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Am J Physiol Regul Integr Comp Physiol 277: R1051-R1056, 1999;
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Vol. 277, Issue 4, R1051-R1056, October 1999

Role of ETB receptors and nitric oxide in adrenal catecholamine secretion in anesthetized dogs

Akio Hosokawa1, Takahiro Nagayama1, Kimiya Masada1, Makoto Yoshida1, Mizue Suzuki-Kusaba1, Hiroaki Hisa1, Tomohiko Kimura2, and Susumu Satoh 1

1 Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578; and 2 Department of Dental Pharmacology, The Nippon Dental University School of Dentistry at Niigata, Niigata 951-8580, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

We examined the effects of sarafotoxin 6c (S6c), an endothelin-B (ETB) receptor agonist, on adrenal catecholamine secretion in response to cholinergic stimuli in pentobarbital sodium-anesthetized dogs. Drugs were administered intra-arterially into the adrenal gland through the phrenicoabdominal artery. Infusion of S6c attenuated increases in adrenal catecholamine output induced by splanchnic nerve stimulation. The inhibitory effect of S6c on the catecholamine secretion response was suppressed with a selective ETB receptor antagonist N-cis 2,6-dimethylpiperidinocarbonyl-L-gamma -methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine (BQ-788), a nitric oxide synthase (NOS) inhibitor Nomega -nitro-L-arginine methyl ester, and a neuronal NOS inhibitor 7-nitroindazole monosodium salt (7-NINA). Similar results were obtained with the catecholamine secretion response induced by injection of ACh. 7-NINA alone did not affect these catecholamine secretion responses. These results suggest that ETB receptors play an inhibitory role in adrenal catecholamine secretion by activating neuronal NOS, whereas neuronal NOS is unlikely to be involved in regulation of adrenal catecholamine secretion in the absence of simultaneous ETB receptor stimulation.

sarafotoxin 6c; neuronal nitric oxide synthase; splanchnic nerve stimulation; acetylcholine; 7-nitroindazole monosodium salt


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

ENDOTHELINS, A FAMILY OF potent vasoconstrictor peptides that consist of three distinct isoforms endothelin (ET)-1, -2, and -3, play important roles in the control of cardiovascular functions (as reviewed by Schiffrin, Ref. 20). These isopeptides exert their effects through ETA receptors that are highly specific for ET-1 and -2 and ETB receptors that have almost equal affinity for all three endothelin isopeptides. It is well known that ETA receptors mediate vasoconstriction, whereas ETB receptors mediate both vasoconstriction and vasodilation. The ETB receptor-mediated vasodilation is considered to depend on production of nitric oxide (NO) and prostacyclin.

The adrenal medulla has been reported to contain the endothelin isopeptides and their precursors (3), endothelin converting enzymes (4, 25) and endothelin receptor subtypes (1). Endothelins may therefore be involved in the control of catecholamine secretion from the adrenal medulla. ET-1 is reported to stimulate catecholamine secretion through ETA receptors in the adrenal gland of rats (1) and dogs (23). A previous report from our laboratory demonstrated that ET-1 enhanced catecholamine secretion induced by splanchnic nerve stimulation in the dog adrenal gland in vivo (26). However, little is known about the role of ETB receptors in the cholinergic control of adrenal catecholamine secretion.

The adrenal medulla also contains the NO system. NO synthase (NOS) is classified into three isozymes: neuronal (nNOS), inducible, and endothelial NOS (eNOS; Ref. 5). NO produced by activation of eNOS is known to be involved in ACh- and bradykinin-induced physiological responses. We have recently reported that a nonselective NOS inhibitor Nomega -nitro-L-arginine methyl ester (L-NAME) enhanced and a spontaneous NO donor 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine attenuated the catecholamine secretion induced by exogenous ACh in the dog adrenal gland in vivo (17). These findings suggest that NO interferes with the cholinergic control of adrenal catecholamine secretion. Stimulation of ETB receptors is reported to enhance NO production in bovine adrenal chromaffin cells (6) and the rat adrenal medullary cells (10). It is therefore possible that ETB receptors play an inhibitory role in adrenal catecholamine secretion via NO production.

The present study was undertaken to elucidate the above-mentioned possibility. The presence of nNOS in the adrenal medulla has been reported in various species (18, 21), but its physiological role is unclear. Therefore, a role of nNOS in the adrenal catecholamine secretion was also investigated. We examined the effect of sarafotoxin 6c (S6c), a selective ETB receptor agonist (19), on catecholamine secretion induced by splanchnic nerve stimulation and ACh injection in the absence and presence of L-NAME or 7-nitroindazole monosodium salt (7-NINA), a putative nNOS inhibitor, in anesthetized dogs.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animal preparation. The experiments were performed in mongrel dogs of either sex weighing 6-20 kg. After initial anesthesia with pentobarbital sodium (30 mg/kg iv), a constant level of anesthesia was maintained throughout the experiments by intravenous infusion of pentobarbital sodium (4-6 mg · kg-1 · h-1) with an infusion pump (model 201B, Atom, Tokyo, Japan). Artificial respiration was performed with a ventilator (model SN-480-4, Shinano, Tokyo, Japan) with room air at 18 strokes/min (20 ml/kg tidal volume). The surgical procedure used in the present study was described previously (8). The left adrenal gland was exposed by a retroperitoneal flank incision, and a polyethylene catheter was inserted into the left adrenolumbar vein for collection of venous effluent blood from the adrenal gland. A thread was placed around the junction of the adrenolumbar vein with the abdominal vena cava. Adrenal blood samples were obtained by pulling the thread, thus occluding the adrenolumbar vein and causing a retrograde flow of blood. Blood samples of 1 or 2 ml were collected in chilled test tubes containing 6 or 12 mg of EDTA. When not being sampled, adrenal venous blood was returned directly to the vena cava. Coagulation of blood was prevented by an initial intravenous injection of sodium heparin (250 U/kg). Systemic blood pressure and heart rate were measured with a polygraph (model RPM-6008M, Nihon Kohden, Tokyo, Japan) from a signal converted by a pressure transducer (MPU-0.5, Nihon Kohden) simultaneously and recorded on a heat-writing recticorder (model RJG-4128, Nihon Kohden).

Administration of drugs into the adrenal gland. The procedure for intra-arterial administration of drugs into the adrenal gland was reported previously (9). The left phrenicoabdominal artery was dissected to expose its origin from the abdominal aorta. A 27-gauge needle connected to a Y-shaped polyethylene catheter was inserted into the phrenicoabdominal artery at its origin for intra-arterial infusion of 0.9% saline solution, phosphate-buffered saline solution (vehicles), S6c, L-NAME, 7-NINA, or BQ-788 and for intra-arterial injection of ACh.

Splanchnic nerve stimulation. After the diaphragm was incised, the left splanchnic nerves were dissected free from surrounding tissue and cut. A bipolar platinum electrode was placed in contact with the distal end of the splanchnic nerves. The splanchnic nerves were stimulated for 6 min with rectangular pulses of 1 ms and 10 V (supramaximal voltage) delivered by an electronic stimulator (SEN-2101, Nihon Kohden). Stimulus frequency was raised stepwise from 1 to 3 Hz at 3-min intervals during a 6-min stimulus period.

Experimental protocol. The dogs were divided into nine groups. In groups 1 (n = 8) and 2 (n = 8), the effects of S6c on splanchnic nerve stimulation- and ACh-induced increases in catecholamine output were examined, respectively. Splanchnic nerve stimulation (1 and 3 Hz) was repeated four times at 40-min intervals. The first set of splanchnic nerve stimulation during vehicle infusion into the adrenal gland was regarded as a control. A set of ACh injections (1.5 and 3 µg) into the adrenal gland was repeated four times at 40-min intervals. Each dose of ACh in a volume of 200 or 400 µl was injected for 3 s at 5-min intervals. The first set of ACh injections during vehicle infusion was regarded as a control. S6c infusion (0.2, 0.6, and 2 ng · kg-1 · min-1) was started 25 min before the start of the second, third, and fourth sets of splanchnic nerve stimulation or ACh injections, respectively.

In groups 3 (n = 8) and 4 (n = 8), the effects of 7-NINA (3, 9, and 30 µg/min) infusion on the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output were examined, respectively, with the same protocol as used in groups 1 and 2.

In groups 5 (n = 8) and 6 (n = 8), the effects of S6c (0.2, 0.6, and 2 ng · kg-1 · min-1) during 7-NINA (30 µg/min) infusion on the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output were examined, respectively. The protocol was the same as used in groups 1 and 2, except that infusion of 7-NINA was started 25 min before the start of experiments and continued throughout the experiments.

In groups 7 (n = 8) and 8 (n = 8), the effects of S6c (2 ng · kg-1 · min-1) during L-NAME (50 µg · kg-1 · min-1) infusion on the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output were examined, respectively, with the same protocol as used in groups 1 and 2, except that infusion of L-NAME was started 25 min before the start of experiments and continued throughout the experiments. In these groups, the set of splanchnic nerve stimulation or ACh-injection was repeated two times.

In group 9 (n = 8), the effects of S6c (0.2, 0.6, and 2 ng · kg-1 · min-1) during BQ-788 (1 µg · kg-1 · min-1) infusion on the splanchnic nerve stimulation-induced increases in catecholamine output were examined. The protocol was the same as used in the splanchnic nerve stimulation experiments, except that infusion of BQ-788 was started 25 min before the start of experiments and continued throughout the experiments.

Blood sampling and determination of adrenal catecholamine output. In all groups, adrenal venous blood was sampled before and during splanchnic nerve stimulation or ACh injection. Sampling during the basal state was performed 2 min before the start of splanchnic nerve stimulation or ACh injections. The time required to collect 1 (during basal state or splanchnic nerve stimulation) or 2 ml (during ACh injection) of blood served to estimate adrenal venous flow rate. Adrenal blood samples were centrifuged to obtain plasma samples. Catecholamines were extracted from plasma by the alumina adsorption method, and plasma epinephrine and norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection (model LC-304, Bioanalytical Systems), as described previously (8). Adrenal catecholamine (sum of epinephrine and norepinephrine) output (ng/min) was calculated by multiplying plasma catecholamine concentration (ng/ml) by adrenal plasma flow rate (ml/min). Adrenal plasma flow rate was determined from the adrenal venous flow and the hematocrit of adrenal venous blood. The basal catecholamine output was determined from samples collected before splanchnic nerve stimulation or injection of ACh. The splanchnic nerve stimulation- and the ACh-induced increases in catecholamine output were calculated by subtracting the basal catecholamine output from that obtained during the cholinergic stimuli.

Analysis of data. All data are expressed as means ± SE. Multifactor repeated-measures ANOVA was applied to evaluate overall statistical significance of the effects of cholinergic stimulation and the drug in each experimental group. The significance of differences between the control values and those during infusion of S6c or 7-NINA at each dose was evaluated by single-factor repeated-measures ANOVA and Dunnett's test. Differences at P < 0.05 were considered to be statistically significant.

Drugs. S6c (Peptide Institute, Osaka, Japan) was dissolved in 0.1% acetic acid solution and diluted with 0.9% saline. 7-NINA (Sigma, St. Louis, MO) was prepared by using the methods of Silva et al. (22) and dissolved in phosphate-buffered saline. BQ-788 (Banyu Pharmaceutical, Tsukuba, Japan) was dissolved in dimethyl sulfoxide and diluted with 0.9% saline. ACh chloride (Daiichi Pharmaceutical, Tokyo, Japan) and L-NAME (Sigma) were dissolved in 0.9% saline.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Splanchnic nerve stimulation (1 and 3 Hz) or intra-arterial injection of ACh (1.5 and 3 µg) into the adrenal gland produced frequency- and dose-dependent increases in adrenal venous plasma catecholamine concentration (data are not shown). ACh injection also increased adrenal plasma flow rate (data are not shown). Catecholamine output, calculated from the catecholamine concentration and the adrenal plasma flow rate, was increased by the nerve stimulation and ACh injection in a frequency- and dose-dependent manner (Figs. 1-5). We confirmed that the catecholamine output responses were reproducible when the stimuli were applied four times without drug infusion (17).

Infusion of S6c (0.2, 0.6, and 2 ng · kg-1 · min-1) into the adrenal gland attenuated the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output in a dose-dependent manner (groups 1 and 2; Fig. 1). Under pretreatment with BQ-788 (1 µg · kg-1 · min-1; group 9), S6c at any dose used (0.2, 0.6, and 2 ng · kg-1 · min-1) failed to attenuate the nerve stimulation-induced increase in catecholamine output (Fig. 2). Infusion of 7-NINA (3, 9, and 30 µg/min) did not affect the nerve stimulation- and ACh-induced increases in catecholamine output (groups 3 and 4; Fig. 3).


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  		Fig. 1.   Effects of sarafotoxin 6c (S6c) on catecholamine output from the adrenal gland in response to splanchnic nerve stimulation (SNS; A; group 1, n = 8) and injection of ACh (B; group 2, n = 8). ACh was injected into adrenal gland through phrenicoabdominal artery, and S6c was infused into same artery. * P < 0.05 and ** P < 0.01 compared with values before S6c infusion (Control).



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  		Fig. 2.   Effects of S6c on catecholamine output from adrenal gland in response to SNS (group 9, n = 8) in presence of BQ-788 (1 µg · kg-1 · min-1). BQ-788 and S6c were infused into phrenicoabdominal artery. There were no statistically significant differences between values before (BQ-788) and during S6c infusion in each experimental group.



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  		Fig. 3.   Effects of 7-nitroindazole monosodium salt (7-NINA) on catecholamine output from adrenal gland in response to SNS (A; group 3, n = 8) and injection of ACh (B; group 4, n = 8). ACh was injected into adrenal gland through phrenicoabdominal artery, and 7-NINA was infused into same artery. There were no statistically significant differences between values before (Control) and during 7-NINA infusion in each experimental group.

Infusion of S6c (0.2, 0.6, and 2 ng · kg-1 · min-1) did not affect the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output during 7-NINA infusion (30 µg/min; groups 5 and 6; Fig. 4). L-NAME (50 µg · kg-1 · min-1) also abolished the inhibitory effects of S6c (2 ng · kg-1 · min-1) on the splanchnic nerve stimulation- and ACh-induced increases in catecholamine output (groups 7 and 8; Fig. 5).


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  		Fig. 4.   Effects of S6c on catecholamine output from adrenal gland in response to SNS (A; group 5, n = 8) and injection of ACh (B; group 6, n = 8) in presence of 7-NINA (30 µg/min). ACh was injected into adrenal gland through phrenicoabdominal artery, and 7-NINA and S6c were infused into same artery. There were no statistically significant differences between corresponding values before (7-NINA) and during S6c infusion in each experimental group.



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  		Fig. 5.   Effects of S6c on catecholamine output from adrenal gland in response to SNS (A; group 7, n = 8) and injection of ACh (B; group 8, n = 8) in presence of Nomega -nitro-L-arginine methyl ester (L-NAME; 50 µg · kg-1 · min-1). ACh was injected into adrenal gland through phrenicoabdominal artery, and L-NAME and S6c were infused into same artery. There were no statistically significant differences between corresponding values before (L-NAME) and during S6c infusion in each experimental group.

Neither S6c nor 7-NINA affected basal catecholamine output (Table 1). Basal adrenal plasma flow rate decreased during S6c infusion alone (Table 1), which was also observed in the presence of 7-NINA or L-NAME but not in the presence of BQ-788 (Table 2). 7-NINA infusion alone did not affect adrenal plasma flow rate (Table 1). S6c alone slightly reduced mean blood pressure (Table 1), which also occurred in the presence of 7-NINA (30 µg/min) but not in the presence of L-NAME (50 µg · kg-1 · min-1) or BQ-788 (1 µg · kg-1 · min-1; Table 2). Infusion of 7-NINA alone did not affect mean blood pressure (Table 1). Slight reductions in heart rate were observed during the experiments (Tables 1 and 2).

                              
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  		Table 1.   Effects of S6c (groups 1 and 2) and 7-NINA (groups 3 and 4) on MAP, HR, CA output, and APF under basal conditions


                              
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  		Table 2.   Effects of S6c during 7-NINA (groups 5 and 6), L-NAME (groups 7 and 8), or BQ-788 (group 9) infusion on MAP, HR, CA output, and APF under basal conditions

Ratios of epinephrine output response to norepinephrine output response induced by 1- and 3-Hz splanchnic nerve stimulation (group 1) were 9.6 ± 1.8 and 5.6 ± 0.7, respectively, and those by 1.5 and 3 µg ACh (group2) were 4.4 ± 0.4 and 4.8 ± 0.5, respectively, in the control period. These values did not change during S6c infusion (data are not shown), indicating that S6c attenuated the secretion of these two catecholamines to the same extent. For this reason, total output of epinephrine and norepinephrine was expressed as catecholamine output.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

This study was performed to elucidate a role of ETB receptors in adrenal catecholamine secretion and its relation to NO production. Effects of S6c on catecholamine output responses induced by splanchnic nerve stimulation and ACh injection were examined in the absence and presence of NOS inhibitors in the adrenal gland of anesthetized dogs in vivo.

S6c infused intra-arterially into the adrenal gland attenuated the increases in catecholamine output in response to splanchnic nerve stimulation and ACh injection in a dose-dependent manner. S6c has been reported to bind ETB receptors with a high selectivity in various kinds of tissues (19). Moreover, in this study the selective ETB receptor antagonist BQ-788 (7) abolished the inhibitory effect of S6c on splanchnic nerve stimulation-evoked adrenal catecholamine output. These results suggest that activation of ETB receptors suppresses cholinergic adrenal catecholamine secretion. It was reported that S6c suppressed norepinephrine release from the kidney evoked by renal nerve stimulation in anesthetized dogs (11, 12) and exerted both inhibitory and facilitatory effects on norepinephrine release from the rat tail artery evoked by electrical field stimulation (16). However, there has been little information on its action on adrenal catecholamine release. This study is the first to demonstrate the inhibitory effect of S6c on adrenal catecholamine secretion evoked by cholinergic stimuli.

Our previous study has suggested that NO plays an inhibitory role in catecholamine secretion from the dog adrenal gland (17). Stimulation of ETB receptors is demonstrated to induce NO and cyclic GMP production in the rat adrenal medulla (10) and bovine adrenal chromaffin cells (6). It was also reported that the inhibitory effect of S6c on the nerve stimulation-evoked norepinephrine efflux was susceptible to NOS inhibition in the dog kidney (11). On the basis of these findings, we hypothesized that NO is involved in the ETB receptor-mediated modulation of adrenal catecholamine secretion, and we examined the effect of S6c in the presence of NOS inhibitors. Pretreatment with the nonselective NOS inhibitor L-NAME or the putative nNOS inhibitor 7-NINA suppressed the inhibitory effect of S6c on the splanchnic nerve stimulation- and ACh-induced catecholamine output. These results suggest that stimulation of ETB receptors by S6c activates NOS and thereby suppresses adrenal catecholamine output evoked by the cholinergic stimuli. There may be an NO-dependent pathway in the ETB receptor-mediated inhibitory mechanism of adrenal catecholamine secretion.

In our previous study L-NAME reduced adrenal plasma flow rate in the basal state and its increases by ACh injection (17). NO may participate in the control of blood circulation in the adrenal gland. On the other hand, in this study 7-NINA had no influence on basal adrenal plasma flow rate. We also observed that 7-NINA failed to affect the ACh-induced increases in adrenal plasma flow rate (data are not shown). 7-NINA and its freebase 7-NI have been suggested to inhibit nNOS more selectively than other types of NOS (14, 15). In the isolated rat basilar artery, 7-NINA had no significant effect on the resting tone, whereas the general NOS inhibitor Nomega -nitro-L-arginine induced contraction (2). Taken together, 7-NINA at the dose used in this study seems to exert little influence on eNOS, which maintains vascular NO level and can be activated by ACh. Thus activation of nNOS in the chromaffin cells may be involved in the inhibitory effect of S6c on the cholinergic control of adrenal catecholamine secretion.

In bovine adrenal chromaffin cells, catecholamine secretion evoked by depolarizing stimuli was suppressed when the cells were incubated with endothelium, suggesting that NO produced by eNOS participates in the regulation of catecholamine release (24). In our previous study, L-NAME enhanced the increase in catecholamine output in response to ACh injection (17). If NO produced by nNOS also played an inhibitory role in adrenal catecholamine secretion, 7-NINA alone would enhance the catecholamine output response. However, no enhancement of the catecholamine output response was observed during 7-NINA infusion in this study. In this regard, it is unlikely that nNOS in adrenal chromaffin cells plays a significant role in the cholinergic control of adrenal catecholamine release. The cholinergic stimulation itself may not activate nNOS, whereas nNOS can be activated to suppress the cholinergic adrenal catecholamine secretion when the ETB receptors are simultaneously stimulated.

It was reported that stimulation of ETB receptors increased perfusion flow rate through NOS activation in the rat perfused adrenal gland (13). In this study, however, S6c reduced adrenal plasma flow rate. S6c reduced arterial pressure, but it increased adrenal vascular resistance (mean arterial pressure/adrenal blood flow) from 32 ± 5 (basal) to 36 ± 6, 43 ± 7 (P < 0.01), and 44 ± 8 (P < 0.01; during S6c infusion at 0.2, 0.6, and 2 ng · kg-1 · min-1, respectively, n = 16, groups 1 and 2). These changes were not observed in the presence of BQ-788. These results indicate that stimulation of ETB receptors induces vasoconstriction in the dog adrenal gland.

In conclusion, this study demonstrated that S6c suppressed adrenal catecholamine secretion in response to splanchnic nerve stimulation and ACh injection in anesthetized dogs. The pretreatment with L-NAME or 7-NINA abolished the inhibitory effect of S6c on the catecholamine secretion responses. These results suggest that ETB receptors located on adrenal chromaffin cells play an inhibitory role in the release of catecholamine during cholinergic stimulation, the mechanism of which includes activation of nNOS.

Perspectives

Our present study indicates the modulation by ETB receptors of cholinergic catecholamine secretion from the adrenal gland, but does not provide the information on a role of ETA receptors in adrenal catecholamine secretion. ET-1 can enhance catecholamine secretion in response to splanchnic nerve stimulation in the dog adrenal gland (23). We hypothesize that both ETA and ETB receptors are involved in regulation of adrenal catecholamine secretion; the former plays a stimulatory role and the later, as demonstrated in this study, plays an inhibitory role. It is also probable that these endothelin receptor mechanisms interact with each other. In this regard, we are studying the effects of a selective ETA receptor antagonist and a selective ETB receptor antagonist and their combination on the ET-1-evoked enhancement of cholinergic catecholamine secretion in the dog adrenal gland in vivo.


    ACKNOWLEDGEMENTS

BQ-788 was generously provided by Banyu Pharmaceutical, Tsukuba, Japan.


    FOOTNOTES

This work was supported in part by Grant 09470510 (to S. Satoh) and Grant 10877371 (to H. Hisa) for Scientific Research from the Ministry of Education, Science and Culture, Japan.

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: H. Hisa, Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku Univ., Aobayama, Sendai 980-8578, Japan (E-mail: hhisa{at}mail.pharm.tohoku.ac.jp).

Received 30 March 1999; accepted in final form 9 June 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Compar Physiol 277(4):R1051-R1056
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


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