© 1995 American Heart Association, Inc.
Articles |
Interaction Between Conducted Vasodilation and Sympathetic Nerve Activation in Arterioles of Hamster Striated Muscle
From the John B. Pierce Laboratory and Departments of Epidemiology and Public Health and of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Conn.
Correspondence to Steven S. Segal, PhD, The John B. Pierce Laboratory, Yale University School of Medicine, 290 Congress Ave, New Haven, CT 06519.
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Abstract |
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Abstract We tested the hypothesis that sympathetic nerve activity can influence the conduction of vasodilation along the arteriolar wall. Arterioles in the superfused cremaster muscle of anesthetized male hamsters (n=21, 109±4 g) were studied. Microelectrodes were positioned adjacent to the distal end of primary arterioles to stimulate sympathetic nerves throughout arteriolar networks (perivascular nerve stimulation [PNS]). Microiontophoresis micropipettes (tip outer diameter, 1 to 2 µm) filled with acetylcholine (ACh, 1 mol/L) were positioned adjacent to the wall of second-order (2A) or third-order (3A) arterioles
1 mm distal to
their origin to induce local and conducted vasodilation; diameter
responses were recorded at the micropipette tip and at vessel origins,
respectively. For 2A and 3A arterioles (resting diameters, 15 to 54 and
9 to 30 µm, respectively), vasoconstriction with PNS was frequency
dependent (0.5 to 32 Hz); this was attenuated by 65%
(P<.05) with 
-adrenoceptor blockade (phentolamine, 1
µmol/L). Conducted vasodilation was attenuated by >40% during 16-Hz
PNS (P<.05); this effect was reversed by
phentolamine. In a reciprocal fashion, conducted vasodilation
diminished PNS-induced vasoconstriction by 50% (P<.05).
Elevating oxygen (from 0% to 10%) in the superfusion solution induced
vasoconstriction similar to that with 16-Hz PNS yet had no effect on
conduction. Neural blockade with tetrodotoxin (1 µmol/L) eliminated
PNS-induced vasoconstriction and enhanced (P<.05) conducted
vasodilation. These findings indicate that perivascular nerves in
striated muscle can influence cell-to-cell communication along the
arteriolar wall both at rest and during enhanced sympathetic activity.
The attenuation of sympathetic vasoconstriction by conducted
vasodilation suggests a novel explanation for functional sympatholysis.
Key Words: microcirculation • perivascular nerve stimulation • microiontophoresis • acetylcholine • adrenoceptors
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The control of arteriolar diameter reflects the sum of multiple inputs to vascular smooth muscle cells. In skeletal muscle, activation of sympathetic nerves results in vasoconstriction.1 2 3 In contrast, increasing the metabolic activity of muscle fibers induces vasodilation.4 5 Arteriolar diameter also reflects changes in transmural pressure and luminal blood flow.6 7 The interaction between central (ie, neural) and local mechanisms of blood flow control is a long-standing question in cardiovascular and exercise physiology. Of particular interest in the present study is the apparent "competition" between sympathetic vasoconstriction and the vasodilation that occurs during muscular activity.5 8 9 10 11 Sympathetic outflow increases with exercise, yet there is a preferential increase in blood flow to active muscle. In effect, functional vasodilation "overrides" sympathetic vasoconstriction, giving rise to the concept of "functional sympatholysis."5 9 Nevertheless, sympathetic nerve activity can limit muscle blood flow by constricting resistance vessels.11 12 13
The mechanisms of interaction between sympathetic vasoconstriction and
peripheral vasodilation have been studied in some detail. For example,
substances released by muscle fibers1 and motor
nerves14 can inhibit norepinephrine (NE) release and
dilate arterioles. Vasomotor responses can also result from stimuli
delivered to sites well removed from a particular branch of the
arteriolar network. For example, acetylcholine (ACh) microiontophoresis
induces a dilation that is conducted rapidly from cell to cell along
the arteriolar wall over distances encompassing several millimeters and
multiple branch orders.15 16 17 However, the influence of
sympathetic nerve activity on cell-to-cell conduction in arteriolar
networks has not been determined. In the present study, we tested
the hypothesis that sympathetic nerve activity can influence the
conduction of vasodilation along the arteriolar wall. Our findings in
striated muscle show that stimulation of sympathetic nerves
substantially depressed conducted vasodilation via activation of
-adrenoceptors. Furthermore, the conduction of vasodilation
significantly attenuated sympathetic vasoconstriction of arterioles,
suggesting a novel explanation for functional
sympatholysis.5 9
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Care and Preliminary Surgery
All procedures were approved by the Institutional Animal Care and Use Committee of the John B. Pierce Laboratory. Male golden hamsters (n=21, 109±4 g, Charles River) were maintained at 24°C on a 14-h/10-h (light/dark) cycle and provided food (Purina rodent chow) and water ad libitum. Hamsters were anesthetized with pentobarbital sodium (60 mg/kg IP) and tracheotomized to maintain a patent airway. The right carotid artery was cannulated for monitoring arterial pressure (CDX III transducer, Cobe Laboratories). Another cannula was secured in the left femoral vein to replace fluids and maintain anesthesia during experiments (10 mg pentobarbital per milliliter isotonic saline, infused at 0.41 mL/h).
Cremaster Preparation
The right hamster cremaster muscle was prepared as recently
described in detail.16 Briefly, by use of a stereo
microscope (model DRC, Zeiss), the muscle was exposed and positioned
onto a transparent acrylic pedestal. The cremaster muscle was opened
from the apex to the inguinal canal along the ventral surface. The
spermatic artery and vein were ligated, and then the testis and
epididymis were carefully separated from the muscle and removed. Eight
to 12 sutures (6-0 silk, Ethicon) were secured around the edge of the
muscle and used to spread the tissue radially.
The cremaster preparation was superfused continuously (5 mL/min) with a bicarbonate-buffered physiological saline solution (PSS) (34±1°C, pH 7.4) of the following composition (mmol/L): NaCl 131.9, KCl 4.7, MgSO4 1.2, CaCl2 2, NaHCO3 18 (Sigma Chemical Co). Superfusion solutions were gassed continuously with 5% CO2/95% N2 unless noted otherwise; in three experiments, a Clark-type electrode (model PHM 7/MK2, Radiometer Copenhagen) was used to measure PO2 of the PSS on the surface of the preparation. Esophageal temperature was maintained at 38±1°C by positioning the hamster on a copper coil through which warm water (43°C) was circulated. When all experimental procedures for the day were complete, the hamster was given an overdose of pentobarbital through the venous cannula.
Video Microscopy
The preparation was transferred to the stage of an intravital
microscope (model ACM, Zeiss) and equilibrated for 45 minutes.
Second-order (2A; resting diameter, 15 to 54 µm) and third-order (3A;
resting diameter, 9 to 30 µm) arterioles were selected for study on
the basis of optical clarity and resting tone, as demonstrated by a
brisk and reversible dilation in response to topical application of
adenosine (0.1 mmol/L). Microvessels were observed with bright-field
microscopy using Köhler illumination (ACH/APL condenser
[numerical aperture, 0.32]; objectives, Zeiss UD40 [numerical
aperture, 0.41] or Leitz L25 [numerical aperture, 0.35]). A video
camera (CCD model C2400, Hamamatsu) was positioned on a trinocular
imaging tube and coupled to a video monitor (model PVM 1343MD, Sony).
Final magnification on the monitor was x1400 when either objective
was used.
Internal vessel diameters were recorded from the video
monitor by using a video caliper. A stage micrometer (100x0.01=1
mm, Graticules Ltd) was used for calibration; spatial resolution was
1 µm. The direct effect of ACh was assessed at the micropipette tip
(referred to as "local"), and conducted vasodilation was
evaluated at the origin of the stimulated branch, which was typically
1 mm upstream from the ACh micropipette16 17 (Fig 1
). Control experiments eliminated the possibility of
ACh diffusion to the upstream site or of nonspecific effects of
iontophoretic current on arteriolar diameter.15 16 Data
were acquired at 100 Hz by using a MacLab system (AD Instruments)
coupled to a Macintosh IIVX computer.
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Micropipettes and Microelectrodes
Borosilicate glass capillary tubes (Corning No. 7740; outer
diameter, 1.2 mm; inner diameter, 0.68 mm; Warner Instrument Corp) were
pulled (model P-87, Sutter Instruments) to produce micropipettes with
tips (outer diameter) of 1 to 2 µm (for microiontophoresis) or 2 to 3
µm (for perivascular nerve stimulation [PNS]); tip dimensions were
measured at x630 optical magnification with bright-field microscopy.
Micropipettes were backfilled with 1 mol/L ACh (Sigma) or 0.9% NaCl
after filtering to remove particles >0.2 µm (Acrodisc, Gelman
Sciences).
Microiontophoresis
Micropipettes containing ACh were secured in a holder and
connected to an iontophoresis programmer (model 160, World Precision
Instruments) via a Ag/AgCl wire; the programmer was gated externally by
the MacLab system. A second Ag/AgCl wire secured at the edge of the
preparation served as the reference electrode. Micropipettes were
positioned 1 mm distal to the vessel origin (Fig 1
) with a
micromanipulator (model M, Leitz); a large movable stage enabled the
entire preparation and micromanipulators to be moved as a unit without
disturbing the spatial relation between arterioles, micropipettes, and
microelectrodes.16 The retaining current (0.1 to 0.2 mA)
was adjusted to just prevent leakage (indicated by vasodilation) from
the micropipette tip. Based on dose-response curves to ACh
microiontophoresis (data not shown), the amplitude of ejection current
was held at 1 mA; stimulus durations were selected to elicit maximal
and half-maximal conducted responses (500 and 200 ms,
respectively). To quantify the effect of ACh on arteriolar diameter,
the magnitudes of local and conducted responses to microiontophoresis
were calculated as follows: peak response diameter (in micrometers)
minus preceding baseline diameter (in micrometers).
Perivascular Nerve Stimulation
A distal segment of the first-order (1A) arteriole was exposed
by microdissection of adjacent striated muscle fibers. A stimulating
microelectrode was prepared by using a micropipette filled with 0.9%
NaCl; this was secured in a Leitz micromanipulator and positioned
adjacent to the exposed 1A segment (Fig 1). The microelectrode was
connected via a Ag/AgCl wire to the negative terminal of a stimulator
(model S48, Grass Instruments Co); the positive terminal of the
stimulator was connected to the Ag/AgCl reference wire. With constant
pulse duration (1 ms) and stimulation frequency (8 Hz), voltage for PNS
was adjusted (average, 120 V) until maximal constriction was observed
in an arteriolar branch located 5 mm proximal to the microelectrode;
observations at such remote sites ensured that vasoconstriction was not
due to direct depolarization of smooth muscle cells at the
microelectrode tip.
To determine the frequency-response characteristics of arterioles to
PNS, diameter responses were characterized at seven stimulation
frequencies (0.5, 1, 2, 4, 8, 16, and 32 Hz)18 in five
hamsters. The train durations for stimulation were selected to provide
stable diameter responses and varied inversely with stimulation
frequency: 30 s for 0.5 and 1 Hz; 20 s for 2, 4, and 8 Hz; 16 s for 16
Hz; and 8 s for 32 Hz. At 16 Hz, for example, constriction began 3 s
after initiating PNS and peaked within 16 s. To test for activation of
sympathetic nerves, the above procedures were repeated after 30 minutes
of exposure to phentolamine (1 µmol/L, Research Biochemicals Inc), an
-adrenoceptor antagonist, added to the superfusion solution.
For summary frequency-response curves, changes in arteriolar diameter (peak diameter response [in micrometers] minus resting diameter [in micrometers]) at a given frequency of PNS were divided by the maximal diameter change and expressed as percentage of maximum for each arteriole. These summary data were used to ascertain the stimulus frequencies required to elicit 50% and 100% of the maximal PNS responses (4 and 16 Hz, respectively), which were used in subsequent experiments. Although 32 Hz was often the stimulus giving maximum response, preliminary experiments revealed sympathetic "escape" (ie, dilation after constriction during nerve stimulation) in 3A arterioles during stimulation at this frequency.1 Thus, responses to 16-Hz PNS were taken as maximal without escape.
Interaction Between PNS and ACh
For these experiments, eight hamsters were used to test whether
PNS (ie, sympathetic vasoconstriction) would alter conducted
vasodilation in arterioles. After positioning the ACh micropipette as
shown in Fig 1, ACh was applied (1 mA, 500 and 200 ms) under control
conditions; each ACh stimulus was then tested during 4- and 16-Hz PNS.
Because PNS results in arteriolar constriction, control experiments
were necessary to account for the change in diameter per se. Therefore,
responses to identical ACh stimuli were also evaluated during
vasoconstriction induced by elevating superfusate O2
concentration from 0% to 10%. For all experiments, diameter values
were quantified at resting baseline and when responses to experimental
manipulations (eg, PNS or 10% O2) had stabilized. Local
and conducted responses to ACh microiontophoresis were recorded at the
peak of the diameter response at rest and during PNS or 10%
O2. Representative diameter tracings for individual 2A
arterioles are presented in Fig 1 to illustrate experimental
protocols.
Conduction and PNS With Sympathetic Blockade
These experiments tested whether inhibition of -adrenoceptors
with phentolamine (1 µmol/L) or blockade of nerve action potentials
with tetrodotoxin (TTX, 1 µmol/L; Sigma) would alter the influence of
PNS on conducted vasodilation. On the basis of the similarity of
results between 2A and 3A branches in the above experiments (see
"Results"), only 2A arterioles were studied with these protocols.
Micropipettes containing ACh were positioned as in Fig 1. Responses to
PNS (16 Hz) and ACh (1 mA, 500 ms) were studied before and after 30
minutes of exposure to either phentolamine or TTX in the superfusion
solution (Fig 1). Eight hamsters were studied with these protocols
(phentolamine, n=3; TTX, n=5). Arteriolar diameters at rest and in
response to PNS were measured under control conditions and in the
presence of phentolamine or TTX (Table). Responses to
ACh microiontophoresis at rest and during PNS were recorded locally and
at upstream (conducted) sites in the absence and presence of
phentolamine or TTX as described above.
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Statistics
One to three arterioles were studied in each preparation; each
vessel was treated as a separate experiment.16 17
Experimental treatments affecting the entire preparation (eg, PNS, 10%
O2, TTX, and phentolamine) are referred to as
"global." Unpaired t tests were performed to determine
whether responses to PNS or to ACh varied between 2A and 3A arterioles.
Repeated-measures ANOVA was used to compare the effect of global
treatments on resting diameter and on vasomotor responses to ACh. Post
hoc comparisons of cell means were performed by multiple linear
comparisons with the family-wide error rate adjusted to
P.05. Thus, critical P values for individual
comparisons were determined by dividing .05 by the number of
comparisons of interest as determined a priori for each analysis.
All statistical comparisons were performed with
SUPERANOVA (Abacus Concepts Inc). Summary data are
presented as mean±SEM.
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Results |
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Preparations were stable throughout each day's experiments (duration, 3 to 5 hours) as assessed by the maintenance of vasomotor tone (2A and 3A arterioles typically increased diameter 50% to 100% with adenosine) and the stability of mean arterial pressure from the beginning (96±3 mm Hg, n=20) to the end (98±4 mm Hg) of the experiments. Mean arterial pressure during PNS (95±1 mm Hg) was not different from control pressure. Responses to 200-ms ACh and 4-Hz PNS were similar in direction yet reduced in magnitude when compared with 500-ms ACh and 16-Hz PNS; therefore, only the latter data are presented for clarity.
Perivascular Nerve Stimulation
The magnitude of vasoconstriction increased with the frequency of
stimulation in both 2A and 3A arterioles (Fig 2); there
were no differences between responses (percentage of maximal response)
of 2A or 3A arterioles at either 4 or 16 Hz. The greatest
vasoconstrictions occurred at 16 or 32 Hz, irrespective of vessel
order.
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Responses to Global Stimuli
The PO2 of control PSS (gassed with 5%
CO2/95% N2) averaged 30 mm Hg on
the surface of the preparation and increased to 100 mm Hg when
gassed with 10% O2/5% CO2/85%
N2. The vasoconstriction induced by 10% O2 was
not different from that elicited with 16-Hz PNS in either 2A or 3A
branches (Fig 3). Whereas phentolamine did not affect
baseline diameter, arterioles stabilized at smaller (P<.05)
diameters in the presence of TTX (Table). Arteriolar constriction to
PNS was reduced by 65% in the presence of phentolamine (Fig 2) and
eliminated completely during TTX exposure (P<.05).
Vasoconstrictor responses to PNS returned after washout (45 minutes) of
phentolamine or TTX with control PSS (data not shown).
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Local Responses to Vasomotor Stimuli
At the tip of the ACh micropipette, diameter increased
significantly in response to ACh in both 2A and 3A arterioles (Fig 4). During vasoconstriction with 16-Hz PNS or elevated
O2, ACh elicited greater dilation of 2A arterioles
than was elicited during control conditions.
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Conducted Responses
Representative tracings of conducted vasodilation in 2A
arterioles are presented in Fig 1. As shown
previously,15 16 a 2- to 3-s delay preceded dilation,
which peaked 10 s thereafter. Conduction increased arteriolar
diameter at the vessel origin under all conditions (P<.05);
the amplitude of conducted responses did not differ between 2A and 3A
branches (Fig 4). Conducted vasodilation was significantly less during
16-Hz PNS than during control conditions or equivalent vasoconstriction
with 10% O2 (Fig 4); this effect of PNS on conduction was
not different between branch orders. In four arterioles,
vasoconstriction was not observed during PNS; nevertheless, PNS
attenuated conducted vasodilation in each case.
Phentolamine had no affect on conducted vasodilation under control
conditions (Fig 5), yet it eliminated the PNS-induced
depression of conducted responses. In the presence of TTX, conducted
vasodilation was enhanced by 25% at rest and was more than twofold
greater during PNS (Fig 5).
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Discussion |
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We have investigated the interaction between perivascular nerve activity and conducted vasodilation in arterioles of striated muscle. In response to PNS, frequency-dependent vasoconstriction occurred in 2A and 3A arterioles, which was suppressed by phentolamine and abolished with TTX. Whereas local vasodilation to ACh (ie, at the site of direct action) increased during PNS, the corresponding conducted responses were diminished by nearly half (Fig 4
). The suppression of conduction
by PNS was eliminated with TTX or phentolamine; TTX also enhanced
conduction at rest. The present data are the first to demonstrate
an interaction between sympathetic nerve activity and the conduction of
vasomotor responses along arterioles. Our findings indicate the
presence of neural modulation of cell-to-cell communication in
arterioles of striated muscle both at rest and during elevated
sympathetic outflow.
Perivascular Nerve Stimulation
Previous studies in the rat have activated sympathetic nerves by
stimulating paravertebral ganglia.2 18 In the hamster, we
have found these ganglia to be extremely difficult to isolate.
Therefore, an alternative approach was taken. Because sympathetic
nerves run as a plexus around the arteriolar network of striated
muscle2 3 (S.S. Segal and B.D. Walker, unpublished data,
1994), we reasoned that action potentials triggered distally in the
network should propagate in a retrograde direction. Thus, a segment of
the primary arteriole was exposed near the distal edge of the tissue
and the stimulating microelectrode positioned adjacent to the exposed
vessel. In response to PNS, vasoconstriction propagated into arterioles
located in the central region of the muscle, which confirmed our
reasoning.
Arterioles constricted in response to PNS over the range of 0.5 to 32
Hz, which is consistent with previous functional
studies2 18 and recordings of sympathetic activity from
peripheral nerves.19 The attenuation of PNS-induced
vasoconstriction by phentolamine confirmed the activation of
sympathetic nerves. The slight dilation observed at the lowest PNS
frequencies in the presence of phentolamine (Fig 2) may have reflected
activation of ß-adrenoceptors.14 Alternatively, this
vasodilation may have resulted from other substances released by
perivascular nerves.20 21 Nevertheless, the effects of PNS
observed in the present study primarily involved the release of NE
(Figs 2 and 5).
The frequency-response characteristics of rat cremaster arterioles to
sympathetic stimulation were found to vary with network location: 2A
branches were less sensitive to low-frequency stimulation (0.2 to 4 Hz)
than 3A branches.18 These differences have been explained
by corresponding variation in the distribution of -adrenoceptors
within the arteriolar network (1A and 2A, 1 and
2; 3A and 4A, 2)18 22 and
provided a rationale for our studying both 2A and 3A arterioles in the
hamster cremaster muscle. Although the direct effect of ACh on 2A
arterioles was enhanced by vasoconstriction (Fig 4), we found no
difference between branch orders in sensitivity to PNS (Fig 2) or to
the interaction between conduction and PNS (Fig 4). Hamster arterioles
may have more uniform -adrenoceptor distribution than observed in
the rat18 22 ; however, this remains to be ascertained.
Responses to ACh
Local responses to ACh were either maintained or increased by
global treatments (eg, PNS and elevated O2); in no case was
the direct effect of ACh attenuated. In contrast, PNS attenuated
conducted vasodilation (Figs 4 and 5). This reduction was not dependent
on vasoconstriction per se because equivalent constriction with 10%
O2 did not affect conduction. Because phentolamine
eliminated the attenuation of conduction during PNS, we conclude that
the effect of PNS on conducted vasodilation is mediated via NE
activation of -adrenoceptors.
In a reciprocal fashion, ACh-induced vasodilation overcame the PNS-induced vasoconstriction both directly and at sites of conduction. In addition to its direct action as a vasodilator, ACh could attenuate sympathetic vasoconstriction via presynaptic inhibition of NE release.14 However, this effect would occur only at the site of ACh release. Because NE is released throughout the perivascular nerve plexus,2 3 23 conducted vasodilation must interact with sympathetic vasoconstriction by a mechanism other than presynaptic inhibition.
The conduction of vasodilation occurs via coupling between endothelial cells and smooth muscle cells along the arteriolar wall; a key component appears to involve the spread of hyperpolarization triggered locally by ACh.17 24 In the hamster cheek pouch, micropipette application of depolarizing KCl solution (137 mmol/L) or the microiontophoresis of NE onto arterioles was found to induce vasoconstriction that conducted along arterioles and attenuated conducted vasodilation.15 17 Nevertheless, the cheek pouch microcirculation is devoid of sympathetic nerves,25 and the influence of sympathetic nerve activity on conduction in arterioles has not previously been investigated. Arteriolar smooth muscle cells depolarize in response to sympathetic nerve stimulation or exposure to NE.23 26 Therefore, the present findings lead us to hypothesize that depolarization of arteriolar smooth muscle cells induced by NE release during PNS may underlie the attenuation of hyperpolarization and conducted vasodilation triggered by ACh.
Alternatively, NE may alter cell-to-cell coupling in the arteriolar
wall and thereby reduce the amplitude of conduction. In support of this
argument are the findings that NE increases intracellular
Ca2+ in smooth muscle cells through binding to
-adrenoceptors,27 which may reduce gap junctional
conductance.28 Whereas the present results are the
first to indicate that PNS depresses conducted vasodilation via
-adrenoceptor activation in vivo, further experiments are required
to identify the subsequent event(s) that influence conduction.
Tetrodotoxin
TTX blocks the fast voltage-sensitive Na+
channels and thereby inhibits the propagation of action potentials. In
previous studies, administration of TTX to cheek pouch arterioles had
no affect on conduction.16 17 This finding argued against
a role for nerves in conduction and contributed to the conclusion that
cell-to-cell coupling was the basis of conduction in
arterioles.17 24 In contrast to the cheek
pouch,25 arterioles of the hamster cremaster muscle are
richly invested with perivascular nerve fibers18 21 (S.S.
Segal and B.D. Walker, unpublished data, 1994); therefore, TTX should
inhibit neurotransmitter release. In the presence of TTX, the
elimination of PNS-induced vasoconstriction and augmented conducted
responses (Fig 5) are consistent with this interpretation.
Arterioles developed sustained constriction during exposure to TTX. In
fact, the magnitude of constriction to TTX was not different from that
obtained with PNS (Table). Although the cause of this response is
unclear, vasoconstriction by itself (eg, with 10% O2) does
not influence conduction (Fig 4). In addition, TTX does not directly
affect the membrane potential of vascular smooth muscle
cells.29 Therefore, whereas enhanced conduction during TTX
exposure may be explained by elimination of perivascular nerve
activity, the inability of phentolamine to alter conduction at rest
suggests than neuromodulators in addition to NE could influence
cell-to-cell coupling in arterioles.
Significance
Functional hyperemia occurs in the cremaster muscle in response to
electrical stimulation30 and during physical
exercise31 ; cremaster preparations have proven highly
useful in studies of blood flow control in the microcirculation of
striated muscle.2 7 16 18 21 22 30 Muscular exercise also
increases the activity of the sympathetic nervous
system.5 11 The mechanism by which active muscle overrides
this vasoconstrictor stimulus is unclear in spite of the volume of
research on this topic1 5 8 9 10 12 13 ; the products of
muscle metabolism cannot completely account for this phenomenon. ACh
release at neuromuscular junctions increases greatly during exercise.
As shown in the present study and in previous
studies,15 16 this molecule is highly effective in
triggering conducted vasodilation. Recent work suggests that
neuromuscular junctions in striated muscle could provide a vasomotor
stimulus to arterioles.32 Therefore, we speculate that
conducted vasodilation triggered at neuromuscular junctions may
contribute to functional sympatholysis. Although the present
findings demonstrate that the direct effects of ACh are not impaired in
the presence of increased sympathetic activity, conduction is clearly
suppressed. Nevertheless, the persistence of conducted vasodilation
during PNS indicates that it may still contribute to the rapid increase
in capillary surface area that occurs with the onset of muscular
exercise.9 16
Summary and Conclusion
Perivascular nerve stimulation at the distal end of primary
arterioles activated sympathetic nerves throughout arteriolar networks
in hamster striated muscle. During PNS, ACh microiontophoresis reversed
vasoconstriction in 2A and 3A arterioles locally and by triggering
conducted vasodilation. The magnitude of conducted vasodilation was
diminished similarly by PNS in both vessel orders, and this effect was
reversed with phentolamine. In the presence of TTX, responses to PNS
were eliminated, and the magnitude of conducted vasodilation was
increased. These findings indicate that sympathetic nerves can
influence cell-to-cell communication along the arteriolar wall, both at
rest and during enhanced sympathetic activity. The attenuation of
sympathetic vasoconstriction by conducted vasodilation suggests a novel
explanation for functional sympatholysis.
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Acknowledgments |
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This study was supported by National Institutes of Health grant R29-HL-41026 (Dr Segal) and by predoctoral and postdoctoral fellowships (Dr Kurjiaka) from the American Heart Association, Pennsylvania and Connecticut Affiliates, Inc, and was performed during the tenure of an Established Investigatorship Award (Dr Segal) from the American Heart Association and Genentech, Inc.
Received August 10, 1994; accepted January 23, 1995.
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