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Am J Physiol Regul Integr Comp Physiol 281: R1562-R1567, 2001;
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Vol. 281, Issue 5, R1562-R1567, November 2001

Role of endogenous PACAP in catecholamine secretion from the rat adrenal gland

Yasuo Fukushima1, Hirohiko Hikichi1, Kazuhiko Mizukami1, Takahiro Nagayama1, Makoto Yoshida1, Mizue Suzuki-Kusaba1, Hiroaki Hisa1, Tomohiko Kimura2, and Susumu Satoh1

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


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

We elucidated the contribution of endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) to neurally evoked catecholamine secretion from the isolated perfused rat adrenal gland. Infusion of PACAP (100 nM) increased adrenal epinephrine and norepinephrine output. The PACAP-induced catecholamine output responses were inhibited by the PACAP type I receptor antagonist PACAP- (6-38) (30-3,000 nM) but were resistant to the PACAP type II receptor antagonist [Lys1,Pro2,5,Ara3,4,Tyr6]-vasoactive intestinal peptide (LPAT-VIP; 30-3,000 nM). Transmural electrical stimulation (ES; 1-10 Hz) or infusion of ACh (6-200 nM) increased adrenal epinephrine and norepinephrine output. PACAP-(6-38) (3,000 nM), but not LPAT-VIP, also inhibited the ES-induced catecholamine output responses. However, PACAP-(6-38) did not affect the ACh-induced catecholamine output responses. PACAP at low concentrations (0.3-3 nM), which had no influence on catecholamine output, enhanced the ACh-induced catecholamine output responses, but not the ES-induced catecholamine output responses. These results suggest that PACAP is released from the nerve endings to facilitate the neurally evoked catecholamine secretion through PACAP type I receptors in the rat adrenal gland.

transmural electrical stimulation; acetylcholine; pituitary adenylate cyclase-activating polypeptide receptor antagonists; pituitary adenylate cyclase-activating polypeptide -(6-38); adrenal chromaffin cells


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

ALTHOUGH CATECHOLAMINE SECRETION from chromaffin cells of the adrenal medulla is controlled by ACh released from the splanchnic nerve endings, noncholinergic neurotransmitters or neuromodulators are released with ACh to participate in the neural control of adrenal catecholamine secretion (8). Vasoactive intestinal peptide (VIP) has been regarded as one of these substances (27). Pituitary adenylate cyclase-activating polypeptide (PACAP) is also reported to act as a noncholinergic neurotransmitter or neuromodulator in the adrenal gland (11, 21).

PACAP was first isolated from ovine hypothalamus and named for its ability to activate adenylate cyclase in rat anterior pituitary cells (14). PACAP shows 68% homology with VIP in the amino acid sequence and is classified into the secretin/glucagon/VIP family (14). PACAP has two biologically active forms, PACAP-38 and its NH2-terminal residues PACAP-27 (15). There are at least two types of receptors for PACAP, PACAP type I receptors, for which PACAP has a higher affinity than VIP, and PACAP type II receptors, for which PACAP and VIP have similar affinities (2, 25). The PACAP-binding sites are widely found not only in the brain (13, 20) but also in the peripheral tissues (23, 25).

Among rat peripheral tissues, the adrenal medulla contains a high concentration of PACAP (1). Autoradiography shows abundant PACAP-specific binding sites in rat adrenal chromaffin cells (25). Moreover, PACAP induces catecholamine secretion from rat (28), porcine (10), and bovine (19) adrenal chromaffin cells. The potency of PACAP to induce adrenal catecholamine secretion is higher than that of VIP (8, 28).

However, it has not been fully understood whether endogenous PACAP participates in the neural control of adrenal catecholamine secretion. To clarify this issue, in the present study we examined the effects of PACAP-(6-38), a PACAP type I receptor antagonist, and [Lys1,Pro2,5,Ara3,4,Tyr6]-VIP (LPAT-VIP), a PACAP type II receptor antagonist, on catecholamine secretion from the isolated perfused rat adrenal gland during activation of adrenal nerves by transmural electrical stimulation (ES).


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

Preparation. All procedures for handling animals were approved by the Animal Experimentation Committee of Tohoku University Graduate School of Pharmaceutical Sciences. Male Wistar rats, weighing 200-320 g, were housed at 21-24°C and maintained on a standard diet and water ad libitum. Rats were anesthetized with pentobarbital sodium (50 mg/kg ip). The surgical procedure used in the present study was described previously (18). A polyethylene cannula for perfusion of the adrenal gland was inserted into the adrenal vein through the renal vein. Then the adrenal gland was carefully removed, and a small slit was made into the adrenal cortex just opposite the entrance of the adrenal vein. Perfusion of the adrenal gland was started to ensure that the perfusate escaped only from the slit of the adrenal gland. The adrenal gland was put on a platinum bipolar electrode, and they were placed in a water-jacketed chamber, the temperature of which was maintained at 37°C with thermostatically controlled water circulator (NTT-1200, EYELA, Tokyo, Japan). After extraction of the adrenal gland, the animal was killed by exsanguination.

Perfusion of the adrenal gland. The adrenal gland was perfused by means of a peristaltic pump (MP-3A, EYELA) at a rate of 0.2 ml/min with Krebs-Henseleit solution of the following composition (mM): 118 NaCl, 4.7 KCl, 1.2 MgSO4, 2.6 CaCl2, 1.2 KH2PO4, 24.9 NaHCO3, 11.1 glucose; Krebs-Henseleit solution was maintained at 37°C by the thermostat bath and bubbled with a mixture of 95% O2 and 5% CO2. Perfusate samples were collected in chilled tubes containing 50 µl of 0.1 M perchloric acid to prevent oxidation of catecholamines.

Agonist infusion and ES. PACAP (PACAP-27) or ACh solution was infused into the perfusion stream through a branching polyethylene catheter by using a microsyringe pump (CMA/200, Bioanalytical Systems, West Lafayette, IN) at a rate of 0.02 ml/min. The PACAP infusion was performed for 3 min in each experimental period. The calculated concentration of PACAP in the perfusate was 100 nM. Stimulus concentration of ACh in the perfusate was raised stepwise from 6 to 20, 60, and 200 µM at 5-min intervals, infusion at each concentration being performed for 40 s. ES (duration, 1 ms; supramaximal voltage, 50 V) was applied through the bipolar platinum electrode with an electronic stimulator (SEN-3301, Nihon Kohden, Tokyo, Japan) and an isolation unit (SS-302J, Nihon Kohden). Stimulus frequency was raised stepwise from 1 to 2, 5, and 10 Hz at 5-min intervals, stimulation at each frequency being applied for 40 s.

Experimental protocols. Before the start of experiments, infusion of 100 nM PACAP was twice performed for 5 min at 10-min intervals to obtain stable catecholamine output responses (3). We had confirmed that after these conditioning infusion periods, catecholamine secretion responses induced by 100 nM PACAP for 3 min were almost the same in four consecutive experimental periods (3).

In group 1 (n = 8), the effects of PACAP-(6-38) on the increases in catecholamine output induced by PACAP were examined. The first infusion of PACAP (100 nM; after the conditioning infusion periods) was regarded as control (1st trial). Perfusion with Krebs-Henseleit solution containing 30, 300, and 3,000 nM of PACAP-(6-38) was started 5 min before the start of the second, third, and fourth trials, respectively. In group 2 (n = 8), the effect of LPAT-VIP (30, 300, and 3,000 nM) on the PACAP-induced increases in catecholamine output was examined with the same protocol as described above.

In groups 3 and 4, the effects of PACAP-(6-38) on the increases in catecholamine output induced by ES (group 3, n = 8) or ACh infusion (group 4, n = 7) were examined. The first set of ES (1, 2, 5, and 10 Hz) or ACh infusion (6, 20, 60, and 200 µM) was regarded as control (1st trial). Perfusion with Krebs-Henseleit solution containing 30, 300, and 3,000 nM of PACAP-(6-38) was started 5 min before the start of the second, third, and fourth trials, respectively. We had previously confirmed that the repetitive application of ES or ACh in the absence of drugs caused reproducible adrenal catecholamine secretion (17). In group 5 (n = 8), the effects of LPAT-VIP (30, 300, and 3,000 nM) on the ES-induced increases in catecholamine output were examined with the same protocol as described above.

In groups 6 and 7, the effects of PACAP (0.3, 1, and 3 nM) on the increases in catecholamine output induced by ES (group 6; n = 7) or ACh (group 7; n = 7) were examined with the same protocol as used in group 3.

Perfusate sampling. Perfusate was sampled before and during the stimulation to determine catecholamine output. In groups 1 and 2, the sampling during the basal state was performed for 60 s just before the stimulation, and the sampling during infusion of PACAP was performed for 200 s. The sampling before and during the stimulation was performed for 60 s in groups 3-7.

Determination of adrenal catecholamine output. As an internal standard, 25 ng of 3,4-dihydroxybenzylamine, contained in 50 µl of 0.1 M perchloric acid, was added to each chilled tube containing perfusate sample. Catecholamines in perfusate sample were measured by high-performance liquid chromatography (pump, LC-100; autoinjector, CMA/200; column, Biophase ODS-IV 4.0-mm inside diameter × 110 mm; Bioanalytical Systems) with electrochemical detection (LC-4C, Bioanalytical Systems). The mobile phase (0.1 M tartaric acid-0.1 M sodium acetate, pH 3.2) was delivered to the column at a flow rate of 0.5 ml/min. The effluent was passed through an amperometric detector cell with a glassy carbon electrode and an Ag-AgCl reference electrode. The potential between the electrodes was kept constant at 700 mV. The amount of catecholamines was calculated from the area in the chromatogram on the basis of internal calibration methods. Epinephrine (Epi) and norepinephrine (NE) output (ng/min) were calculated by multiplying perfusate catecholamine concentration (ng/ml) by perfusion rate (0.2 ml/min). The increases in catecholamine output induced by the stimulation were calculated by subtracting catecholamine output obtained before each stimulation (basal catecholamine output) from that obtained during the stimulation.

Analysis of data. The results are expressed as means ± SE. In groups 1 and 2, single-factor repeated-measures ANOVA and Scheffé's test were applied to analyze effects of PACAP- (6-38) or LPAT-VIP on PACAP-induced catecholamine output responses. In groups 3-7, total effects of ES or ACh and of the drug treatment [PACAP- (6-38), LPAT-VIP, or PACAP] were evaluated by multifactor repeated-measures ANOVA. When the ANOVA revealed a statistical significance due to the drug treatment, single-factor repeated-measures ANOVA and Dunnett's test were applied to analyze the drug effect on catecholamine output responses induced by ES at each frequency or ACh at each concentration. P values <0.05 were considered to be statistically significant.

Drugs. The drugs used were PACAP-27, PACAP-(6-38) (Peptide Institute, Osaka, Japan), ACh chloride, and LPAT-VIP (Sigma Chemical, St. Louis, MO). All drugs were dissolved in Krebs-Henseleit solution.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Basal Epi and NE output from the adrenal gland before the first trial were 23.9 ± 2.3 ng/min (n = 53) and 4.0 ± 0.4 ng/min (n = 53), respectively, in all groups. There were no significant differences in these basal values among the experimental groups, and the basal Epi and NE output did not change throughout the experimental periods in each group (data not shown). Infusion of PACAP (100 nM) into the adrenal gland increased Epi and NE output in the first trial (groups 1 and 2, Fig. 1). ES (1-10 Hz) or infusion of ACh (6-200 µM) into the adrenal gland frequency or concentration dependent increased Epi and NE output (groups 3-7, Figs. 2-4).


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  		Fig. 1.   Effects of pituitary adenylate cyclase-activating polypeptide (PACAP)-(6-38) (A; group 1) and [Lys1,Pro2,5,Ara3,4,Tyr6]-vasoactive intestinal peptide (LPAT-VIP; B; group 2) on the PACAP-induced increases in epinephrine (Epi) and norepinephrine (NE) output from the perfused rat adrenal glands. PACAP (100 nM) was applied in the absence or presence of PACAP-(6-38) or of LPAT-VIP. Values are means ± SE of changes in Epi and NE output from basal output levels. *P < 0.05, **P < 0.01 compared with corresponding control values obtained before the PACAP-(6-38) or LPAT-VIP treatment. dagger P < 0.05, dagger dagger P < 0.01 compared with values obtained during the 30 nM PACAP-(6-38) or LPAT-VIP treatment. §P < 0.05 compared with values obtained during the 300 nM LPAT-VIP treatment.



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  		Fig. 2.   Effects of PACAP-(6-38) on the increases in Epi and NE output from the perfused rat adrenal glands in response to transmural electrical stimulation (ES; A; group 3) and ACh infusion (B; group 4). ES or ACh infusion was applied in the absence or presence of PACAP-(6-38). Values are means ± SE of changes in Epi and NE output from basal output levels. **P < 0.01 compared with corresponding control values obtained before the PACAP-(6-38) treatment.



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  		Fig. 3.   Effects of LPAT-VIP on the increases in Epi and NE output from the perfused rat adrenal glands in response to transmural ES (group 5). ES was applied in the absence or presence of LPAT-VIP. Values are means ± SE of changes in Epi and NE output from basal output levels. There were no significant differences (P > 0.05) in catecholamine responses before and during the LPAT-VIP treatment.



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  		Fig. 4.   Effects of PACAP on the increases in Epi and NE output from the perfused rat adrenal glands in response to transmural ES (A; group 6) and ACh infusion (B; group 7). ES or ACh infusion was applied in the absence or presence of PACAP. Values are means ± SE of changes in Epi and NE output from basal output levels. *P < 0.05, **P < 0.01 compared with corresponding control values obtained before the PACAP treatment. The 60-µM ACh-induced NE output responses during PACAP treatment at all concentrations were significantly different from the corresponding control response (note that the symbols are overlapped).

Effects of PACAP receptor antagonists on PACAP-induced catecholamine output responses. The PACAP type I receptor antagonist PACAP-(6-38) at 300 nM significantly inhibited the PACAP-induced increases in Epi and NE output (group 1, Fig. 1A). The highest concentration (3,000 nM) of PACAP-(6-38) abolished the PACAP-induced output responses. The PACAP-induced increases in Epi and NE output were not affected by the PACAP type II receptor antagonist LPAT-VIP at 30 and 300 nM and inhibited by LPAT-VIP at 3,000 nM (group 2, Fig. 1B).

Effects of PACAP receptor antagonists on ES- or ACh-induced catecholamine output responses. PACAP- (6-38) at 3,000 nM significantly inhibited the increases in Epi and NE output induced by ES (group 3, Fig. 2A) but not the output responses induced by ACh infusion (group 4, Fig. 2B). LPAT-VIP (30, 300, and 3,000 nM) did not affect the ES-induced increases in Epi and NE output (group 5, Fig. 3).

Effects of PACAP on ES- or ACh-induced catecholamine output responses. PACAP (0.3, 1, and 3 nM) did not affect the ES-induced increases in Epi and NE output (group 6, Fig. 4A). In contrast, the ACh-induced increases in Epi and NE output were significantly enhanced by PACAP (group 7, Fig. 4B). Potencies of the enhancement were almost the same among 0.3, 1, and 3 nM PACAP.


    DISCUSSION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In the present study, infusion of PACAP (100 nM) into the isolated perfused rat adrenal gland increased Epi and NE output, as observed in the bovine (19, 26), porcine (10), and rat (28) cultured adrenal chromaffin cells or in the isolated perfused rat adrenal gland (8). PACAP-(6-38), a PACAP type I receptor antagonist (22), at 300 nM inhibited and at 3,000 nM abolished the PACAP-induced catecholamine output responses. PACAP-(6-38) at the highest concentration (3,000 nM) abolished the catecholamine output responses. On the other hand, the PACAP-induced catecholamine output responses were resistant to LPAT-VIP, a PACAP type II receptor antagonist (7). LPAT-VIP only at the highest concentration (3,000 nM) inhibited the PACAP-induced catecholamine output responses by ~40%. PACAP type II receptors are reported to occupy only 7% of total PACAP-binding sites in rat adrenal chromaffin cells (25). Taken together, PACAP type I receptors may predominantly mediate the PACAP-induced adrenal catecholamine secretion.

To elucidate a role of endogenous PACAP in the adrenal gland, we examined whether the blockade of PACAP receptors could affect neurally evoked adrenal catecholamine secretion. We applied ES to the isolated adrenal gland, the method of which has been confirmed to be adequate to evaluate drug actions on adrenal catecholamine secretion in response to neural release of endogenous ACh (16-18). PACAP-(6-38) (3,000 nM), but not LPAT-VIP, inhibited the increases in Epi and NE output induced by ES. Our present study is the first that demonstrates an inhibitory effect of the selective PACAP type I receptor antagonist on endogenous ACh-induced adrenal catecholamine secretion. On the other hand, PACAP-(6-38) did not affect the increases in Epi and NE output induced by ACh infusion. It is therefore likely that PACAP released from the nerve endings together with ACh plays a facilitatory role in neurally evoked catecholamine secretion via PACAP type I receptors in the rat adrenal gland.

Whereas the ES-induced catecholamine output responses in the rat adrenal gland are mainly mediated by nicotinic receptors (19), the inhibition by PACAP- (6-38) of the ES-induced responses was ~60%. This large inhibition indicates that neurally released PACAP may not only directly induce catecholamine secretion but also modulate the cholinergic mechanisms of adrenal catecholamine secretion. It is unlikely that PACAP-(6-38) blocks or PACAP activates the cholinergic receptors, because PACAP-(6-38) failed to affect the exogenous ACh-induced catecholamine output responses in this study (the responses are also mediated by nicotinic receptors as well as muscarinic receptors, Ref. 18), and neither nicotinic nor muscarinic receptor antagonist inhibits exogenous PACAP-induced catecholamine secretion from the rat adrenal medulla in vivo (29). It has been reported that exogenous PACAP enhances the cardiac parasympathetic neurotransmitter release (9, 24) and the ACh-induced adrenal catecholamine secretion (11) in anesthetized dogs. Taken together, we postulated that neurally released PACAP acts on the nerve endings (presynaptic site) to accelerate neural ACh release or acts on the chromaffin cells (postsynaptic site) to amplify processes of the ACh-induced responses in the rat adrenal gland.

To confirm the modulation by PACAP of the postsynaptic events, we examined whether PACAP at concentrations that do not induce catecholamine secretion affects exogenous ACh-induced catecholamine secretion. PACAP at 0.3 nM enhanced the ACh-induced catecholamine output responses without affecting basal catecholamine output. Similar enhancement was observed by administration of PACAP at a dose that increased basal catecholamine secretion in the dog adrenal gland in vivo (11). Our finding indicates that the increased adrenal PACAP level, even though it does not directly induce catecholamine secretion, can influence cholinergic mechanisms of adrenal catecholamine secretion. Because PACAP at higher concentrations (1 and 3 nM) did not further enhance the ACh-induced catecholamine output responses, 0.3 nM of PACAP may be a supramaximal concentration to modulate the cholinergic mechanisms. Although the possibility that the presynaptic action of PACAP affects the postsynaptic events still remains, the neurally released PACAP may act on the postsynaptic site to amplify the processes of cholinergic adrenal catecholamine secretion. On the other hand, PACAP (0.3-3 nM) did not affect the ES-induced adrenal catecholamine secretion. The failure of exogenous PACAP to enhance the ES-induced responses would imply that the neurally released PACAP maximally facilitates the catecholamine secretion.

It has been suggested that VIP is released from the nerve endings and contributes to neurally evoked adrenal catecholamine secretion (12, 27). Exogenous VIP causes catecholamine secretion, and [Ac-Tyr1,D-Phe2]-growth hormone-releasing factor 1-29 amide, a VIP receptor (PACAP type II receptor) antagonist, inhibits both the VIP- and ES-induced catecholamine secretion in the isolated perfused rat adrenal gland (27). In the present study, however, the PACAP type II receptor antagonist LPAT-VIP had no effect on the ES-induced catecholamine output responses. This difference may be due to experimental conditions; ES was applied at 1 Hz for 5 min in the previous study (27), whereas we performed ES at 1-10 Hz for 40 s each. ES applied for the short period in our study may not elevate VIP concentration over the threshold to modulate or induce adrenal catecholamine secretion.

A recent report suggests that PACAP type I receptors also mediate exogenous VIP-induced adrenal catecholamine secretion in dogs in vivo (4). However, binding affinity of VIP for PACAP type I receptors is 500-1,000 times less than that for PACAP type II receptors (6), and micromolar levels of VIP are required to induce catecholamine secretion from the isolated perfused rat adrenal gland (27). It is therefore unlikely that the PACAP type I receptor antagonist PACAP-(6-38) inhibited the facilitatory action of endogenous VIP in the present study. In our experimental condition, VIP may play little or no role in adrenal catecholamine secretion.

In conclusion, the present study suggests that neurally released PACAP modulates cholinergic mechanisms via PACAP type I receptors and thereby plays a facilitatory role in the peripheral neural control of catecholamine secretion in the rat adrenal gland. The facilitation by PACAP may occur at the postsynaptic site, but the possibility still remains that PACAP also acts on the presynaptic site to enhance neural ACh release.

Perspectives

The present study suggests that neurally released PACAP facilitates cholinergic adrenal catecholamine secretion. To obtain direct evidence for the neural PACAP release, we measured PACAP concentration in the perfusate by radioimmunoassay. A tendency that ES increased adrenal PACAP output was observed, but precise output values were not obtained due to low sensitivity of the assay method we used.

PACAP activates adenylate cyclase and also evokes the calcium influx from extracellular fluid or the calcium release from intracellular stores in adrenal chromaffin cells (19, 21, 26). Our recent study has also demonstrated the roles of adenylate cyclase and extracellular calcium in the PACAP-induced catecholamine secretion from the isolated perfused rat adrenal gland (3). One or more of these cellular events may modulate pathways involved in the ACh-induced adrenal catecholamine secretion. As we noted in the DISCUSSION, however, the present study cannot rule out the possibility that PACAP acts on the presynaptic site and thereby facilitates the postsynaptic response. Elevation by PACAP of cytosolic cAMP or free calcium level at the nerve endings would enhance the ACh release.

Determination of neural PACAP and ACh release in the adrenal gland will be required to clarify the role of endogenous PACAP in the control of adrenal catecholamine secretion.


    ACKNOWLEDGEMENTS

This work was supported in part by Grant No. 10877371 for Scientific Research from The Ministry of Education, Science and Culture, Japan.


    FOOTNOTES

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).

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.

Received 14 February 2001; accepted in final form 5 July 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Regul Integr Comp Physiol 281(5):R1562-R1567
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society


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