Local action of exogenous nitric oxide (NO) on the skin blood flow of rock pigeons (Columba livia) is affected by acclimation and skin site
1 Department of Basic Veterinary Sciences, Physiology, 00014 University of
Helsinki, PO Box 66, FIN 00014 Helsinki, Finland
2 Department of Biology, University of Oulu, PO Box 3000, FIN 90014 Oulu,
Finland
* Author for correspondence (e-mail: liisa.m.peltonen{at}helsinki.fi)
Accepted 22 April 2004
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Summary |
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Our results show that acclimation state and skin site affect the action of exogenous NO on local skin blood flow, and we suggest that the differences reflect acclimation-induced changes in the vascularity of the skin and in its sensitivity to thermal stimuli and that the roles of the abdominal and dorsal skin are different with respect to environmental changes.
Key words: skin blood flow, nitric oxide, temperature, acclimation, cold-induced vasodilatation, laser Doppler velocimetry, pigeon, Columba livia
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Introduction |
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Cutaneous blood flow (BF) is regulated by the vasomotoric tone of the
different structural components of the cutaneous vascular tree. The
sympathetic nerves release neuronal factors that act on the small arterioles
supplying the skin capillaries, on the post-capillary venules draining blood
from the skin and on the AVAs. Neuronal regulation is mediated in mammals by
an adrenergic vasoconstrictor system and an active vasodilator system that
involves cholinergic cotransmission
(Kellogg et al., 1995), while
the resting vascular tone seems to be regulated by both vasoconstrictor fibres
and nitric oxide (NO; Kellogg et al.,
1999
; Pergola et al.,
1993
). Capillary blood flow per se is thought to be
primarily regulated by local factors, of which NO seems to be the most
powerful (Hales et al., 1978
;
Pergola et al., 1993
;
Kellogg et al., 1999
).
The corresponding BF control mechanisms in birds are still unclear,
although recent studies on the effects of various adrenergic stimuli on the
SBF in pigeons have revealed that the vasoconstrictory tone is maintained by
the adrenergic sympathetic nerves. Thermal vasodilatation takes place, at
least in part, passively through the release of the vasoconstrictory tone
mediated by ß- and -adrenergic receptors (ARs;
Arieli, 1998
;
Ophir et al., 2000
). It is
important to note that there seems to be a clear difference in the functional
role of these receptors between birds and mammals. Passive vasodilatation,
which is mediated by
2-ARs in mammals, seems also to be
mediated by the ß-adrenergic pathway in birds, at least in the pigeon
(Marder and Raber, 1989
;
Ophir et al., 2000
). Even
though the ß2 subtype predominates in the central nervous
system (CNS) of the pigeon (Fernandez-Lopez
et al., 1997
), the ß1 subtype seems to be more
responsive to changes in acclimation state, thus contributing to the
fine-tuning of responses to thermal stimuli
(Ophir et al., 2000
). Recent
results suggest that the fundamental difference between birds and mammals in
the haemodynamic control exercised by the sympathetic nervous system could be
partly explained by differences in the distribution, number and affinity of
- and ß-ARs (Arieli,
1998
) and, furthermore, by the hierarchical relationship between
the receptor subtypes in the CNS and periphery
(Ophir et al., 2000
).
Even though no evidence so far exists for an active vasodilatory mechanism
in birds, speculations that an NO-dependent local mechanism may exist have
been put forward by Arieli et al.
(2002).
The aim of the present work was to elucidate the role of NO in the local control of BF by measuring the action of non-invasively administered NO on the cutaneous BF in different acclimation states and at different skin sites.
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Materials and methods |
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Animals
Winter-acclimatized (WAC; N=5) and thermally non-challenged (NOC;
N=6) pigeons (Columba livia Gmelin 1789) were used. The WAC
pigeons were exposed to cold in an outdoor aviary in Finland during the
winter, with an air temperature (Ta) ranging from +7°C
to 29°C, while the NOC birds were acclimated to room temperature
(2123°C) for at least three weeks. All the birds had free access to
water and food.
Laser Doppler velocimetry
Skin blood flow was measured by laser Doppler velocimetry, which uses
monochromatic laser light and the frequency shift of back-scattered light from
the tissues to assess the number and velocity of the blood cells
(Shepherd and Öberg,
1990). The equipment used was an Oxford Array flowmeter (Oxford
Optronix, Oxford, UK). The signals were recorded as blood perfusion units
(BPU), which is a relative unit scale defined by reference to a controlled
motility standard. Two fibre-optic button probes (diameter 1.5 cm) were
attached to the patches over the dorsal and abdominal skin. To avoid erroneous
readings resulting from movement of the probes, the birds were anaesthetized
(see below) and the buttons kept in steady contact with the skin. The baseline
flow in each intact skin area was measured for 1015 min, or until
stabilized, after which the probes were detached and the blood flow was
stimulated locally as described below. The probes were reattached on the
treated patch, and the stabilized flow was again measured for 1015 min.
The changes in blood flow in each skin patch were determined relative to the
baseline flow (zero line). Means were calculated from the stabilized 10-min
flow recordings for use in the baseline, control and `treatment' flow
assessments. All measurements were performed at room temperature in a dim
light and at a relative humidity of 3035%. To prevent possible
interference from external illumination, the probes were covered with a piece
of cloth.
Anaesthesia and experimental set-up
In order to ensure the immobility required for laser Doppler velocimetry,
the pigeons were anaesthetized with intraperitoneal ketamine in combination
with xylazine, at doses of 25 mg kg1 (Ketalar®; Pfizer,
Espoo, Finland) and 15 mg kg1 (Rompun®; Bayer,
Leverkusen, Germany), respectively. This combination, which is frequently used
for avian anaesthesia, results in good muscle relaxation (xylazine), analgesia
and calm recovery. Xylazine, a specific 2-agonist, occupies
the presynaptic receptors, leading to reduced release of endogenous
catecholamines from the sympathetic nerve endings
(Adams, 1995
). At the central
level, this leads to reduced adrenergic tone and sedation. On the other hand,
ketamine induces a dissociative anaesthesia in which cardiac function and
circulation are stimulated via central sympathetic activation
(Adams, 1995
). We therefore
hypothesized that the stimulatory effect of ketamine on the vasomotoric tone
would be able to balance the depressant effects of xylazine, leaving the
central factors affecting the skin blood flow relatively unaltered.
When measuring blood flow in the dorsal skin, the pigeons were placed in a Styrofoam frame, which minimized heat loss and allowed free movement of the thoracic cage. During the abdominal measurements, they were placed on their backs on a Styrofoam frame without any additional attachments, thus allowing appropriate free orientation.
For blood flow stimulation, a vasoactive agent and a vehicle gel were applied bilaterally to the patches on the dorsal and abdominal skin. The patches on the dorsal skin were at the level of the scapulae on both sides of the spinal column, and those on the abdominal skin were on both sides of the mid-sternum.
Local stimulation of skin blood flow by nitric oxide
A gel generating nitric oxide was prepared as described in detail by Tucker
et al. (1998). Briefly, NO can
be generated in large amounts through the rapid reduction of nitrite (A) by
ascorbic acid (B). Substance A contained sodium nitrite (5% w/v) in a sterile
lubricant gel (KY-Jelly; Johnson & Johnson, Maidenhead, UK), and it was
added to substance B (5% w/v) by gently mixing equal volumes (0.02 ml) on the
skin with a cotton bud. The reaction was allowed to proceed for 1 min, after
which it was stopped by cleansing the skin with a soft tissue.
Statistics
Paired and unpaired t-tests and one-way and two-way analyses of
variance (ANOVA) were used for the statistical analyses. If the variances of
the two populations were revealed as `unequal' by Bartlett's test, the Welch
correction was used in obtaining the P-value in the unpaired
t-test. To confirm the validity of the probabilities obtained from
statistical tests, we randomised the order of the skin site (dorsal/abdominal)
and patch (right/left) chosen for stimulation by tossing a coin.
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Results |
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Effect of the vehicle gel on blood flow
The measurements indicated that even the vehicle gel, as such, was not
totally inert but affected the SBF, the response being variable and depending
on the acclimation state and skin site
(Table 2). The difference
between the dorsal and abdominal skin (Fig.
1) disappeared in the NOC birds, since application of the vehicle
gel to the abdominal skin led to a reduction in flow suggestive of
vasoconstriction of the superficial vessels
(Table 2). By contrast, the
mean abdominal SBF in the WAC pigeons was significantly higher than the
corresponding baseline (P=0.0016), indicating vasodilatation of the
vessels over the measurement area (Table
2; Fig. 2C).
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The dorsal skin seemed to be unresponsive in the WAC pigeons (Fig. 2A), while displaying higher flow velocities in the NOC birds (Table 2). Analysis with two-way ANOVA did indeed indicate that the differences between the skin sites caused by the vehicle gel were not consistent for the two acclimation states (interaction, P=0.017; skin site, P=0.292; acclimation state, P=0.038).
Effect of the NO-generating gel on blood flow
Topical application of the NO gel induced a significant increase in BF
velocity over the abdominal skin in both acclimation states
(Table 3; Figs
2D,
3D), and a moderate stimulation
of the BF was also seen over the dorsal skin of the WAC pigeons, although that
of the NOC birds was less responsive (Table
3). The changes induced by the vehicle and NO gel in two adjacent
patches on the dorsal and abdominal skin are summarized in Figs
4,
5, which show that a specific
response to topically administered NO is present in the abdominal vascular
network of the NOC pigeons (Table
4; Fig. 5), while
in the WAC pigeons NO seems to amplify the vasodilator action of the vehicle
gel (Figs 2C,D,
4). The mean BPU values for the
vehicle and the NO treatment differ significantly (P=0.0015), being
473.4±35.73 and 1084±96.48, respectively (Tables
2,
3).
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The superficial vessels on the dorsal skin of the WAC pigeons seem to respond only moderately to the vasodilator action of exogenous NO (Table 3), while the dorsal skin of the NOC pigeons seems to be practically unresponsive to NO action.
Two-way ANOVA analysis of the mean changes caused by application of the NO gel strongly points to the skin site as the major source of the variation (interaction, P=0.1333, not significant; skin site, P<0.0001; acclimation state, P=0.0554, not significant).
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Discussion |
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Aspects of basic skin blood flow
The results suggest that acclimation to cold is associated with a higher
basic SBF over the dorsal and abdominal skin areas than is found in thermally
non-challenged birds. These findings are in line with the few in vivo
studies of the effects of acclimation on BF. Vogel and Sturkie
(1963) found that the
peripheral resistance of the vascular system is lower in winter-acclimatized
chickens than in summer-acclimatized ones. Data on humans suggest that the
basic peripheral blood flow in arctic regions is higher in cold-acclimatized
than in non-acclimatized subjects (Adams
and Smith, 1962
; Naidu and
Sachdeva, 1993
).
Why was the BBF velocity higher in the WAC pigeons? It is well known that a
higher flow velocity may be caused by either release of the tonic
vasoconstriction induced by the sympathetic adrenergic nerves or by
stimulation of the activity of a vasodilator mechanism. These mechanisms are
known to cooperate in the presence of thermal stress, for example, so that the
thermal vasodilatation observed in humans is far greater than that caused by
blockade of the noradrenergic vasoconstrictor nerves alone
(Kellogg et al., 1999;
Wilson et al., 2002
). Ophir
and coworkers showed recently that release of the vasoconstrictor tone by the
non-specific ß-adrenergic antagonist propranolol does not solely account
for the maximal vasodilatory response induced by heat in heat-acclimated
pigeons (Ophir et al., 2002
).
Contrary to mammals, in which
-ARs primarily mediate vasoconstriction
in the peripheral vessels (Kellogg et al.,
1999
), ß-ARs seem to be involved in the pigeon. Depending on
the location and function within the vascular tree, different receptors seem
to be employed. A recent hypothesis on the interplay between receptor types in
the pigeon's cutaneous vasculature suggests that, while the ß-ARs
(especially ß2) primarily act on precapillary sites, the
-ARs (especially
2) act on postcapillary sites
(Ophir et al., 2002
).
Nevertheless, in order to produce appropriate physiological effects, the
process of acclimation to a changing external environment seems to be crucial
in modulating the function of these receptors.
The reasons for the higher SBF over the abdominal skin than over the dorsal
skin may be both physiological and anatomical. The skin, as a site for dry
heat flux, is functionally heterogeneous. The areas covered with feathers do
not offer as effective a route for dry heat loss as those that are without
feathers. On the other hand, the apteria do not offer as good insulation
against heat loss as do the feathered skin areas. The constantly higher BBF
over the abdominal skin documented here in both acclimation states can be seen
as reflecting the crucial role of the abdominal apteria in dry heat flux,
since the brooding patch and associated thoracic areas (and their heat
transfer) are important for successful incubation and offspring survival. On
the ventral side of the bird, the high vascular density and the active
vascular responses seem to correspond to the sparse feather layer
(Lucas and Stettenheim, 1972).
The fivefold response of the total SBF to total body warming over the skin of
the ventral side relative to that on the back is thought to be associated with
the presence of AVAs in these areas
(Wolfenson et al., 1981
). In
general, AVAs have been found in areas that are important for temperature
regulation (Jones and Johansen,
1972
; Lucas and Stettenheim,
1972
; Molyneux and Harmon,
1982
; Midtgård,
1984
,
1986
;
Midtgård et al., 1985
).
The present findings suggest indirectly that AVAs may be present in the
anterior areas of the featherless abdominal skin of pigeons as well. We found
that topical application of the vehicle gel, which had a cooling effect at the
site of application, resulted in a specific dilatory response over the
abdominal skin that was similar to the AVA-mediated CIVD reaction to cold
observed in birds (Johansen and Millard,
1974
; Midtgård et al.,
1985
).
Cold-induced vasodilatation over the non-brood patch abdominal skin
The results regarding the WAC pigeons suggest the existence of CIVD over
the non-brood patch areas of the apterial ventral skin. Moreover, the CIVD
response seems to be augmented by NO. The increased blood flow in the WAC
pigeons therefore seems to be due to at least two separate mechanisms. The
initial reaction to local cooling seems to be an acclimation-dependent axon
reflex. There is strong evidence for the fact that the main targets of
neuronal control are the richly innervated AVAs, while the capillary flow is
under local control (Kellogg et al.,
1995). The local mechanisms, on the other hand, are thought to be
largely, if not completely, independent of neurogenic control
(Roberts et al., 2002
). This
independence has also been demonstrated in birds. Artificial cooling of hens'
eggs, for instance, induced purely local vasodilatation, which was unaffected
by nerve blockade (Midtgård et al.,
1985
).
If CIVD is indeed controlled by nerves, functional cold receptors are
mandatory. We suggest that, despite the analgesia, the epidermal cold
receptors may have been stimulated under ketamine anaesthesia. Ketamine tends
to increase adrenergic tone in the CNS, so that animals remain sensitive to
sound, for example (Plumb,
2002). Thus, the sensory input from the epidermal cold receptors
may have induced CIVD, possibly by intervening in the nerve traffic
controlling the thermoregulatory AVA flow.
In addition to a neural mechanism, a CIVD response may have been induced
locally by the temperature around the vessel. Temperature seems to be able to
modulate the vessel's response to neuronal transmitters. Local cooling has
been shown to change the sensitivity of ARs within these structures by
reducing the amount of noradrenaline (NA) released from the nerves
(Vanhoutte and Verbeuren,
1976), by reducing the enzymatic degradation of NA within the
vessel wall (Roberts et al.,
1986
) and by altering the binding affinity of NA for
1- and
2-ARs
(Janssens and Vanhoutte, 1978
;
Roberts et al., 1986
). A 1-min
application of the vehicle gel alone resulted in a 1.22±0.67 °C
(N=11) drop in the abdominal skin temperature (L.M.P., unpublished
information), but it is uncertain whether the temperature around the
superficial vessels is reduced as well. A direct action of cooling on the
vascular nerves would nevertheless be able to cause a temporary release of the
vasoconstrictor tone and thereby an increase in the SBF.
The CIVD reaction is a protective response of the cutaneous vessels to cold
injury. This was first reported in humans after immersion of an extremity to
cold water (Lewis, 1930). Cold
stimulus leads to a rapid decrease in skin temperature, accompanied by
pronounced vasoconstriction of the cutaneous vessels. After a few minutes, the
skin temperature starts to increase as a consequence of vasodilatation and an
increase in the superficial BF. Depending on the species, acclimation state
and skin site, several mechanisms may lie behind CIVD. It has been suggested
that cholinergic, ß-adrenergic and purinergic nerves may be involved in
the control of CIVD in birds (Johansen and
Millard, 1974
; Murrish and
Guard, 1977
; Hillman et al.,
1982
), and Midtgård
(1988
) has suggested that the
VIP-immunoreactive fibres may be mediators of CIVD, in view of their abundance
in the AVAs of the brood patch in the chicken. The proposed mechanisms in
humans are axon reflex via peripheral pain fibres and the release of
vasodilator substances (Lewis,
1930
; Daanen and Ducharme,
2000
), CNS involvement
(Werner, 1977
;
Kunimoto, 1987
) and
sympathetic activation to modulate the dilatory response
(Sendowski et al., 2000
). The
most common explanation, though, may be the interruption of adrenergic
neurotransmission by cold (Johnson et al.,
1986
; Daanen and Ducharme,
2000
). Just as in humans
(LeBlanc, 1975
), cold
acclimation also seems to enhance the CIVD reaction in the pigeon. Acclimation
to mesic environmental conditions seems to abolish the vasodilatory response,
indicating that it further modulates the systems that control cutaneous blood
flow.
Aspects of the local effects of NO on skin blood flow
Nitric oxide, due to its short half-life of only a few seconds
(Feelisch and Stamler, 1996),
is considered to be a strictly local regulating factor. Various cells that may
be associated with the control of SBF have the capacity to produce NO, notably
the endothelial cells, perivascular nervous cells and keratinocytes, which can
all produce it either by a constitutive or an inducible mechanism (reviewed in
Bruch-Gerharz et al., 1998
). In
order to find out the effects and possible targets of NO action in the case of
the pigeon skin, we studied the effects of exogenous NO on the SBF in small
areas on the dorsal and abdominal skin. Methodologically, the topical
applications used here can be considered to represent a non-invasive
procedure, and we can therefore exclude any stimulatory effects of tissue
trauma on BF. NO most probably acted directly on the contractile elements
around the vessel walls of the small skin patches, as it diffuses freely
through cell membranes and acts on smooth muscle cells, which may be present
adjacent to the precapillary arterioles or postcapillary venules draining from
the skin, or on the AVA, if present. In smooth muscle cells, NO binds to
soluble guanylyl cyclase, the source of second-messenger cGMP
(Feelisch and Stamler,
1996
).
The present results show that the dorsal vasculature is far less responsive
to exogenous NO than the ventral vasculature. This is an unexpected result,
since NO is a very potent vasodilator and the present NO-generating system
could be expected to yield local concentrations high enough to cause
vasodilatation (Tucker et al.,
1998). Since the structural characteristics of the dorsal and
abdominal epidermis are similar (Peltonen
et al., 1998
), the barrier to penetration by NO would be similar
in these areas. Hence, a reduction in the number of vessels with contractile
perivascular structures seems to be the most probable reason for the moderate
haemodynamic changes. We have previously shown that acclimation to different
thermal environments may lead to local changes in the vascular tree and in the
number of superficial microvessels
(Peltonen et al., 1998
). The
capillary bed over the dorsal skin tends to become more dense when pigeons are
acclimated to heat. The WAC pigeons appeared to be devoid of microvessels in
an area reaching from epidermal basal lamina to the depth of at least twice
the thickness of the viable epidermis, whereas the NOC pigeons possessed an
intermediate number of superficial vessels, and heat-acclimated pigeons (HAC)
are known to have the greatest abundance of microvessels adjacent to the
epidermal basement membrane. The abdominal skin, on the other hand, seems to
maintain its superficial vascularity in WAC and NOC states, while its tendency
for a dense vascularity in the HAC pigeons is similar to that in the dorsal
skin (Peltonen et al.,
1998
).
The role of NO in the SBF of birds is still unclear, but studies made in
mammals on its interactions with the catabolism of cAMP, the second messenger
system of the adrenergic pathway, suggest that the second messenger of the NO
pathway, cGMP, is able to inhibit phosphodiesterase III, which catalyses the
transformation of cAMP to AMP (Vanhoutte,
2001). The net effect would thus be an increase in the cAMP
concentration and an enhancement of the biological effects of adrenergic
stimuli. Acclimation to cold probably modulates the sensitivity of various
receptors and thereby adjusts the character of the response to thermal
stimuli.
To summarize, the response of the skin to exogenous NO is affected by the skin site. The abdominal skin of the NOC pigeon shows a specific response to NO, whereas in the WAC pigeon NO seems to amplify the dilatory action of the vehicle, which exercises a cooling effect. We suggest that this may be due to different vascular arrangements in the dorsal and abdominal skin, reflecting their functional differences in dry and wet heat loss, and that the moderate responsiveness of the dorsal skin may be due to lack of AVAs in the measurement area. The consistently higher flow velocity over the dorsal and abdominal skin that is associated with cold acclimation is thought to be caused by an acclimation-dependent reduction in the tonic vasomotor tone. The acclimation process seems to affect the local CIVD reaction by modifying the sensitivity of the skin to thermal stimuli. CIVD seems to be enhanced by cold acclimation and amplified by NO. Acclimation to a mesic environment, on the other hand, seems to abolish the local response. These functional differences between acclimation states are probably associated with the acclimation-dependent modulation of the sensitivity of the local BF for thermal protection of the cutaneous tissue or the offspring.
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Acknowledgments |
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References |
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