Second Department of Medicine, Asahikawa Medical College, Asahikawa 078, Japan
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ABSTRACT |
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Central
neuropeptides play a role in many physiological regulatory processes
through the autonomic nervous system. Thyrotropin-releasing hormone
(TRH) is distributed in the central nervous system and acts as a
neurotransmitter to regulate gastric functions through vagal-muscarinic
pathways. The central effect of the TRH analog on hepatic blood flow
was investigated in urethan-anesthetized rats. Hepatic blood flow was
determined by the hydrogen gas clearance technique. Intracisternal
injection of the stable TRH analog RX-77368 (5-100 ng) dose
dependently increased hepatic blood flow with peak response at 15 min
after the peptide was administered (net change from basal
for vehicle and 5, 10, 100, and 500 ng RX-77368 was 2.0 ± 0.2, 8.9 ± 0.8, 19.4 ± 2.6, 32.6 ± 3.3, and 28.5 ± 6.8 ml · min1 · 100 g
1, respectively), and this
stimulatory effect returned to baseline at 90 min. The stimulation of
hepatic blood flow by the intracisternally administered TRH analog was
abolished by atropine methyl nitrate (0.15 mg/kg ip), indomethacin (5 mg/kg ip), NG-nitro-L-arginine
methyl ester (10 mg/kg iv), and hepatic branch vagotomy but not by
cervical spinal cord transection (C6 level). Intravenous injection of
RX-77368 did not have any effect on hepatic blood flow. These results
indicate that TRH acts in the central nervous system to stimulate
hepatic blood flow through vagal-muscarinic and indomethacin- and
nitric oxide-dependent pathways.
hydrogen gas clearance technique; vagus nerve
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INTRODUCTION |
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SEVERAL LINES OF ANATOMIC and physiological evidence suggest a role for the central and autonomic nervous systems in regulating hepatic functions (9, 16). However, the role of neurotransmitters in the central nervous system in mediating this regulation has been poorly understood. In addition to acetylcholine and norepinephrine, neuropeptides have been recognized as novel neurotransmitters in the central and peripheral nervous systems (20). These neuropeptides are reported to act in the brain to induce alterations of physiological functions, including respiratory, cardiovascular, and gastric functions (2, 10, 17). In particular, the effect of central thyrotropin-releasing hormone (TRH) on the physiological, pharmacological, and pathophysiological regulatory processes of the gastrointestinal tract has been reported (22). With respect to the stomach, central administration of TRH or the TRH analog stimulates gastric motility and secretions (19, 22, 28). There is also evidence that gastric mucosal blood flow is increased by intracerebroventricular and intracisternal injection of TRH or the TRH analog through vagal-muscarinic pathways (24, 25).
In the brain, TRH-immunoreactive nerve fibers and terminals and TRH receptors are localized in the hypothalamus and the dorsal vagal complex. The latter includes the dorsal nucleus of the vagus nerve and the nucleus of the solitary tract (11, 13), which are important sites for the autonomic nervous regulation of the digestive system, including the hepatobiliary system (3, 14). TRH causes a direct postsynaptic excitatory effect on preganglionic neurons in the dorsal nucleus of the vagus nerve and increases efferent vagal activity (12, 26). Moreover, the liver is richly innervated (14), and electrical stimulation of the hypothalamus and vagus nerve induces alterations in the hepatic circulation and microvascular filling pattern in the rat liver sinusoids (6, 27).
This evidence has prompted us to examine a possible role for TRH as a centrally acting neurotransmitter involved in the central nervous system regulation of hepatic microcirculation. Therefore, in this study, the effect of central TRH on hepatic blood flow was investigated in rats by the hydrogen gas clearance method.
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MATERIALS AND METHODS |
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Animals. Male Wistar rats weighing 240-350 g (Charles River Japan, Yokohama, Japan) were housed in group cages under conditions of controlled temperature (22-24°C) and illumination (12:12-h light-dark cycle starting at 6 AM) for at least 7 days before experiments. Animals were maintained on laboratory chow and tap water. Experiments were performed in rats deprived of food for 24 h but given free access to water up to the beginning of the study.
Drugs.
We used the following substances: the stable TRH analog RX-77368,
p-Glu-His-(3,3'-dimethyl)-Pro-NH2,
from Reckitt and Colman (Kingdom-upon-Hill, UK), and atropine methyl
nitrate, indomethacin, and
NG-nitro-L-arginine methyl ester
(L-NAME), all from Sigma
Chemical (St. Louis, MO). Although similar to natural TRH in binding
characteristics on rat brain membranes, RX-77368 is more stable (4, 5). RX-77368 was aliquoted in 0.5% bovine serum albumin (Sigma Chemical) and 0.9% saline at a concentration of 1.5 nmol/µl and kept frozen at
20°C. The stock solution was diluted in 0.9% saline (pH
7.4) before the experiment and injected intracisternally in 10 µl
using a 50-µl microsyringe (Hamilton, Reno, NV). Atropine methyl
nitrate was dissolved in 0.9% saline and injected intraperitoneally
(0.15 mg/kg), indomethacin was dissolved in 1%
NaHCO3 solution and injected intraperitoneally (5 mg/kg), and
L-NAME was dissolved in 0.9% saline and injected intravenously (10 mg/kg) in a volume of 1.0 ml/kg.
Animal preparation. All experiments were done in rats anesthetized with urethan (1.5 g/kg ip). Tracheotomies were performed on the rats, and PE-260 tubing (Clay Adams, Parsippany, NJ) was inserted into the trachea to ensure an airway for administration of hydrogen in air. The right carotid artery was cannulated with PE-50 tubing (Clay Adams), and blood pressure was continuously monitored and recorded using a pressure transducer (Uniflow, Baxter, Valencia, CA), a pressure amplifier (PA-001, Star Medical, Tokyo, Japan), and a computer (PowerBook 150, Apple Computer, Cupertino, CA) equipped with a data recording and analysis system (MacLab, AD Instruments, Castle Hill, Australia). Rats were mounted on ear bars of a stereotaxic apparatus (model 900, David Kopf Instruments, Tujunga, CA), and each rat was positioned to expose the abdomen. A 3-cm midline abdominal incision was made, and the pylorus was ligated. Next, a cannula was placed into the nonglandular portion of the stomach to divert gastric secretion, avoiding the possibility of secondary influence of duodenal acidification and gastric distension to hepatic functions. Then a platinum needle-type electrode (diameter, 0.3 mm; MH-50N, MT Giken, Tokyo, Japan) was inserted into the hepatic left lateral lobe, and an Ag-AgCl reference electrode (MH-10, MT Giken) was placed into the lower peritoneal cavity against the lateral abdominal wall. The platinum contact electrode and a reference electrode were connected to a polarographic and amplifying unit (model DHM-3001, MT Giken) and a computer (PowerBook 150, Apple Computer) equipped with a data recording and analysis system (MacLab, AD Instruments). Body temperature was kept at 37°C by external heating, and the liver surface was continuously rinsed with 0.9% saline (37°C, pH 7.4) to keep it moist.
Experimental design.
After the surgical preparation was completed, the animal was left
undisturbed for 60 min to allow temperature, heart rate, and blood
pressure stabilization. Hepatic blood flow was determined by
administering hydrogen gas in air through a tube placed over the
tracheotomy tubing to achieve tissue saturation. The saturation of
hydrogen gas required ~7-8 min and was ascertained by a plateau of the saturation curve. The basis for the measurement of blood flow by
clearance of hydrogen gas is the Fick principle applied by Auckland et
al. (1). The current is generated at the surface of the platinum
electrode by oxidation of hydrogen to hydrogen ions and electrons. When
rats breathe hydrogen, the current increases and reaches a plateau
after the tissue becomes saturated with hydrogen. When the source of
hydrogen is removed, the current slowly declines and returns to
baseline. Because hydrogen can be removed only by blood flow perfusing
the tissue, the rate at which desaturation occurs provides an estimate
of blood flow. The desaturation curves were recorded and analyzed by a
computer (Power Macintosh 8100, Apple Computer) equipped with an
analog-to-digital conversion program (Chart V 3.0, AD Instruments).
Hepatic blood flow was then calculated by a computer program that
involved multiple iterations of a nonlinear least-squares regression
and was expressed in milliliters per minute per 100 g. After two
consecutive measurements of basal hepatic blood flow, either the TRH
analog RX-77368 (5, 10, 100, or 500 ng) or 0.9% saline vehicle was
injected intracisternally. The accuracy of the intracisternal injection
was ascertained by the aspiration of cerebrospinal fluid before and
after injection of the peptide. Hepatic blood flow was observed for 90 min after intracisternal injection every 15 min. In another experiment, RX-77368 (100 ng) or 0.9% saline vehicle was injected through the
femoral vein under identical conditions. In some experiments, atropine
methyl nitrate (0.15 mg/kg) or 0.9% saline vehicle was injected
intraperitoneally 15 min before, indomethacin (5 mg/kg) or 1%
NaHCO3 vehicle was injected
intraperitoneally 30 min before, L-NAME (10 mg/kg) or 0.9%
saline vehicle was injected intravenously 15 min before, and hepatic
branch vagotomy, spinal cord transection (C6 level), or respective sham
operation was performed 120 min before the peptide was administered
(23, 30). To evaluate the specificity of the effect of
L-NAME on hepatic blood flow stimulated by central TRH analog, we administered
L-arginine (800 mg/kg bolus iv
followed by continuous 200 mg · kg1 · h
1
iv infusion throughout the experiment; Sigma Chemical) just before the
administration of L-NAME to an
additional group.
Statistical analysis. Results are expressed as means ± SE. Comparison of hepatic blood flow after peptide injection with the average of basal blood flow of two consecutive periods was calculated by analysis of variance (ANOVA) repeated measurement followed by Fisher's protected least significant difference test. Multiple group comparisons were performed by ANOVA followed by Dunnett's post hoc test. P < 0.05 was considered statistically significant.
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RESULTS |
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Effect of intracisternal TRH analog on hepatic blood flow.
Basal hepatic blood flow before peptide injection in
urethan-anesthetized rats as measured by hydrogen gas clearance
technique was 55.6 ± 1.1 ml · min1 · 100 g
1
(n = 52). Although intracisternal
injection of saline vehicle did not influence hepatic blood flow, when
the stable TRH analog RX-77368 was injected intracisternally at a dose
of 100 ng, it increased hepatic blood flow from the first 15-min
observation period after the injection by 50 ± 11%, and the
enhanced hepatic blood flow returned to baseline at 90 min (Fig.
1). The stimulatory action of RX-77368 on
hepatic blood flow was dose related in doses ranging from 5 to 100 ng
as observed at 15 min after peptide injection (net change from basal
for vehicle and 5, 10, 100, and 500 ng RX-77368 was 2.0 ± 0.2, 8.9 ± 0.8, 19.4 ± 2.6, 32.6 ± 3.3, and 28.5 ± 6.8 ml · min
1 · 100 g
1, respectively) (Fig.
2). RX-77368 injected intravenously at 100 ng did not alter hepatic blood flow (Table
1).
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Effect of atropine, indomethacin,
L-NAME, hepatic branch vagotomy, and
spinal cord transection on hepatic blood flow in response to
intracisternal TRH analog.
Hepatic branch vagotomy performed 120 min before, atropine methyl
nitrate (0.15 mg/kg) injected intraperitoneally 15 min before, indomethacin (5 mg/kg) injected intraperitoneally 30 min
before, or L-NAME (10 mg/kg)
injected intravenously 15 min before the peptide abolished the hepatic
blood flow in response to intracisternal injection of RX-77368 (100 ng)
(Fig. 3,
A-D).
Cervical cord transection at the C6 level performed 120 min before the
peptide injection did not modify the stimulation of hepatic blood flow
induced by intracisternal RX-77368 (100 ng) (Fig.
3E).
L-Arginine (800 mg/kg bolus iv
followed by continuous 200 mg · kg1 · h
1
iv infusion) abolished the inhibitory effect of
L-NAME on central TRH
analog-induced stimulation of hepatic blood flow (Fig.
3D). Although hepatic branch
vagotomy, atropine, or indomethacin pretreatment did not influence
basal hepatic blood flow before the intracisternal injection of the TRH
analog, L-NAME pretreatment or
spinal cord transection decreased it (Fig. 3).
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Effect of intracisternal TRH analog on mean arterial blood pressure. Intracisternal injection of RX-77368 at 100 ng enhanced mean arterial blood pressure within 15 min, and this stimulatory effect was maintained over 90 min after the peptide injection (Table 2). Although atropine treatment 15 min before, indomethacin treatment 30 min before, L-NAME treatment 15 min before, or hepatic branch vagotomy 120 min before the peptide injection did not influence intracisternal TRH analog-induced increase of mean arterial blood pressure, spinal cord transection 120 min before the peptide injection inhibited the rise in mean arterial blood pressure induced by central injection of the TRH analog (Table 2). Although spinal cord transection suppressed and L-NAME treatment increased basal mean arterial blood pressure, hepatic branch vagotomy and atropine and indomethacin treatment did not modify basal mean arterial blood pressure (Table 2).
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DISCUSSION |
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In the present study, we demonstrate that the stable TRH analog RX-77368 (5-500 ng) injected intracisternally stimulates hepatic blood flow in urethan-anesthetized rats as determined by the hydrogen gas clearance technique, which is known to measure only regional tissue blood flow. The stimulatory effect of intracisternal injection of RX-77368 is dose related in doses ranging from 5 to 100 ng. Intracisternal RX-77368 (100 ng) injection significantly increases hepatic blood flow with peak response at the first 15-min observation period, and thereafter the enhanced hepatic blood flow returns to baseline at 90 min. RX-77368 at a dose of 100 ng induces a change of 50 ± 11% (at 15 min after the peptide), which represents the maximal response because 500 ng of RX-77368 does not further stimulate hepatic blood flow. In contrast, when injected intravenously at the dose that was maximally effective when given intracisternally, RX-77368 did not influence hepatic blood flow. These results indicate that RX-77368, injected into the cisterna magna, acts in the central nervous system to stimulate hepatic blood flow and not through leakage into the peripheral circulation.
The pathways through which central administration of the TRH analog enhanced hepatic blood flow were investigated in the present study. The stimulated hepatic blood flow by intracisternal injection of TRH analog was abolished by hepatic branch vagotomy and atropine treatment, whereas cervical spinal cord transection had no effect. The results indicate that TRH acts centrally to stimulate hepatic blood flow in rats through vagal-muscarinic pathways. Previous reports also indicate that central TRH-induced stimulation of gastric acid, pepsin, and prostaglandin secretion and gastric mucosal blood flow is mediated through vagal-muscarinic dependent mechanisms (21, 25, 28). Furthermore, using an in vivo microscopic technique in rats, dilatation of the liver sinusoid after electrical vagal stimulation and acetylcholine application has been observed (6, 7). Taken together, these functional findings suggest that central TRH activates parasympathetic outflow to the digestive system. This is further supported by anatomic studies that show TRH immunoreactive fibers and terminals in the dorsal vagal complex (13). In addition, a high density of TRH receptors are also present in the dorsal vagal complex (11). Moreover, electrophysiological studies have provided evidence that central TRH administration activates vagal efferent discharge in rats (18).
In regard to the stomach, central administration of TRH increases nitric oxide and prostaglandin release through activation of the vagus nerve (15, 29), and central TRH-induced stimulation of gastric mucosal blood flow is mediated through the nitric oxide pathway (23). In the present study, the role of prostaglandin and nitric oxide was investigated using the synthesis blockades indomethacin and L-NAME, respectively. Both indomethacin and L-NAME reversed the stimulatory effect of central TRH analog on hepatic blood flow, suggesting involvement of prostaglandin and nitric oxide in central TRH-induced modulation of hepatic blood flow. It would be interesting to know whether vagal activation by central TRH stimulates hepatic nitric oxide and prostaglandin synthesis by direct measurement of hepatic prostaglandin and nitric oxide.
Hepatic blood flow is regulated by multiple factors (8). The liver is perfused by two main blood supplies, the portal vein and the hepatic artery. The liver sinusoid is also considered to regulate hepatic blood flow. In agreement with previous findings (17, 24, 25), we also observed stimulation of mean systemic blood pressure induced by intracisternal injection of the TRH analog, and this stimulation of blood pressure was not influenced by L-NAME and vagotomy. This enhanced systemic blood pressure was maintained over 90 min after the peptide injection, whereas the stimulatory effect of the central TRH analog on hepatic blood flow was attenuated after the peak response at 15 min. Moreover, central TRH-induced stimulation of systemic blood pressure, but not hepatic blood flow, is blocked by spinal cord transection. Furthermore, although the central TRH analog-stimulated hepatic blood flow was abolished by vagotomy, atropine, indomethacin, and L-NAME, these treatments had no effect on the central TRH analog-induced stimulation of blood pressure in the present study. Taken together, it is not likely that central TRH-induced stimulation of hepatic blood flow is accomplished indirectly through modulation of systemic blood pressure. Portal blood flow is supplied by splanchnic veins. Central TRH has been reported to constrict splanchnic vessels and reduce the splanchnic blood flow through sympathetic pathways in rats (17). In the present study, the stimulation of hepatic blood flow by the central TRH analog is dependent on the hepatic branch of the vagus nerve. These facts indicate that central TRH analog-induced stimulation of hepatic blood flow is not secondary to the change in splanchnic blood flow. Electrical vagal stimulation and acetylcholine administration produce dilatation of the sinusoids as assessed by the in vivo transillumination technique (6, 7). From these findings, the liver sinusoidal dilatation is the most likely mechanism through which central TRH stimulates hepatic blood flow. Although it is difficult to establish an adequate method for rats mounted in a stereotaxic apparatus, it is of interest to identify the origin of the blood supply to induce the increase of hepatic blood flow in response to central TRH, using the radioactive microsphere technique or in vivo microscopy.
The liver is known to be richly innervated (14), and there has been abundant evidence indicating important roles for the central and autonomic nervous systems in hepatic function, including hepatic microcirculation (27). Very little is known about central neuropeptides acting as neurotransmitters to induce modulation of hepatic function. To date, only relation of central neuropeptide Y with bile secretion has been reported (30, 31). In the present study, we have found that central administration of the TRH analog induces the stimulation of hepatic blood flow through vagal-muscarinic and prostaglandin- and nitric oxide-dependent pathways, and it is speculated that TRH is one of the most likely candidates to act in the brain as a neurotransmitter in the central regulation of hepatic circulation.
In summary, the present data indicate that the TRH analog injected intracisternally acts in the brain to stimulate hepatic blood flow in rats. Peptide action is mediated through vagal-muscarinic and prostaglandin- and nitric oxide-dependent pathways. The TRH analog provides a useful tool to further investigate brain sites of action to increase hepatic blood flow. In addition, it is of interest to know the role of endogenous TRH in hepatic blood flow by using the TRH antibody to elucidate the physiological relevance of central TRH in hepatic function.
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ACKNOWLEDGEMENTS |
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We thank Dr. Gordon Ohning [Assistant Professor, University of California Los Angeles (UCLA) School of Medicine] for editorial assistance and Dr. Yvette Taché (Professor, UCLA School of Medicine) for valuable discussion.
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FOOTNOTES |
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This work was supported by Grants-in-Aid 0767554 and 09670503 from the Ministry of Education, Science, and Culture of Japan.
Address for reprint requests: M. Yoneda, Second Dept. of Medicine, Asahikawa Medical College, Nishikagura 4-5-3-11, Asahikawa 078, Japan.
Received 16 December 1996; accepted in final form 28 October 1997.
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