(Hypertension. 1997;30:957-961.)
© 1997 American Heart Association, Inc.
Articles |
Attenuation of Neurogenic Vasoconstriction by Nitric Oxide in Hindlimb Microvascular Beds of the Rat In Vivo
From the Physiologisches Institut, Christian-Albrechts-Universität, Kiel, Germany.
Correspondence to Dr H.-J. Häbler, Physiologisches Institut, Christian-Albrechts-Universität, Olshausenstrasse 40, 24098 Kiel, FRG. E-mail j.haebler{at}physiologie.uni-kiel.de
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Abstract |
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Abstract There is evidence that sympathetic nerve activity leads to endothelium-derived nitric oxide release, which in turn attenuates neurogenic vasoconstriction. Here we tested in vivo (1) whether the magnitude of the vasoconstriction induced by NG-nitro-L-arginine methyl ester given systemically is altered when ongoing sympathetic activity is abolished by sectioning the lumbar sympathetic trunk, and (2) whether hindlimb sympathetic vasoconstriction elicited by electrical stimulation of the lumbar sympathetic trunk is enhanced after inhibition of nitric oxide synthesis. Blood flow in the microvascular beds of hairless skin and skeletal muscle of the rat hindlimb was measured with laser Doppler flowmetry. Sectioning the lumbar sympathetic trunk resulted in an increase of blood flow in both tissues, indicating that tonic neurogenic vasoconstriction was abolished. Inhibition of nitric oxide synthesis resulted in vasoconstriction in both vascular beds. This vasoconstriction was more pronounced after abolition of sympathetic activity than with intact sympathetic supply in skin but was smaller in skeletal muscle. The vasoconstriction elicited by graded electrical stimulation of the centrally sectioned lumbar sympathetic trunk with frequencies less than 5 Hz was significantly enhanced after blockade of nitric oxide in skeletal muscle but not in skin microvasculature. These findings suggest that under physiological conditions, sympathetic nerve impulses directly promote the release of nitric oxide in skeletal muscle but not in cutaneous blood vessels. Therefore, basal nitric oxide release is probably in part dependent on sympathetic activity in skeletal muscle, whereas it appears to be mainly due to flow-dependent shear stress in hairless skin microvasculature.
Key Words: nitric oxide • L-NAME • sympathetic nervous system • vasoconstriction • microcirculation • hindlimb
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Introduction |
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Blockade of NO synthesis by systemic application of substituted L-arginine analogues evokes an increase of arterial blood pressure in experimental animals1 2 3 and humans.4 The blood pressure rise is due to the vasoconstriction that occurs in a variety of vascular beds.1 3 Thus, it is well established that there is a continuous "basal" release of NO from the endothelium that counteracts ongoing vasoconstriction.
Probably the most important factor that controls ongoing vasoconstriction is the sympathetic nervous system. Many postganglionic vasoconstrictor neurons have ongoing activity5 6 7 that evokes sustained vasoconstriction in many vascular beds. Basal release of NO may diminish the efficacy of sympathetic nerve impulses. It is not clear, however, whether NO is released specifically in response to sympathetic nerve impulses. In vitro experiments on isolated arteries have shown that removal of the endothelium or application of NO antagonists enhances the vasoconstriction generated by stimulation of perivascular nerves or application of norepinephrine, suggesting that this is indeed the case.8 9 10 Only few in vivo studies addressed this question experimentally. A study on the pithed rat showed that after blockade of NOS, the magnitude of the blood pressure increase is proportional to the level of sympathetic vasomotor activity.11 The latter was induced by electrical stimulation of preganglionic neurons with different frequencies. Another study using ganglionic blockade and vasopressor drugs and analyzing changes of blood pressure and vascular resistance after application of NG-nitro-L-arginine in anesthetized rats concluded that part of basal NO release was sympathetically mediated.12 In contrast, a similar study on anesthetized rats concluded that the sympathetic nervous system is not necessary for basal NO release.13 Only a few studies addressed the problem by investigating regional rather than systemic vasoconstriction induced by sympathetic nerve stimulation before and after inhibition of NOS.14 15 16 17 Nerve stimulation–induced vasoconstriction in the rabbit and rat knee joint,14 15 in the vascular bed controlled by the maxillary artery in the pig,16 and in rat mesenteric arterioles17 was enhanced after blockade of NO but was not changed in the pig hindlimb.16
Thus, it remains unclear to what extent sympathetic vasoconstriction is actually curtailed by NO under in vivo conditions and whether this effect differs among vascular beds. The present study tries to answer these questions. We specifically, and exclusively, stimulated sympathetic motor fibers in the LST and studied the microvasculature of hairless skin and skeletal muscle of the rat hindlimb. Furthermore, we analyzed whether the vasoconstriction in these vascular beds generated by blockade of NOS differs before and after abolition of ongoing sympathetic activity.
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Methods |
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Anesthesia and Animal Maintenance
Forty-four Wistar rats of either sex (215 to 450 g) were anesthetized with 60 mg/kg pentobarbital sodium IP (Nembutal). Anesthesia was maintained with additional doses (10 mg/kg, 1:4 vol/vol in Tyrode's solution) injected intravenously every hour through a cannulated jugular vein and judged sufficient by the absence of withdrawal reflexes in response to toe pinching and the absence of gross fluctuations of blood pressure and heart rate. After a cannula had been inserted into the trachea, the animals were paralyzed (Pancuronium, Organon; 1 mg/kg initially, maintenance with 0.4 mg/kg when necessary) and artificially ventilated with O2-enriched room air (in total, 40 vol% O2) (RUS-1300, FMI). End-tidal CO2 (FM1, ADC), blood gases, and blood acid-base status were measured at intervals (ABL 30, Radiometer). Arterial blood pressure was recorded in the ventral caudal artery (LM-22 transducer, List). Rectal temperature was kept constant close to 37°C by means of a servo-controlled heating blanket.
At the end of the experiments, the animals were killed under deep anesthesia by intravenous injection of a saturated solution of potassium chloride. All experiments had been approved by the local animal care committee of the state administration and were conducted in accordance with German federal law.
Surgery
The left LST was exposed between paravertebral ganglia L2 and
L418 using a retroperitoneal approach and was carefully
freed from connective tissue. A pool was formed from skin flaps, and
exposed tissue was covered with warm paraffin oil.
Blood Flow Measurement
Microvascular blood flow was measured on the plantar skin of the
hind paw (LD flux-c) and, after an appropriate incision in the skin and
the superficial fascia, on the surface of the gluteal muscle (LD
flux-m) using a dual-channel laser Doppler flowmeter (MBF3D, Moors
Instruments). The flux signals were low pass–filtered with the time
constant set to 3 seconds. The exposed muscle was kept moist with
physiological saline.
Experimental Protocols
Generally, NOS was blocked with a single intravenous
bolus injection (35 mg/kg) of L-NAME, which has been reported to
evoke maximal increases of blood pressure in anesthetized
rats.2 In six control rats, administration of
L-arginine (50 to 200 mg/kg IV) led to a temporary
reversal of the blood pressure increase and to a partial reversal of
flow decreases.
In 17 animals, L-NAME was administered with the LST left intact, ie, during normal ongoing sympathetic activity. In 15 animals, the LST was sectioned caudally to paravertebral ganglion L2 or L3, and blood fluxes were allowed to increase to a new steady-state level before L-NAME was given. In 15 animals, the centrally cut LST was placed on a pair of platinum hook electrodes and stimulated electrically with a 50-second train of supramaximal pulses (10 to 15 V; pulse width, 0.5 milliseconds). This was done before and after NOS blockade. The stimulation frequency was varied between 0.5 and 20 Hz within the experiments.
Data Analysis
All changes in blood flow following experimental interventions
(steady-state flow at the end of the 50 seconds of LST stimulation and
after section of LST) were expressed as percentage of baseline flow
prevailing before the intervention with baseline flow set to 100%.
Furthermore, taking into account the changes of blood pressure that
occurred after L-NAME and also during LST stimulation at higher
frequencies, we calculated arbitrary resistance values by dividing
blood pressure by blood flow as described previously.15
Changes in vascular resistance were also expressed as percentages of
baseline resistance before intentional interventions.
Statistical analysis was carried out with Student's t test and paired t test as appropriate. Results are expressed as mean±SEM.
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Results |
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Effects of Acute Sympathetic Denervation on Blood Flow
Sectioning the ipsilateral LST resulted in a prompt increase in blood flow in both skin and skeletal muscle, with a concomitant initial small drop in arterial blood pressure, indicating that skin and muscle microcirculations were under control of ongoing activity in postganglionic sympathetic vasoconstrictor nerves (Fig 1
). Fluxes decreased initially for a few
seconds, mainly due passively to the temporary drop of blood pressure.
A few minutes after the LST was sectioned, new steady-state flow levels
were reached. These were on average more than twofold (112±15%, n=26)
higher in skin but only one fifth (20±4%, n=20) higher in skeletal
muscle. MAP largely recovered after section of the LST, but a small
decrease of 4±1 mm Hg (n=30) compared with control levels
remained.
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Effects of NOS Blockade on Blood Flow
Intact Sympathetic Innervation
After application of L-NAME, blood flow in skin was almost
unchanged. However, MAP increased, and therefore, vascular resistance
rose by about one third (see the Table).
Blood flow through skeletal muscle was reduced to almost one half after
L-NAME. This pronounced vasoconstriction was reflected by a large
increase in vascular resistance (Table).
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Denervated State
After acute sympathetic denervation, inhibition of NO synthesis
led to a decrease in skin perfusion by 10%, whereas MAP again
increased markedly, resulting in an elevation of cutaneous vascular
resistance by about 50% (Table
). In skeletal muscle, blood flow
decreased by 26%, and vascular resistance almost doubled (Table).
Thus, NOS blockade caused a moderate vasoconstriction in skin but a
larger one in skeletal muscle. The relative increase of cutaneous
vascular resistance induced by NOS blockade was significantly more
pronounced after sympathetic denervation than with intact vasomotor
innervation, whereas the opposite applied to skeletal muscle
(Table).
Electrical Stimulation of the LST Before and After NOS
Blockade
Skin
Electrical stimulation of the centrally cut LST induced a decrease
in skin blood flow and a frequency-dependent increase in
arterial blood pressure due to the vasoconstriction in the
hindquarter (Fig 2A and 2B). After
inhibition of NOS, the electrically evoked vasoconstriction was
significantly enhanced at stimulation frequencies greater than or equal
to 5 Hz (Figs 2B and 3). By contrast,
low-frequency stimulation (<4 Hz) resulted in a vasoconstriction that
was almost identical before and after inhibition of NOS (Figs 2A and 3). Baseline vascular resistance was 121±16% higher when sympathetic
innervation was intact than after section of the LST (see above). This
difference corresponds well with the evoked increase of vascular
resistance, when the sectioned LST was stimulated with frequencies less
than or equal to 4 Hz. Therefore, ongoing sympathetic activity in
cutaneous vasoconstrictor neurons probably was in this low-frequency
range. In accordance, neurophysiological
experiments have demonstrated that cutaneous vasoconstrictor neurons
have ongoing activities of 0.3 to 3.6 impulses per second (see
Reference 55 ).
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) and after (
) L-NAME. Vascular resistance
was calculated in arbitrary units from changes of blood flow and blood
pressure during stimulation and expressed as a percentage of resistance
before each stimulation (percent baseline resistance). Data are
presented as mean±SEM; n=8-14. *P<.05,
***P<.001, paired t test. There was no
significant enhancement of vasoconstriction after L-NAME at stimulation
frequencies of 1 to 4 Hz.
Skeletal Muscle
LST stimulation led to a frequency-dependent vasoconstriction in
skeletal muscle microcirculation that was significantly enhanced after
L-NAME at stimulation frequencies of 5 Hz or lower (Figs 4 and 5). At
stimulations of 10 and 20 Hz, the differences in vasoconstriction
before and after L-NAME were no longer significant. Overall,
stimulation-induced vasoconstriction in skeletal muscle was much weaker
than in skin, especially at low and very high frequencies. A comparison
of the vasoconstriction evoked by electrical stimulation of the
sectioned LST and the ongoing vasoconstriction due to spontaneous
vasoconstrictor activity with intact LST revealed the following:
vascular resistance was 25% higher with intact than with sectioned
LST. This is equivalent to the increase of resistance elicited by LST
stimulation with 0.5 to 2 Hz (Fig 5), which agrees well with the rate
of spontaneous activity (range, 0.3 to 2.4 Hz) determined in
postganglionic vasoconstrictor neurons projecting to skeletal
muscle in the rat (see Reference 55 ).
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) L-NAME. Presentation of data (n=7-10) as in
Fig 3 |
Discussion |
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Systemic blockade of NOS leads to a generalized vasoconstriction that includes the vascular beds of skin and skeletal muscle.1 2 3 4 Here we report experiments which suggest that activity in sympathetic vasoconstrictor neurons at physiological frequencies is involved in the release of basal NO in skeletal muscle but not in hairless skin. We measured microvascular blood flow in hairless skin and skeletal muscle before and after blockade of NOS under two different interventions on the sympathetic supply. First, we abolished ongoing vasoconstrictor activity by sectioning the LST and second, we selectively stimulated sympathetic vasoconstrictor axons supplying the hindlimb to study whether neurogenic vasoconstriction in the two vascular beds is enhanced after blockade of NOS. It was important to stimulate the LST rather than the peripheral nerves to avoid antidromic activation of afferents, which elicits vasodilation.
In hairless skin, the increase in vascular resistance generated by
blockade of NOS was significantly larger in preparations with
decentralized LST than in preparations with intact LST. By contrast, in
skeletal muscle, the increase in vascular resistance after L-NAME was
significantly larger in the LST-intact than the LST-decentralized
preparation (Table). These results are in accordance with the
observation that sympathetic stimulation–induced vasoconstriction at
frequencies less than 5 Hz was significantly enhanced after L-NAME in
skeletal muscle but not in hairless skin. Therefore, we suggest that
under physiological conditions, sympathetic nerve
impulses are directly involved in basal NO release from the
endothelium in blood vessels of skeletal muscle but not
in those of hairless skin.
The main driving force evoking basal release of NO in hairless skin is probably the local vascular shear stress,19 20 which would be expected to be enhanced proportionally with blood flow21 after sectioning of the LST. In accordance, skin vasoconstriction after L-NAME was greater in the functionally denervated state than with the sympathetic supply intact. In skeletal muscle circulation, L-NAME was able to evoke vasoconstriction also after functional sympathetic denervation. This indicates that in addition to the NO release that is dependent on postganglionic activity, there is probably also shear stress–induced NO release. The complex interplay between flow-dependent shear stress and sympathetic transmitter(s) in liberating endothelial NO may explain why some investigators who studied blood pressure changes after systemic administration of L-NAME found no obligatory role of the sympathetic nervous system in basal NO release,13 whereas others found that part of the NO released depended on sympathetic vasoconstrictor activity.12
However, L-NAME enhanced stimulation-induced vasoconstriction at high, presumably unphysiological, sympathetic frequencies of 10 to 15 Hz also in skin. A possible explanation would be that shear stress increased in parallel with the considerable rise in systemic blood pressure accompanying hindquarter vasoconstriction at these frequencies, or that now the amount of sympathetic transmitter was high enough to evoke NO release. Furthermore, our results indicate that at 20 Hz, NO is no longer capable of attenuating neurogenic vasoconstriction.
Our data on skeletal muscle, but not skin microvasculature, agree with
in vitro studies on isolated arteries showing that vasoconstriction
evoked by stimulation of perivascular nerves or application of
norepinephrine was enhanced after inhibition of NOS or
removal of the endothelium.8 9 10 22 23
Furthermore, our data on skeletal muscle are in accordance with a
recent in vivo study in which vasoconstriction of rat mesenteric
arterioles induced by perivascular nerve stimulation was enhanced after
local inhibition of NOS.17 Interestingly, nerve
stimulation resulted in a reduction of vessel wall shear
rate.17 There is evidence that norepinephrine
released from sympathetic varicosities by nerve impulses binds to
endothelial
2-receptors,8 24 25 26 leading to enhanced NO
production, which results in a postjunctional attenuation of
neurogenic vasoconstriction. A prejunctional inhibition of
norepinephrine release at the sympathetic varicosity by NO
has also been proposed,27 28 but apparently this mechanism
does not apply to all arteries.10 22 However, it is
unclear how neurally released norepinephrine can reach the
endothelium that quickly.
The possibility exists that NO, which counteracts neurogenic vasoconstriction, originates from sympathetic vasodilator neurons29 rather than being endothelium-derived. However, from our work this seems unlikely because in recent studies, (1) no vasodilation upon LST stimulation was observed after sympathetic vasoconstriction was pharmacologically blocked (unpublished observations, 1997), and (2) no sympathetic postganglionic neurons were found that exhibited reflex responses appropriate to being involved in the regulation of active vasodilation.5 Furthermore, a histochemical study found that NOS was absent from most sympathetic varicosities.30
Functionally, it may be important that vasoconstriction in resistance vessels during blood pressure regulation attenuates itself by liberating NO from the endothelium in order to limit the sudden increase of afterload to the heart. On the other hand, the lack of attenuation of neurogenic vasoconstriction by endothelial NO in hairless skin under physiological sympathetic discharge rates5 6 may be useful for thermoregulation in cold environments, in which a strong cutaneous vasoconstriction must be executed promptly.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Deutsche Forschungsgemeinschaft. The technical help of Eike Tallone and Ulla Klosa is gratefully acknowledged.
Received December 24, 1996; first decision January 9, 1997; accepted March 24, 1997.
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