were applied overnight at room temperature. Sections were washed and incubated for 1 h either with a fluorescein isothiocyanate (FITC)-conjugated secondary antibody or with a biotinylated secondary antibody, washed again, and incubated for 1 h with streptavidin-conjugated Texas red to label the biotinylated secondary antibody (see Table 1). After incubation, sections were rinsed in PBS and coverslipped in carbonate-buffered glycerol at pH 8.6. The slides were evaluated by epifluorescence microscopy by using a band-pass 470- to 490-nm excitation filter and band-pass 515- to 550-nm barrier filter for FITC-labeled antibodies, and a band-pass 545- to 580-nm excitation filter and a long-pass 610-nm barrier filter for fluorescence of Texas red (Fluorescence microscope BX 60, Olympus, Hamburg, Germany).
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Preincubation with antigen (ChAT: amino acids 168-189, NOS
purified from porcine cerebellum) at a concentration of 20 µg/ml antiserum diluted to working concentration resulted in a complete absence of staining with the corresponding antisera in the lung (Fig.
1). Specificity of the other antisera for
immunohistochemistry of guinea pig lung was established by
preabsorption controls in a preceding study (20).
NADPHd Histochemistry
Sections were incubated in 1 mM NADPH (Biomol, Hamburg, Germany) and 0.3% Triton X-100 (Sigma Chemical, Deisenhofen, Germany) in 0.1 M phosphate buffer (pH 7.4) for 30-45 min at 37°C, rinsed in 0.1 M phosphate buffer, and coverslipped in carbonate-buffered glycerol (pH 8.6).Quantification of Vascular Innervation
Pulmonary arteries and veins were classified into four groups according to the size of their luminal, i.e., inner diameter: 1) vessels >700 µm in diameter (located between the heart and lung hilum), 2) vessels 350-700 µm in diameter (located at the hilum), 3) intraparenchymal vessels with a diameter between 100 µm and 350 µm, and 4) intraparenchymal vessels with a diameter between 50 µm and 100 µm.For each group the number of innervated section profiles was counted
and expressed as percentage of the total number of vascular section
profiles. In each animal, five different levels, each being at least
200 µm apart in craniocaudal direction, were investigated, and at
each level at least five sections were quantitatively evaluated. Differences in the percentages of innervated section profiles between
1) different vessel sizes in a given
neurochemical class and 2) different
neurochemically defined types of axons in a given vascular size class
were evaluated by F- and
t-tests. Differences were considered
as significant for P values 
0.05.
RESULTS
ChAT-Immunoreactive (irChAT) Nerve Fibers at Pulmonary Vessels
Pulmonary arteries and veins of the guinea pig were supplied by a sparse-to-moderately dense plexus of perivascular nerve fibers with immunoreactivity to ChAT. The varicose irChAT axons were located at the adventitial-medial border of the vascular wall (Figs. 2 and 3).
Arteries. Pulmonary arteries with diameters ranging from >700 µm to <100 µm were innervated by irChAT axons (Fig. 2). Approximately two-thirds of the smallest intraparenchymal vessels (50-100 µm) showed irChAT perivascular axons, whereas, for larger pulmonary arteries, irChAT nerve fibers occurred on almost all vessels (Table 2). The percentage of innervated section profilein the size class of 50-100 µm was significantly lower than for TH-immunoreactive (irTH) (P
0.01) and
SP-immunoreactive (irSP) axons (P 0.05). On the other hand, it was significantly higher
(P 0.001) than for NADPHd-positive
axons in all vessels <700 µm in luminal diameter.
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0.01) than
for irTH and irSP axons and significantly higher (P 0.05) than for NADPHd-positive
axons.
NADPHd-Positive Nerve Fibers at Pulmonary Vessels
NOS immunohistochemistry and NADPHd reaction gave identical results with regard to vascular innervation. The quantitative analysis was performed at NADPHd-labeled sections. Arteries. Nerve fibers labeled by NADPHd reaction were seen at large vessels. All section profiles of pulmonary arteries >700 µm in diameter received NADPHd-positive axons. At the hilar region, 62% of section profiles were innervated. For parenchymal vessels >100 µm in diameter, 10% were supplied, and the smallest intraparenchymal vessels were only occasionally innervated with NADPHd-positive nerve fibers (Table 2, Fig. 4). The percentage of innervated section profiles in vessels <700 µm was significantly lower (P 0.001) than for all other
neurochemically defined types of axons.
Veins. NADPHd-positive nerve fibers were present at all pulmonary veins from their exit from the lung to their entrance into the left atrium. Only one-fifth of smaller vessels 350-700 µm in diameter received NADPHd-positive axons (Table 2, Fig. 5b). No nerve fibers could be labeled at pulmonary veins <350 µm in diameter (Fig. 5, c and d). The percentage of innervated section profiles in vessels <350 µm in diameter was significantly lower (P
0.05) than for all other
neurochemically defined types of axons, except for NADPHd-positive
fibers in the size class of 100-350 µm, in which a
P value of 0.055 was evaluated.
irSP Nerve Fibers at Pulmonary Vessels
Arteries. irSP fibers were found from the main arteries, which were invariably innervated, down to small arteries, which still received irSP axons by 90% (Table 2). The vessels showed a moderate-to-dense perivascular nerve plexus that did not vary considerably in density along the vascular tree (Fig. 6, a-d). The percentage of innervated section profiles was practically identical to irTH axons; differences compared with irChAT- and NADPHd-positive axons are reported in ChAT-Immunoreactive (irChAT) Nerve Fibers at Pulmonary Vessels and NADPHd-Positive Nerve Fibers at Pulmonary Vessels.
Veins. irSP nerve fibers supplied all large pulmonary veins (Fig. 7a). Axons with irSP were noted at 62% of all investigated veins from 350 to 700 µm in diameter (Fig. 7b). About 20% of pulmonary veins <350 µm in diameter received irSP nerve fibers (Table 2, Fig. 7, c and d). The percentage of innervated section profiles of the smallest veins (50-100 µm) was significantly (P
0.01) higher than
for any other neurochemical class.
irTH Nerve Fibers at Pulmonary Vessels
Arteries. irTH was shown in nerve fibers at virtually all pulmonary arteries from >700 µm in diameter down to arteries 100-350 µm in diameter (Fig. 8). Ninety-two percent of section profiles of smallest intraparenchymal vessels (50-100 µm) were still supplied with irTH axons (Table 2). Differences in the percentages of innervated section profiles compared with other axons are reported in ChAT-Immunoreactive (irChAT) Nerve Fibers at Pulmonary Vessels and NADPHd-Positive Nerve Fibers at Pulmonary Vessels.
Veins. All pulmonary veins >700 µm in diameter received irTH axons. Veins of the hilar region were supplied by 70% with irTH nerve fibers, whereas TH-innervation was shown at only 10% of section profiles of vessels <350 µm (Table 2, Fig. 9). Differences in the percentage of innervated section profiles compared with other axons are reported in ChAT-Immunoreactive (irChAT) Nerve Fibers at Pulmonary Vessels and NADPHd-Positive Nerve Fibers at Pulmonary Vessels.
DISCUSSION
The present study demonstrates a caliber-specific distribution of four functionally and neurochemically distinct classes of perivascular axons along the pulmonary vascular tree of the guinea pig. In general, innervation of pulmonary veins was much less developed than that of pulmonary arteries and was mainly restricted to the veins at the lung hilum close to their entrance into the left atrium. Although not quantitatively investigated, a predominant arterial vs. venous innervation has been reported for acetylcholinesterase-positive (5, 10) and catecholamine-fluorescent axons (4, 28) in the lungs of several mammals. The different morphologies of pulmonary arterial and venous innervations are accompanied by heterogeneities in the pharmacological responsiveness of these vessels to neural and endothelial mediators. In full-term fetal lambs, acetylcholine induces endothelial-dependent relaxation of fourth-generation pulmonary veins but not arteries (15). On the other hand, data obtained in the isolated blood-perfused canine left lower lung lobe suggest that acetylcholine constricts the venous segments while moderately relaxing the arterial segment under conditions of elevated tone (11). The close neighborhood of irChAT axons to both cardiac and smooth muscle cells in the venous wall observed in this study suggests that both types of myocytes are targets of neurally released acetylcholine. In line with this assumption, M2 muscarinic receptors have been pharmacologically identified on cardiomyocytes from guinea pig left atria (24), and binding sites of the muscarinic agonist, [3H]quinuclidinyl benzilate, have been reported on the smooth muscle of rat pulmonary vein (8). However, systematic studies on the differential responses of pulmonary veins of various diameters and comparison with corresponding arterial segments are missing, because due to its clinical relevance, e.g., in pulmonary hypertension, the arterial innervation and regulation of arterial tone have attracted much more interest.
In accordance with previous reports based on aldehyde-induced
catecholamine fluorescence (4, 28), sympathetic noradrenergic axons as
identified by immunoreactivity to the rate-limiting enzyme of
catecholamine synthesis, TH, innervated all pulmonary arterial ramifications from the pulmonary trunk down to arteriolar level. This
distribution is shared with irSP axons, which, in the guinea pig,
invariably also contain calcitonin gene-related peptide (CGRP) and are
derived from sensory neurons (21). Thus the entire pulmonary arteriolar
level is addressed by both vasoconstrictor (noradrenergic via
1-adrenoreceptors; Refs. 19,
23) and vasodilator (SP- and CGRP-containing fibers via CGRP release;
Ref. 3) axons. Interactions between these separate but
closely neighboring fiber types are likely to occur because it has been
demonstrated that CGRP-induced relaxation of guinea pig pulmonary
arteries in response to electrical field stimulation is attenuated by
2-adrenoreceptor agonists (3).
This ubiquitous distribution along the arterial tree is in sharp
contrast to that of perivascular axons of presumably parasympathetic origin, i.e., those containing NOS and/or ChAT. Nitrergic axons are regularly present at the pulmonary trunk and the extraparenchymal right and left pulmonary arteries (12) but invade the lung only minimally and are absent at arteriolar level. This differential distribution of nitrergic fibers explains the inhomogenous
pharmacological results obtained for guinea pig pulmonary arteries of
different calibers: endogenous NO counteracts the
-adrenoreceptor-mediated pulmonary vasoconstriction (6, 22, 23). In
the main pulmonary artery, this endogenous NO is of neuronal origin
because, after endothelium removal, an inhibitor of NOS is still
effective in reducing vasorelaxation in response to electrical field
stimulation (23). In contrast, endothelium removal largely reduces
nonadrenergic noncholinergic vasorelaxation in preparations of branches
of the guinea pig pulmonary artery (23) so that neurally generated NO
does not contribute to regulation of vascular tone at this arterial
segment. Thus pharmacological and immunohistochemical data coincide in
that extrapulmonary but not intrapulmonary segments of the guinea pig
pulmonary artery are controlled by vasodilatory nitrergic axons. Hence,
in contrast to other vascular beds such as the cerebral arteries (1),
NO cannot be regarded as the primary mediator of neurally induced
relaxation of guinea pig intrapulmonary arteries. This may be different
at the main pulmonary artery. At this vascular segment, there is a
cholinergic component of neurogenic vasodilation, but the dominant part
is mediated by other mechanisms because atropine reduces relaxation
induced by electrical field stimulation only by ~30% (19). These
pharmacological data correspond well with the presence of both
peptide-containing sensory and nitrergic nerve fibers in addition to
irChAT perivascular axons at this vascular segment, as demonstrated in
the present study. It has to be stressed, however, that the nitrergic
axons at the main pulmonary artery might well be a subpopulation of the
cholinergic nerve fibers so that individual axons at this vascular
segment contain both ChAT and NOS, as it is highly likely in the
innervation of cerebral vessels (27).
The distribution of cholinergic axons as identified by immunoreactivity against the acetylcholine synthesizing enzyme ChAT holds an intermediate position between that of noradrenergic and peptide-containing sensory axons on the one side and that of nitrergic axons on the other, in that these fibers do enter the parenchymal regions of the lung but are observed at only approximately two-thirds of arteriolar section profiles. This immunohistochemical observation suggests a heterogenous influence of neurally released acetylcholine on arteriolar vasomotion. Direct data obtained at guinea pig pulmonary small arteries are not available, but observations made on guinea pig intestinal small arteries correspond well with the incomplete cholinergic innervation pattern demonstrated here. Recording simultaneously small-artery diameter and smooth muscle membrane potential, Kotecha and Neild (18) observed vasodilation induced by acetylcholine accompanied by rapidly developing hyperpolarization in 79% of small arteries but no involvement of acetylcholine in arteriolar vasomotion in 21%. These figures are remarkably similar to our quantitative immunohistochemical data demonstrating 69% ChAT-innervated vs. 31% noninnervated arteriolar section profiles in the lung. Thus, in contrast to the ubiquitous adrenergic regulation of arteriolar tone, there is morphological and functional evidence for a mosaic pattern of cholinergic arteriolar regulation. Physiological and pharmacological data in the cat suggest that axonally released acetylcholine diffuses through the thin muscular coat of small pulmonary arteries and small arteries to the endothelium where stimulation of muscarinic receptors results in the release of NO that activates soluble guanylyl cyclase in smooth muscle cells (25, 26). In favor of this assumption are 1) the presence of nerve terminals with the ultrastructural characteristics of cholinergic axons at the medioadventitial border of these vessels in the cat (17) and of irChAT axons in the guinea pig (this study), 2) the ability of perivascularly applied [3H]acetylcholine to permeate the vascular wall as demonstrated for rabbit central ear arteries (16), and 3) the immunohistochemical demonstration of muscarinic receptors on guinea pig pulmonary arterial endothelium (20). This does not exclude, however, the presence of other pathways of cholinergic vasodilation either involving the endothelium also or being endothelium independent.
ACKNOWLEDGEMENTS
We thank Dr. B. Mayer (Graz, Austria) for kindly supplying the NOS antiserum. Thanks are due to S. Wiegand and K. Michael for skillful technical and photographic assistance and to P. Berger and U. Peppler for secretarial assistance.
FOOTNOTES
Address for reprint requests: R. Haberberger, Institut für Anatomie and Zellbiologie, Justus-Liebig-Universität, Aulweg 123, D-35385 Giessen, Germany (E-mail: rainer.v.haberberger{at}anatomie.med.uni-giessen.de).
Received 4 December 1995; accepted in final form 1 October 1996.
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