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1 Department of Physiology and 2 Department of Pharmacology and Therapeutics, School of Medicine, Queen's University Belfast, Medical Biology Centre, Belfast, BT9 7BL United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the contributions of
the cotransmitters norepinephrine (NE), ATP, and neuropeptide Y (NPY)
to sympathetically evoked vasoconstriction in the rat tail artery in
isolated vascular rings by using 1-100 stimulation impulses at 20 Hz. Phentolamine (2 µM), the 
-adrenoceptor antagonist, markedly
reduced responses to all stimuli, although responses to lower impulse
numbers were reduced less than responses to longer trains. The
purinergic receptor antagonist suramin (100 µM) reduced all
responses, but to a much greater extent with few impulse trains.
Responses were further reduced or abolished by addition of the second
antagonist. Any remaining responses were abolished by the
NPY-Y1 receptor antagonist BIBP-3226 (75 nM). NPY had a
direct agonist action and potentiated sympathetically mediated
responses. NPY (75 nM) potentiated responses and BIBP-3226 decreased
responses to 2- and 20-impulse trains. Both affected responses from 2 impulses to >20 impulses, but there was no preferential effect on
purinergic contributions to responses because neurally released NPY
potentiated both "pure" NE and ATP responses equally. We conclude
that all three cotransmitters contribute significantly to vascular
responses and their contribution varies markedly with impulse numbers.
There is considerable synergy between cotransmitters, especially with
lower impulse numbers where NPY contributions are greater than expected.
norepinephrine; ATP; neuropeptide Y; impulse patterning; synergy
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NOREPHINEPHRINE (NE), ATP, and neuropeptide Y (NPY) are major transmitters mediating sympathetic vasoconstriction, but their contributions vary between species, vascular beds, and specific vessels within each vascular bed, along with actual impulse patterns of sympathetic activity that evoke neurogenic responses (2, 18, 21, 29, 30, 39). Sympathetic nerve activity that ultimately determines the release of transmitters occurs in bursts that vary in intraburst frequency, time between bursts, and number of impulses per burst: bursts of between one and seven impulses have been recorded in rat tail artery, and tonic activity may occur between bursts (20). Thus it is of great importance to understand how subtle changes in impulse patterning may alter cotransmitter contributions and end-organ responses.
The rat tail artery has been widely used to study sympathetic control
of muscular arteries. All three transmitters are present in the
sympathetic nerves that innervate this artery, but the contribution of
each, especially NPY, to sympathetic vasoconstriction is unclear. NE
acts postjunctionally at both 1- and
2-adrenoceptors (2, 3), whereas ATP binds
to postjunctional P2X1 purinoceptors (28). In
vitro, NE makes a major contribution, especially with longer trains of
impulses, whereas ATP is involved more with lower impulse numbers
(2, 4). Nonetheless, in vivo, NE is the dominant
transmitter in all responses evoked in rat tail and hindlimb flow by
both modeled and natural patterns of activity (recorded from
sympathetic nerves to tail artery; see Ref. 19).
The role of NPY in vascular control is particularly unclear. It is released from sympathetic nerves innervating many smooth muscle targets (26, 31), and responses are generally mediated by the NPY-Y1 receptor subtype (7, 10, 13, 35). Exogenously applied NPY may have a direct agonist effect as well as a potentiating effect on neurogenic contraction (12, 16, 29, 32, 43, 44). Yet some studies (11, 14) have failed to demonstrate a role for endogenously released NPY in vasoconstriction of rat tail artery. Furthermore, a recent in vivo study found that rat tail vascular responses were usually abolished in the presence of antagonists for NE and ATP (19). Early studies (22, 34) in vivo suggested that NPY is released from sympathetic nerves only by sustained, high-frequency stimulation (>60 impulses at >8-10 Hz). However, more recent studies (16, 29, 30), both in vitro and in vivo, have indicated that NPY may contribute to responses evoked by less- intense stimuli.
Further studies are needed to understand how impulse patterns determine cotransmitter release and the responses elicited, particularly for NPY. Variation in reported transmitter contributions, especially in the same tissue, may be due to variations in experimental procedures, especially in stimulation parameters and antagonist protocols. Therefore, we have investigated contributions of all three endogenous transmitters to sympathetic vasoconstriction in isolated rat tail artery by using combinations of antagonists for each. We have also examined whether impulse number influences contributions from each transmitter, particularly whether NPY contributes to responses evoked by low numbers of impulses. We used some of the same stimulation parameters in each protocol, examining individual contributions to provide valid comparisons.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tail artery ring segments (2-4 mm) were taken from ~5 cm of male Sprague-Dawley rat tails (250-350 g) after asphyxiation with CO2 and cervical dislocation. All animals were euthanized on Home Office-licensed premises with a Home Office-approved procedure [Animals (Scientific Procedures) Act 1986]. Segments were mounted on small stainless steel hooks and positioned in 4-ml tissue baths perfused at 2 ml/min with Krebs-Hanseleit solution composed of the following (in mM): 118.4 NaCl, 4.75 KCl, 25 NaHCO3, 1.19 KH2PO4, 1.18 MgSO4, 0.95 CaCl2, and 11.66 glucose. This was kept at 37°C and bubbled with a mixture of 5% CO2-95% O2, achieving a pH of 7.3-7.4. When the protocols involved the addition of NPY to the baths, the apparatus were initially rinsed with 0.1% bovine serum albumin to preserve the action of NPY. Segments of vessels were suspended with cotton thread in the baths and attached to force transducers (25 g; model UF1, Piodem). Vessel responses were amplified (model NL108, Neurolog) and recorded onto a computer using a laboratory interface (model Micro 1401, CED) and data-acquisition software (model Spike 2, CED). The tension on the vessel segments was set to 0.75 g and left to stabilize for 1 h. Field stimulation was delivered by two parallel platinum wires placed on either side of the vessel (~5 mm separation) with a supramaximal voltage of up to 6 V and pulse duration of 1 ms. Electrically evoked responses were completely abolished by 1 µM tetrodotoxin (n = 8) or 10 µM guanethidine (n = 5) when tested. Before being mounted, the vessels were denuded of endothelium by the rotation of straight wires around the inner surface of the lumen. The effectiveness of this procedure was tested by precontracting the vessel with NE (1 µM) and by observing no reduction in tension (vasodilatation) on addition of acetylcholine (1 µM) on each occasion (n = 10).
Protocols.
Responses before and after -adrenceptor or P2
purinoceptor antagonists were examined with the use of impulse numbers
between 1 and 100 (at 20 Hz for 
2 impulses) and were delivered as the following battery: 1, 2, 4, 8, and 10 impulses were delivered with
60 s in between; 12, 16, and 20 impulses were delivered with 90 s in between; and then 30 and 100 impulses were delivered with 120 s in between. The battery was delivered during control
conditions and then in the presence of either the -adrenoceptor
antagonist, phentolamine (2 µM), or in the presence of the
P2 purinoceptor antagonist, suramin (100 µM).
Phentolamine is an antagonist at both 1- and
2-receptor subtypes and was selected because both receptors are known to contribute postjunctionally in the rat tail
artery (2). In each case, the second antagonist was then given in addition to the first and the stimulation battery was delivered to assess the combined contributions of NE and ATP. Occasionally, if a response remained in the presence of suramin and
phentolamine, the specific antagonist for NPY-Y1 receptor BIBP-3226 (13) was also added (75 nM).
Data analysis. Results are expressed as means ± SE. Responses evoked by electrical stimulation during control conditions are expressed in absolute values (g). Statistical comparisons were made between absolute values and assessed with the use of one-way ANOVA, followed by Student-Newman-Keuls post hoc test when appropriate, although the responses evoked by electrical stimulation in the presence of an antagonist are expressed as a percentage of the previous control. Comparisons made between normalized data were assessed with the use of a paired Wilcoxon signed-rank test (stated). Statistical significance was assumed at P < 0.05.
Drugs used. The following drugs were used: norepinephrine tartrate (Abbott; Queensborough, UK), phentolamine hydrochloride (Sigma-Aldrich; Dublin, Ireland), ATP disodium salt (Sigma-Aldrich), suramin sodium, guanethidine sulfate (Sigma-Aldrich), BIBP-3226 (Bachem; St. Helens, UK), and NPY (human and rat, Bachem). All of the drugs were added to the baths under stop-flow conditions while being constantly bubbled with the CO2-O2 mixture, so that the final concentration of drug in the bath was as indicated.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Responses to electrical stimulation.
A contractile response was usually induced by single impulses
(0.07 ± 0.01 g, n = 19), and the amplitudes
of evoked responses increased with the number of impulses (100 impulses
at 20 Hz: 1.02 ± 0.09 g; see Fig.
1, A and B).
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Contractile responses in presence of -adrenoceptor blockade.
Contractile responses (0.55 ± 0.2 g, n = 11)
to 1 µM exogenous NE (approximately EC50 for tail artery
from preliminary experiments, data not shown) were abolished in the
presence of phentolamine (2 µM; Fig. 1A). All subsequent
electrically evoked responses were markedly reduced or abolished
(P < 0.01 for all impulse numbers, Figs. 1A
and 2A). However, the reduction in response was greater with
higher impulse numbers: the response to two impulses was reduced
(18 ± 4%) to a significantly smaller amount than the response to
20 impulses (7 ± 2%; P < 0.05, n = 11, paired Wilcoxon signed-rank test; Fig.
2, A and C). This
leads to the conclusion that NE is more important to responses evoked
by higher impulse numbers compared with lower impulse numbers. The
remaining responses were abolished (8/11) or further reduced (3/11;
Figs. 1A and 2A) in the additional presence of
suramin (100 µM). Finally, the addition of BIBP-3226 abolished all
remaining responses (3/3). During time-matched controls under stop-flow
conditions there were no significant differences in responses evoked
between the first, second, and third deliveries of impulse batteries.
For example, the percentage of differences in responses evoked by two
impulses in the second and third deliveries were 92 ± 29% and
105 ± 17% of the first delivery (n = 4); the percentage of differences in responses evoked by 100 impulses were
110 ± 3% and 104 ± 4% compared with the first delivery
(n = 4).
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Contractile response in presence of purinergic antagonists.
Exogenous ATP (100 µM) caused a monophasic constriction (0.38 ± 0.05 g, n = 8) that was usually abolished after
incubation of the tissue with suramin (100 µM) for 30 min (Fig.
1B), although on two occasions a small contraction remained
after 30 min, which was not abolished by further addition of suramin
(to 300 µM). Data from these experiments were not included in
statistical analysis (the ATP dose-response curve did not plateau, data
not shown). Electrically evoked responses in the presence of suramin
were reduced (impulse numbers 
6, not significant; impulse numbers 8, P < 0.01, n = 8; Figs.
1B and 2, B and C). The responses
evoked by lower impulse numbers were affected differently from
responses evoked by higher impulse numbers: the responses to two
impulses were reduced to 18 ± 4% (n = 8),
whereas the responses to 20 impulses were reduced to only 69 ± 10% (Fig. 2, B and C). The amount by which each
response was reduced was significantly different (P < 0.01, paired Wilcoxon signed-rank test). This implies that ATP is of
greater importance to responses evoked by lower impulse numbers. The
subsequent addition of phentolamine usually abolished the remaining
responses (6/8), although small responses to higher impulse numbers
occasionally remained.
Effects of NPY and BIBP-3226 on contractile responses.
Because sympathetic responses to our stimuli were usually abolished in
the combined presence of blockers for both ATP and NE, we predicted
that NPY would contribute little to sympathetic responses. However,
this was not the case. In initial experiments, trains of five impulses
at 20 Hz were delivered every minute to investigate the effects of 75 nM NPY (EC75 for potentiating effects in preliminary
experiments, data not shown). This concentration produced a direct
agonist effect, increasing baseline tension by 0.24 ± 0.05 g
(n = 9), and control sympathetically evoked responses (0.20 ± 0.02 g) were potentiated, increasing the evoked
response to 181 ± 21% (P < 0.01; Fig.
3). The agonist effect increased over
3-4 min and then declined, whereas the potentiating effect remained for 8-12 min. After a 15-min washout, the baseline and evoked responses had returned to control values. Addition of BIBP-3226 (75 nM) always decreased the size of the evoked response, resulting in
a mean reduction to 57 ± 6% of control (P < 0.01), blocked the potentiating effect of exogenous NPY (Fig. 3) and
usually blocked the direct agonist effect of a second exposure to NPY (7/9), although a small increase in baseline tension occasionally remained (2/9). Time-matched controls were performed by comparing baselines and the mean of five responses in an initial period with
those of a similar period 10 min later, and no significant differences
were found (second mean baseline was 100 ± 1% of the first;
second mean response was 96 ± 6% of the first; n = 4).
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Effects of impulse number on NPY potentiation.
We investigated whether the effects of NPY and BIBP-3226 were dependent
on the number of impulses delivered but used only two impulse numbers,
2 and 20 (both at 20 Hz), due to the transient nature of the NPY
effects. These two impulse trains could be delivered with 1 min in
between at the peak of NPY effects. NPY had a significant potentiating
effect on both trains (Fig. 4): the
couplet response (0.11 ± 0.02 g) increased to 177 ± 26%, and the response to 20 impulses (0.6 ± 0.07 g)
increased to 128 ± 7% (P < 0.001, n = 11) compared with first control responses. However,
the degree to which the response to two impulses was increased was
significantly >20 impulses (P < 0.05, paired Wilcoxon
signed-rank test). In the presence of BIBP-3226, responses to 2 and 20 impulses were significantly decreased to 47 ± 10% and 88 ± 4%, respectively, of a second control period (P < 0.001 in each case). Again, the response to the couplet was decreased
significantly more than the response to 20 impulses (P < 0.05, paired Wilcoxon signed-rank test). There were no significant
differences between control stimulations.
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Potentiating effects of NPY on pure NE or ATP responses.
The observation that NPY and BIBP-3226 affected the responses evoked by
2 and 20 impulses differentially raised the possibility that NPY may
have a preferential effect on the actions of ATP as opposed to NE. We
investigated this by comparing the response to a single train of five
impulses at 20 Hz, first in the presence of phentolamine or suramin,
and then in the additional presence of BIBP-3226 (Fig.
5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have clearly demonstrated involvement of three neurotransmitters, NE, ATP, and NPY, in responses evoked by sympathetic stimulation of the rat tail artery. Although NE provides the dominant contribution at higher impulse numbers, ATP and NPY also provide significant contributions, especially at lower impulse numbers. All three transmitters have synergistic actions with each other, the combined actions of all three together being greater than the sum of individual contributions. Sympathetically released NPY has little or no direct agonist effects but markedly potentiates the actions of sympathetically released NE and ATP with all impulse numbers tested (1-100). This potentiation is greater with lower impulse numbers, but this is not due to a preferential effect on ATP because NPY potentiates pure NE and ATP responses equally.
Contributions of NE and ATP to vascular responses.
The conclusion that NE contributes more to responses evoked by higher
impulse numbers, and that ATP contributes more to responses evoked by
lower impulse numbers, confirms several previous in vitro studies
(5, 21, 38, 39). For example, in the presence of
1- and 2-adrenceptor antagonists the
reductions in responses to 10 impulses were similar [87.5%
(5) vs. 82% in our study]. Similarly the reductions in
responses to 10 impulses in the presence of suramin were similar to
those reported previously [57% (5) vs. 51%]. However,
when these authors used suramin at concentrations of 200 µM or
higher, they observed a marked potentiation of neurogenic responses,
concluding that ATP has dual excitatory and inhibitory effects. In our
study we found only occasional evidence of an inhibitory action of ATP
with suramin (100 µM). The occasional nature of this observation was
also seen in vivo (20).
Contributions of NPY to vascular responses. We have clearly shown involvement of NPY receptors in rat tail artery that contribute to neurogenic contraction, as reported in some studies in this tissue (8, 32) but not others (11, 14). However, because the combined antagonism of adrenergic and purinergic receptors usually abolished neurally evoked responses, the NPY contribution as a direct transmitter is minimal. Rather, sympathetically released NPY acts as a neuromodulator, markedly potentiating actions of other cotransmitters. This was demonstrated both by potentiation of responses evoked by five impulses in the presence of exogenous NPY and by reduction of responses when the action of neurally released NPY acting at NPY-Y1 was blocked by BIBP-3226. Therefore, NPY receptors do not exclusively contribute to longer trains of high-frequency impulses reported in earlier studies (see INTRODUCTION). Indeed, we found that NPY contributes more to responses evoked by the couplet compared with that evoked by 20 impulses. Because our initial studies, and those of others (see INTRODUCTION), indicated that ATP contributes more to responses evoked by lower impulse numbers, the question was raised as to whether NPY has a preferential effect on the actions of ATP. However, when the effects of NPY on pure ATP- or NE-mediated responses were investigated with the use of either phentolamine or suramin in combination with BIBP-3226, we found no difference in NPY contributions to responses in either. Rather than NPY having a preferential effect on ATP, a possible explanation for our observations is that NE contributes more to responses as the number of impulses increases due to NE clearance mechanisms becoming saturated, causing NE to accumulate at postsynaptic receptor sites (2, 5, 41). Furthermore, per-pulse release of ATP is reduced as train length increases (2, 5, 41). Thus the effects of NPY and ATP may become more apparent at lower impulse numbers, before accumulation of NE associated with higher numbers of impulses begins to dominate responses.
Our conclusions that NPY-Y1 receptors in rat tail artery mediate a vasoconstriction in the presence of exogenous NPY, and that sympathetically released NPY contributes to neurogenic contraction, primarily as a modulator, contrasts markedly with other studies in the same tissue. Duckles and co-workers (14) concluded that NPY only has an indirect constrictor action by potentiating the action of subthreshold, spontaneously released NE revealed in the presence of cocaine or in tissue previously exposed to NE. No such prior exposure to NE had occurred in our protocols. Furthermore, in the hands of Duckles and co-workers (11), BIBP-3226 failed to inhibit sympathetically evoked constrictions, even in the presence of peptidase inhibitors (to enhance the actions of NPY). Differences in stimulus parameters between studies (e.g., 100 impulses at 1-16 Hz) are unlikely to be the sole explanation for conflicting results, as we have also found similar results using larger impulse numbers (e.g., 100 impulses at 20 Hz). The rat species were identical and experiments were performed in a similar manner, so that discrepancies are difficult to explain, although because our apparatus was pretreated with serum albumin, and stock NPY was stored with Krebs and serum albumin, NPY was possibly more active in our study. Blockade of NPY effects by BIBP-3226 at the concentrations used in this study implies that in this tissue NPY is acting via NPY-Y1 receptors, in agreement with several other studies (6, 10, 16, 29, 35). However, because BIBP-3226 sometimes failed to block the direct effects of NPY, it is possible that other NPY receptors are present in this tissue, as they are in others (15).Overall contributions of NE, ATP, and NPY to sympathetically evoked contraction. It is now clear that all three transmitters contribute to sympathetic responses and that individual contributions from each can vary markedly with impulse numbers. Furthermore, we have shown that actions of each individual transmitter are synergistic with actions of the others, as the sum of individual contributions (as judged by responses remaining in the presence of two antagonists) are less than the size of the original response. For example, acting as direct agonists, the pure NE- or ATP-mediated responses to the five-impulse train add up to only 50% (43 + 7%, respectively) of the control response, and the pure NPY response was negligible (as judged from experiments in the presence of both phentolamine and suramin). This observation of synergy confirms those of earlier studies in which interactions between NE, ATP, or NPY with other substances were investigated (1, 9, 12, 17, 36). The large potentiating effects and overall contribution of NPY to sympathetic vasoconstriction, particularly at low impulse numbers, was surprising because NPY has previously been thought to make only a small contribution to sympathetically mediated vasoconstriction in rat tail artery (2, 5, 11, 14). However, because no previous studies have used these particular combinations of antagonists and stimulation parameters, they are unlikely to have made this observation.
There may be several mechanisms involved in such synergy. Ralevic and Burnstock (35) hypothesized either an interaction of NE and ATP signal transduction pathways or a depolarization of muscle membrane associated with binding of ATP to P2X purinoceptors leading to a change in ionic conduction, and, hence, intracellular calcium concentration. NPY may also lead to potentiating effects via smooth muscle depolarization (1) or second-messenger systems (26): a recent study (9) suggested that NPY potentiates actions of receptor agonists linked to phospholipase C. Although not examined, it is unlikely that prejunctional adrenergic or purinergic receptors were active in our study, as previous studies in tail artery concluded that neither were activated by short trains, and-autoinhibition was only activated by trains of 150 impulses (at 20 Hz) or greater (2, 3, 41). Furthermore, the use of the
nonselective -adrenergic antagonist phentolamine will have blocked
both pre- and postsynaptic receptors. In addition, prejunctional
purinergic receptors only influenced responses to much lower
frequencies (<4 Hz) (7) than used in our study. It is
unlikely that NPY effects were mediated by prejunctional NPY receptors
because NPY effects are almost exclusively mediated by
NPY-Y1 receptors in this tissue, the presence of
NPY-Y2 receptors being functionally negligible (10,
43).
The observation of differential contributions of NE and ATP to neurally
evoked responses has been made in other smooth muscle tissue. A recent
study (42) in guinea pig vas deferens noted that responses
to impulses of 8 Hz or lower were mainly purinergic. Responses to
impulses of >8 Hz were increasingly dominated by NE, although in this
case we believed this to be due to a diminished role for
2-adrenocepter autoinhibition of NE release at higher frequencies. Thus both our study and that of Todorov et al.
(42) agree with a concept that has been emerging over
recent years: patterning of neuronal activity contains information that
may be translated into discrete neurochemical messages with differing proportions of cotransmitter release from presynaptic fibers and then
decoded by postjunctional receptors for the participating cotransmitters (42). This concept underlines the
importance of understanding ways in which natural patterns of
sympathetic activity can influence end-organ responses by altering the
contributions of cotransmitters involved.
Comparison with in vivo studies.
Our in vitro study, and those of others (21, 39), have
shown some marked differences from our recent study conducted in vivo,
namely that NE is the dominant transmitter in responses to both small
and larger numbers of impulses, when delivered either in regular
computer-generated trains of impulses or as part of a natural pattern
of activity in vivo (19). This may reflect that endogenous
nucleotidases are more active in vivo (45), reducing
actions of ATP (40). Therefore, responses remaining in the
presence of -adrenoceptor antagonism in vitro may overemphasize the
size of the purinergic component of responses to lower impulse numbers.
Nevertheless, both in vitro and in vivo, ATP does make a substantial
contribution to evoked responses due to its synergism with NE and NPY.
NPY has a profound effect on blood pressure and on blood flow in vivo
(22, 25, 29, 33, 34), including flow in rat cutaneous
microcirculation (33). Because -adrenergic and
purinergic blockade usually abolished tail artery vasoconstriction in
vivo (19), it is likely that NPY exerts its effects in a similar modulatory role as found in vitro.
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ACKNOWLEDGEMENTS |
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We thank Drs. Sean Roe and Keith Thornbury for help in the preparation of this manuscript.
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FOOTNOTES |
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E. Bradley was partly funded by a Physiological Society (UK) Vacation Studentship.
Preliminary accounts of this work have been published as abstracts (8, 24).
Address for reprint requests and other correspondence: C. D. Johnson, Dept. of Physiology, Medical Biology Centre, Queen's Univ. of Belfast, 97 Lisburn Rd., Belfast, BT9 7BL, UK (E-mail: c.johnson{at}qub.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.01061.2002
Received 9 December 2002; accepted in final form 13 February 2003.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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) vs.
phentolamine (
); B: **P < 0.01, control vs. suramin. The combined presence of both antagonists
virtually abolished responses to all numbers of impulses (A
and B, 
). C: responses in the
presence of phentolamine or suramin as percentages of control. The
reduction of the response to two impulses was significantly smaller
than the reduction in the response to 20 impulses in the presence of
phentolamine (*P < 0.05). The reduction of the
response to 2 impulses was significantly greater than the reduction in
the response to 20 impulses in the presence of suramin
(++P < 0.001).
