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2-adrenergic autoreceptors on sympathetic nerves associated with mesenteric arteries and veins in DOCA-salt hypertension
Department of Pharmacology and Toxicology and the Neuroscience Program, Michigan State University, East Lansing, Michigan 48824
Submitted 23 June 2003 ; accepted in final form 4 December 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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2-adrenergic autoreceptors and increased transmitter release from sympathetic nerves associated with mesenteric arteries and veins from DOCA-salt rats. High-performance liquid chromatography was used to measure the overflow of ATP and norepinephrine (NE) from electrically stimulated mesenteric artery and vein preparations in vitro. In sham arteries, nerve stimulation evoked a 1.5-fold increase in NE release, whereas in DOCA-salt arteries there was a 3.9-fold increase in NE release over basal levels (P < 0.05). In contrast, stimulated ATP release was not different in DOCA-salt arteries compared with sham arteries. In sham veins, nerve stimulation evoked a 2.9-fold increase in NE release, whereas in DOCA-salt veins there was a 8.4-fold increase in NE release over basal levels (P < 0.05). In sham rats NE release, normalized to basal levels, was greater in veins than in arteries (P < 0.05). The 2-adrenergic receptor antagonist yohimbine (1 µM) increased ATP and NE release in sham but not DOCA-salt arteries. The 2-adrenergic receptor agonist UK-14,304 (10 µM) decreased ATP release in sham but not DOCA-salt arteries. In sham veins, UK-14,304 decreased, but yohimbine increased, NE release; effects that were not observed in DOCA-salt veins. These data show that nerve stimulation causes a greater increase in NE release from nerves associated with veins compared with arteries. In addition, impairment of 2-adrenergic autoreceptor function in sympathetic nerves associated with arteries and veins from DOCA-salt rats results in increased NE release.
norepinephrine; ATP; vasoconstriction; splanchnic circulation
The increased sympathetic nerve activity in DOCA-salt hypertension suggests that there may be alterations in the local mechanisms that modulate sympathetic neurotransmission (26a, 30). 2-Adrenergic autoreceptors on sympathetic nerve terminals mediate feedback inhibition of norepinephrine (NE) release (18). Data from several studies indicate that presynaptic 2-adrenergic receptor function is impaired in hypertensive animals. For example, intravenously administered yohimbine, an 2-adrenergic receptor antagonist, increased plasma NE levels in normotensive but not DOCA-salt hypertensive rats (8, 23). Furthermore, yohimbine potentiated nerve stimulation-evoked NE release into the mesenteric vasculature in normotensive rats but not in DOCA-salt hypertensive rats (30). As nerve stimulation would activate periarterial and perivenous nerves, the source of NE in these studies was unclear.
ATP and NE are cotransmitters released by sympathetic nerves associated with arteries (1, 2, 5, 12). In normotensive rats, ATP is the dominant neurotransmitter in small mesenteric arteries (12, 20); however, in arteries from DOCA-salt hypertensive rats, NE is the major sympathetic neurotransmitter (20). The increased adrenergic component in sympathetic neurotransmission to DOCA-salt arteries is not to be due to an increase in postjunctional reactivity to NE as dose-response curves for exogenous NE and phenylepherine were not different between sham and DOCA-salt arteries (20). Increased adrenergic transmission is, therefore, likely to be due to increased NE release. In addition, it was shown that sympathetic arterioconstriction was increased in DOCA-salt arteries (20). This potentiation appears to be attributable to increased NE release as there was no change in postjuctional reactivity of DOCA-salt arteries to exogenous NE and ATP (20). Whether ATP release is altered in DOCA-salt arteries is yet to be determined.
Sympathetic nerves exert primary control over venomotor tone (18), and NE is the neurotransmitter mediating neurogenic contractions of mesenteric veins from sham and DOCA-salt rats (20). Presynaptic 2-adrenergic receptors associated with sympathetic nerves also regulate NE release in veins (2, 11). The few studies of the function of 2-adrenergic receptors associated with veins in hypertension, however, have yielded controversial results. Increased NE release and attenuated yohimbine effect on NE release occur in the portal vein of spontaneous hypertensive rats (SHRs). However, in the same study (30), it was shown that in portal veins from DOCA-salt hypertensive and one kidney-one clip hypertensive rats there was not an increase in NE release or an attenuation of the yohimbine effect on NE release. As the portal vein makes only a small contribution to total vascular capacitance, this blood vessel may not be an appropriate model to study hypertension-associated changes in the function of perivenous sympathetic nerves.
Veins are more sensitive to the vasoconstrictor effect of sympathetic nerve stimulation than arteries as frequency-response curves caused by nerve stimulation obtained from veins are to the left of those from arteries (14, 16, 20). Accordingly, small increases in sympathetic nerve activity would increase venous tone before changing arterial tone. As 25% of the blood volume is in the splanchnic circulation, increases in mesenteric venomotor tone will lead to an increase in venous return and cardiac output. These changes will have a profound impact on overall hemodynamics (13). Therefore, mesenteric veins are an appropriate system to study hypertension-associated changes in sympathetic nerve function.
Our previous studies showed that there is maintained in vitro neurogenic venoconstriction in the presence of decreased postjunctional reactivity to exogenously applied NE. These data indicate that there must be increased NE release in mesenteric veins from DOCA-salt rats (20). In addition, the steady-state stores of NE in DOCA-salt arteries and veins were reduced, presumably due to increased NE release in DOCA-salt rats (20). Clearly, direct measurements of NE release in mesenteric arteries and veins are needed to substantiate these suggestions.
In the present study, we tested the hypothesis that there is impaired function of 2-adrenergic autoreceptors and increased transmitter release from sympathetic nerves associated with mesenteric arteries and veins from DOCA-salt rats. We examined the changes in sympathetic neurotransmitter release in DOCA-salt hypertension and the function of 2-adrenergic receptors in regulating ATP and NE release from periarterial nerves and NE release from perivenous nerves.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Preparation of DOCA-salt rats. Male Sprague-Dawley rats weighing 175–200 g were anesthetized with pentobarbital sodium (50 mg/kg ip). The skin over the left lateral abdominal wall was shaved and prepared with an iodine-based antiseptic. A 1.5-cm vertical incision was made through the skin and underlying muscle caudal to the rib cage. The left kidney was exteriorized and removed after ligation of the renal artery, vein, and ureter with 4-0 silk sutures. The muscle and skin layers were closed separately with 4-0 silk and 4-0 monofilament nylon sutures, respectively. A 3 x 1.5-cm rectangular area between the shoulder blades of the back was shaved and disinfected for subcutaneous DOCA implantation under a 1-cm incision. The skin was closed with 4-0 nylon sutures. DOCA implants (600 mg/kg) were prepared by mixing DOCA in silicone rubber, resulting in a given dose of 200 mg/kg. Sham-operated rats underwent left kidney removal only. Surgery was performed on a heated pad, and rats recovered in a heated box. An antibiotic (5 mg/kg sc enrofloxacin) and an analgesic (2 mg/kg sc butorphanol tartrate) were administered immediately after surgery. After recovery, rats were housed under standard conditions for 4 wk. DOCA-implanted rats received standard pelleted rat chow and salt water (1% NaCl + 0.2% KCl) ad libitum, whereas sham rats received standard pelleted rat chow and tap water ad libitum. Systolic blood pressure was measured using the tail-cuff method 4 wk after surgery. Rats with systolic blood pressure equal to or higher than 150 mmHg were considered hypertensive.
Tissue preparation. Rats were killed using a lethal pentobarbital sodium injection (50 mg ip). The entire small intestine with the attached mesenteric arcade, including the superior mesenteric artery and vein, was removed and placed in oxygenated (95% O2-5% CO2) Krebs solution of the following composition (in mM): 117 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgCl2, 25 NaHCO3, 1.2 NaH2PO4, and 11 glucose in a silicone elastomer-lined petri dish. The entire mesenteric bed was stretched gently and pinned out flat in a large silastic elastomer-lined petri dish. With the use of fine scissors and forceps, mesenteric arteries or veins were dissected out by carefully cutting away surrounding adipose and connective tissues. Veins and arteries were differentiated visually under a dissecting microscope at x40–63 magnification. Arteries had a smaller diameter with thicker walls than did the veins. In each mesentery preparation, only one kind of blood vessel (veins vs. arteries) was dissected out to maintain the integrity of the blood vessels sampled, and blood vessels were harvested from 
75% of the entire mesentery. The diameter of the blood vessels harvested ranged from 300 to 100 µm in diameter (secondary and tertiary vessels). Blood vessels were transferred to a small silicone elastomer-lined recording bath (1.0 ml volume), and they were anchored to the bottom of the chamber using small pins (50 µm diameter). The recording bath containing the preparation was superfused continuously with warm (36°C) Krebs solution at a flow rate of 7–8 ml/min. The preparation was equilibrated for 1 h before experiments began.
Drug application. Drugs were applied using a system of 3-way stopcocks so that the superfusing Krebs solution could be changed to one containing a known concentration of drug. It took 1 min for drugs to reach the tissue. Agonists or antagonists were applied for 30 min before their effects on transmitter release were tested.
Transmural stimulation of perivascular nerves. Two parallel silver/silver chloride wire electrodes connected to a Grass Instruments stimulator (S88; Quincy, MA) were used for transmural stimulation (30 stimuli, stimulus duration 0.5 ms, frequency 10 Hz, voltage 120–140 V). We have shown previously that a stimulation frequency of 10 Hz causes maximum constrictions in mesenteric arteries and veins (20). Two conditioning trains of stimulation were applied at 20-min intervals for ATP measurement and one conditioning train of stimulation for NE measurement. Nerve-mediated ATP and NE release were stable after the conditioning trains of stimulation (1). The flow of the superfusing solution was stopped during nerve stimulation, and the solution (1 ml) was quickly withdrawn from the bath using a 1-ml syringe. Flow was restarted immediately after sample withdrawal. The superfusate was then processed using HPLC for measurement of ATP and NE concentrations. Basal levels of ATP or NE were measured in superfusate samples collected before nerve stimulation.
Measurement of adenine nucleotides and adenosine by HPLC with fluorescence detection. Our measurements of ATP release include ATP and its metabolites: ADP, AMP, and adenosine. Superfusate samples (500 µl) were analyzed using HPLC in conjunction with fluorescence detection (19). Briefly, chloroacetaldehyde (25 µl) was added to superfusate samples, which were then heated for 40 min at 80°C in an oven (Baxter, Scientific Products) to produce the fluorescent derivative 1,N6-ethenopurine analogs. The derivatization reaction was stopped by cooling the samples on ice. Separation of derivatized ATP, ADP, AMP, and adenosine was achieved using a C-18 column (Biophase ODS, 5 µm, 250 x 4.6 mm, Bioanalytical Systems) and a gradient system in which the concentration of mobile phase buffer B was increased from 0 to 100% in 10 min and maintained at 100% for 5 min, followed by a decrease to 0% in 5 min. The column then was reequilibrated with 100% mobile phase buffer A for 10 min. Mobile phase buffer A consisted of 0.1 mol/l KH2PO4 (pH 6.0), and mobile phase buffer B consisted of 0.1 mol/l KH2PO4 with 25% methanol (pH 6.0). Fluorescence signals were measured using a programmable fluorescence detector (RF-10Axl; Shimadzu, Japan) at an excitation wavelength of 300 nm and emission wavelength of 420 nm. Fluorescence signals were integrated using Gilson 712 software (Gilson Medical Electronics; Middleton, WI). Detection limits were 19 pg for ATP, 252 pg for ADP, 72 pg for AMP, and 75 pg for adenosine. Individual adenine nucleotides and adenosine were identified by retention times established using known standards. The standard curves for each individual adenine nucleotide and adenosine were constructed by using standards dissolved in Krebs solution and plotted using peak height as dependent variables and the standard as the independent variable. The amounts of individual adenine nucleotides and adenosine were then calculated using linear standard curves. Total ATP overflow was a summation of measured ATP plus its metabolites: ADP, AMP, and adenosine.
Measurement of NE by HPLC with electrochemical detection. Aliquots of the collected superfusate (50 µl) were acidified with phosphoric acid (pH 2.6), filtered through a 0.22 µM Cameo 3N syringe filter (1), and injected into an isocratic HPLC system equipped with a C-18 reverse-phase analytical column (5-µm spheres, 250 x 4.6 nm, Biophase ODS, Bioanalytical Systems). The HPLC column was coupled to a single colormetric electrode-conditioning cell in series with dual-electrode analytical cells (ESA). The conditioning electrode potential was set at +0.4 V; the analytical electrodes were set at +0.12 and –0.31 V, respectively, relative to the reference electrodes. The HPLC mobile phase consisted of 1.0 mol/l phosphate-citrate buffer (pH 2.65), with 0.1 mmol/l EDTA, 0.0475% sodium octylsulfate, and 5% methanol. The detection limit for NE was 0.5 pg per sample. The amount of NE in the samples was determined by comparing peak heights (determined by a model 3393A Hewlett-Packard Integrator) with those obtained from standards run on the same day.
Statistical analysis. To minimize differences in release caused by variation in the total number of arteries or veins in each preparation or hypertension-induced structural changes, nerve stimulation-induced ATP and NE release were normalized. This was accomplished by dividing the amount of transmitter released in response to electrically stimulation by basal levels measured before stimulating. All data are expressed as means ± SE, and n values are the number of animals used for each specific protocol. We used 51 sham and 52 DOCA-salt rats. Differences between groups were assessed by ANOVA and Tukey-Kramer multiple-comparisons test or Student's t-test using GraphPad InStat version 3.0 for Windows 95 (GraphPad Software; San Diego CA). P < 0.05 was considered significant.
Drugs. All drugs were obtained from Sigma Chemical (St. Louis, MO). We used the following drugs: tetrodotoxin (TTX; 0.3 µM), a voltge-dependent sodium channel blocker that inhibits axonal action potentials; 5-bromo-6-(2-imidazolin-2-yl-amino)-quinoxaline tartrate (UK-14,304; 10 µM), an agonist of 2-adrenergic receptors; and yohimbine (1 µM), an antagonist of 2-adrenergic receptors.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Because stimulation-induced ATP release stabilized at the third stimulation, release caused by the third stimulation was used as the control level for subsequent assessment of drug effects on ATP release. Drugs were added between the third and fourth stimulation periods. Basal ATP release before nerve stimulation and normalized ATP release were not different between sham and DOCA-salt arteries (Table 1). TTX blocked ATP release caused by nerve stimulation. The normalized release in sham arteries before TTX treatment was 2.9 ± 0.7 and after TTX treatment was 1.1 ± 0.09 (n = 4, P < 0.05). The normalized release before TTX-treatment in DOCA-salt arteries was 4.7 ± 1.5 and after TTX treatment was 0.6 ± 0.1 (n = 5, P < 0.05).
Increased NE release in DOCA-salt arteries and veins. Our previous study (20) demonstrated that NE mediates sympathetic neurotransmission to veins as neurogenic constrictions were blocked completey by the 1-adrenergic antagonist prazosin. Therefore, we only measured NE release from veins in response to nerve stimulation in this study. There were no differences in NE release occurring during three consecutive stimulation periods (Fig. 2). There was a positive correlation between the basal levels and the stimulation-induced NE release by the second stimulation in both arteries and veins (Table 2). Normalized release caused by the second stimulation was used as the control level of NE release for assessment of all drug-induced changes in release occurring during the third stimulation period. The normalized release in sham arteries before TTX treatment was 1.6 ± 0.1 and after TTX treatment was 0.7 ± 0.1 (n = 4, P < 0.05). The normalized release before TTX treatment in DOCA-salt arteries was 4.1 ± 1.4 and after TTX treatment was 0.7 ± 0.2 (n = 4, P < 0.05). The normalized release in sham veins before TTX treatment was 4.6 ± 0.3 and after TTX treatment was 0.7 ± 0.3 (n = 4, P < 0.05). The normalized release before TTX treatment in DOCA-salt veins was 4.4 ± 0.7 and after TTX treatment was 1.3 ± 0.5 (n = 4, P < 0.05). Basal NE release was not different between sham and DOCA-salt arteries or between sham and DOCA-salt veins (Table 2). Normalized NE release caused by nerve stimulation was compared between arteries and veins from sham and DOCA-salt hypertensive rats. The normalized NE release was increased in DOCA-salt arteries and veins compared with their sham counterparts (Table 2). In addition, normalized NE release in sham veins was greater than that in sham arteries (Table 2).
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2-Adrenergic autoreceptors associated with mesenteric arteries and veins are impaired in DOCA-salt hypertensive rats. To determine whether 2-adrenergic autoreceptors regulate ATP release, the effects of the 2-adrenergic receptor antagonist yohimbine (1 µM) and the agonist UK-14,304 (10 µM) on ATP release in arteries from sham rats were studied. Previous studies had shown that these were maximum effective concentrations for antagonist (yohimbine) and agonist (UK-14,304) action on 2-adrenergic receptors (1, 29). In sham arteries, yohimbine increased ATP release, whereas UK-14,304 decreased ATP release, caused by nerve stimulation (Fig. 3A). In DOCA-salt arteries, the normalized ATP release before yohimbine treatment was not different from the release after yohimbine treatment (Fig. 3B). Similarly, ATP release before UK-14,304 treatment was not different from the release after UK-14,304 treatment in DOCA-salt arteries (Fig. 3B).
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Yohimbine increased NE release caused by nerve stimulation in sham arteries (Fig. 4A), but it did not alter evoked NE release in DOCA-salt arteries (Fig. 4B). We also assessed the function of 2-adrenergic autoreceptors associated with veins by examining the effect of yohimbine (1 µM) on NE release. NE release caused by nerve stimulation before and after yohimbine treatment was compared in sham and DOCA-salt rats. Yohimbine increased NE release in sham veins (Fig. 5A) but failed to alter NE release in DOCA-salt veins (Fig. 5B). Conversely, UK-14,304 decreased NE release in sham (Fig. 5A) but not DOCA-salt veins (Fig. 5B).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We normalized nerve stimulation-induced ATP and NE release to their basal levels to minimize differences in release that might be due to hypertension-induced structural changes in blood vessels. For example, hypertrophy of the smooth muscle of arteries occurs in DOCA-salt hypertension (26a). Therefore, it would be problematic for interpretation of the results to normalize the stimulation-induced release to tissue weight or total protein. The correlation between basal release and nerve stimulation-induced ATP and NE release suggests that the basal release of ATP and NE is from nerve terminals. This result also justifies normalization of stimulation-induced release to that occurring under basal conditions. Unaltered basal levels of ATP and NE in arteries and veins from DOCA-salt hypertensive rats suggest that the overall number of nerve terminals associated with mesenteric arteries and veins is not changed in DOCA-salt rats. Therefore, the increased release most likely results from the increased transmitter release per nerve terminal rather than from hyperinnervation of those blood vessels. Upregulation in NE release from nerve terminals in DOCA-salt rats differs from changes known to occur in SHRs, where it has been shown that there is an increased density of sympathetic nerve fibers in the vasculature (6, 28). Nerve stimulation-induced ATP release increased and became stabilized after two stimulation periods, suggesting that there is an increase in size of the readily releasable ATP store in response to the two conditioning stimulations. This increase may represent an augmented mobilization of the ATP stores in structures remote from the release sites. Stimulation-induced NE release was not different over three consecutive stimulation periods, suggesting that the size of the readily releasable NE store is not altered by conditioning stimulation.
There is more NE release from perivenous nerves per stimulus compared with periarterial nerves as NE release caused by nerve stimulation normalized to basal levels is greater in veins than arteries from sham rats. This result could explain in part why veins are more sensitive than arteries to the contractile effects of sympathetic nerve stimulation (14, 20). However, postsynaptic factors could also contribute to increased venous sensitivity to sympathetic neural input. For example, venous smooth muscle cells have a less negative resting membrane potential compared with arterial smooth muscle cells (14). Under these conditions, venous smooth muscle cells would be more sensitive to excitatory stimuli as their membrane potential would be closer to the threshold for activation of voltage-dependent calcium channels.
The greater increase of NE release in veins compared with arteries during nerve stimulation may be related to the different functional properties of sympathetic nerves supplying arteries and veins (4). The notion that sympathetic nerves innervating arteries and veins are different is based on the following evidence: 1) in arteries, stimulation of sympathetic nerves elicits excitatory junction potentials mediated by ATP followed by a slow depolarization mediated by NE, but in veins only slow depolarizations mediated by NE occur (9, 14); and 2) sympathetic nerve cell bodies providing nerve fibers innervating mesenteric arteries and veins differ in their localization in prevertebral ganglia and in their electrophysiological properties (4). Our data showing a greater increase in NE release during sympathetic nerve stimulation in veins compared with arteries provide another important example of the difference in the functional properties of sympathetic nerves supplying arteries and veins.
2-Adrenergic autoreceptors on perivenous nerves are impaired in DOCA-salt rats. Yohimbine increased NE release in sham but not DOCA-salt veins, whereas UK-14,304 decreased NE release in sham but not DOCA-salt veins. These results suggest that the function of presynaptic 2-adrenergic receptors associated with mesenteric veins is impaired in DOCA-salt hypertensive rats. This differs from previous data demonstrating integrity of the autoinbihitory function of 2-adrenergic receptors in portal veins from DOCA-salt rats (31). The difference in results could be attributed to the difference in vascular beds studied. Although the portal vein is linked to the mesenteric circulation, it serves a much smaller capacitance function compared with mesenteric veins and is less likely to be affected by hypertension.
2-Adrenergic autoreceptors on periarterial nerves regulate ATP release and are impaired in DOCA-salt rats. Nerve stimulation with the parameters used in the present study produces vasoconstriction that can be blocked by TTX (20), and the ATP release measured here was TTX sensitive. Therefore, we concluded that ATP release caused by electrical stimulation is nerve mediated. ATP is a cotransmitter released with NE in the vascular system (1, 2, 5, 12), particularly in small mesenteric arteries, where it plays a major role in mediating sympathetic neurotransmssion (10, 20). Our studies show that 2-adrenergic receptors regulate ATP release as yohimbine increased, whereas UK-14,304 decreased, ATP release in sham arteries. These results are consistent with previous studies that showed that yohimbine (1 µM) increased the overflow of ATP caused by electrical field nerve stimulation (2). Taken together, these data indicate that ATP and NE release, at least that caused by 10-Hz stimulation, are regulated in a similar manner.
Our study is the first to directly measure nerve stimulation-induced ATP release from sympathetic nerves in DOCA-salt hypertensive rats. Our study showed that ATP release is not altered in mesenteric arteries in these animals. This result is consistent with a study (3) on ATP release from sympathetic nerves in the isolated kidney from SHRs, where it was shown that ATP release was not altered compared with that occurring in Wistar-Kyoto rats. In DOCA-salt arteries, 2-adrenergic receptor function is impaired as yohimbine or UK-14,304 did not change ATP release. Impaired function of prejunctional 2-adrenergic receptors does not result in an increase in stimulated ATP release. It is possible that changes in other mechanisms regulating ATP release may compensate for the impaired function of 2-adrenergic receptors in hypertension (7). For example, it has been shown that the inhibitory effects of prejunctional prostaglandin E2 receptors on sympathetic neurotransmitter release are enhanced in SHRs (25).
We have shown previously that ATP mediates neurogenic constrictions of small mesenteric arteries from sham rats, whereas ATP and NE mediate neurogenic constrictions in arteries from DOCA-salt rats (20). It was concluded that the increased adrenergic component of neurogenic constriction is due to increased NE release rather than an increase in postjunctional reactivity as constrictor responses to NE are not different between sham and DOCA-salt arteries (20). The present study showed directly that NE release caused by nerve stimulation was increased in DOCA-salt arteries, further demonstrating an alteration of sympathetic neuronal function in DOCA-salt hypertension. Impaired function of prejunctional 2-adrenergic receptors is likely to account for increased NE release in DOCA-salt arteries as NE release was increased when 2-adrenergic receptors were blocked by yohimbine in sham arteries. This result is consistent with studies showing a failure of yohimbine to increase plasma NE level (8, 23) and nerve stimulation-induced NE release by yohimbine in the mesenteric vasculature of DOCA-salt rats (18, 30).
Summary and conclusions. Nerve stimulation causes more NE release in mesenteric veins compared with arteries from sham rats. This result provides further support for the hypothesis that sympathetic nerves with different functional properties innervate arteries and veins. NE release caused by sympathetic nerve stimulation is increased in mesenteric arteries and veins from DOCA-salt hypertensive rats, although ATP release is not altered in arteries. Prejunctional 2-adrenergic receptors on sympathetic nerves regulate ATP release in sham arteries and NE release in sham arteries and veins. Function of these receptors is impaired in DOCA-salt arteries and veins, which would contribute to increased nerve stimulation-induced NE release and increased peripheral arterial and venomotor tone in DOCA-salt hypertension (10, 20).
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ACKNOWLEDGMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grants R01 HL-63973 and P01 HL-70687 (to J. J. Galligan and G. D. Fink) and by an American Heart Association, Midwest Affiliate, Predoctoral Fellowship (to M. Luo).
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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2-adrenoceptor-mediated modulation of adenosine 5' triphosphate and noradrenaline corelease: differences in canine mesenteric artery and vein. J Auton Pharmacol 21: 47–55, 2001.[CrossRef][Web of Science][Medline]
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