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Amine Secretion from the Perfused Rat Adrenal Medulla J Cardiol 2007 Dec; 50（6）: 351–362 Effect of Anabasine on Catechol- amine Secretion From the Perfused Rat Adrenal Medulla Soon-Pyo HONG, MD Min-Gyoo JEONG, MD＊ Dong-Yoon LIM, MD＊ Abstract ───────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────── Objectives. The present study was designed to investigate the characteristic effects of anabasine on secretion of catecholamines（CA）from the isolated perfused rat adrenal gland and to establish its mecha- nism of adrenomedullary secretion. Methods. The adrenal gland was isolated by a modification of the Wakade method, and perfused with normal Krebs-bicarbonate solution. The content of CA was measured using fluorometry. Results. The perfusion of anabasine（30－300 μM）into an adrenal vein for 60min resulted in great increases in CA secretions in a dose-dependent fashion. Upon repeated injection of anabasine（100 μM）at 120min-intervals, CA secretion was rapidly decreased after the third injection of anabasine. However, there was no statistical difference between the CA secretory responses of both 1st and 2nd treated groups by the successive administration of anabasine at 120min-intervals. Tachyphylaxis to the releasing effects of CA evoked by anabasine was observed by repeated administration. Therefore, in all subsequent experi- ments, anabasine was not administered successively more than twice at only 120min-intervals. The CA- releasing effects of anabasine were depressed by pretreatment with chlorisondamine（selective neuronal nicotinic receptor antagonist, 1 μM）, atropine（muscarinic receptor antagonist, 2μM）, nicardipine（L-type dihydropyridine Ca2＋ channel blocker, 1 μM）, TMB-8（anti-releaser of intracellular Ca2＋, 30 μM）, and perfusion of EGTA（Ca2＋ chelator, 5mM）plus Ca2＋-free medium. In the presence of anabasine（100 μM）, the CA secretory responses induced by acetylcholine（5.32mM）, high K＋（direct membrane-depolarizer, 56mM）, DMPP（selective neuronal nicotinic receptor agonist, 10－4 M）, and McN-A-343（selective mus- －4 carinic M1 receptor agonist, 10 M）were maximally enhanced in the first 4min. However, as time elapsed, these responses became more inhibited at later periods. Furthermore, the perfusion of nicotine（30 μM） into an adrenal vein for 60min also caused a great increase in CA secretion, leading to peak response in the first 0－5min period. In the presence of nicotine（30 μM）, the CA secretory responses induced by acetyl- choline, high K＋, DMPP and McN-A-343 were also enhanced for the first 4min, but later reduced to less than the control release. Conclusions. Taken together, these experimental results indicate that anabasine affects rat adrenomedullary CA secretion in a calcium-dependent fashion. This facilitatory effect of anabasine may be mediated by activation of both cholinergic nicotinic and muscarinic receptors, which is relevant to both stimulation of Ca2＋ influx into adrenomedullary chromaffin cells and Ca2＋ release from cytoplasmic Ca2＋. Anabasine may be less potent than nicotine in rat adrenomedullary CA secretion. Anabasine, in addition to nicotine, alkaloids present in tobacco smoke may be a risk factor in causing cardiovascular diseases. ──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Dec; 50（6）: 351－362 Key Words ■ Cardiovascular disease ■ Drug administration（anabasine, nicotine） ■ Epinephrine（catecholamine release, adrenal medulla） ■ Experimental medicine tobacco alkaloids［（＋/－）-nornicotine, anabaseine, INTRODUCTION S（－）-anabasine, and S（－）-N-methylanabasine］ In addition to S（－）-nicotine, several minor are present in tobacco smoke. These alkaloids are ────────────────────────────────────────────── Departments of Internal Medicine（Cardiology）and ＊ Pharmacology, College of Medicine, Chosun University, Korea Address for correspondence: Dong-Yoon Lim, MD, Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501－759, Korea; E-mail: [email protected] Manuscript received February 23, 2007; revised August 8, 2007; accepted August 10, 2007 351 352 Hong, Jeong, Lim found to increase fractional 3H release in a concen- The present study investigated whether anabasine tration-dependent manner from rat striatal slices can modify the release of CA from the isolated per- preloaded with [3H]dopamine, with desensitization fused model of the adrenal gland. Therefore, the of this response.1）The genus Anisothea plant also present study examined the effect of anabasine, a contains the bipiperidyl alkaloid anabasine and the relatively selective α7-nicotinic ACh receptor ago- bicyclic quinolizidine lupinine.2）Anabasine（Fig. nist, on CA secretion from the isolated perfused 1）, caffeine, methylpyrrolidine and several deriva- model of the rat adrenal gland, in comparison with tives have moderate inhibitory activity of acetyl- the responses to nicotine, to establish the mecha- cholinesterase with I50 values in the range of 87－ nism of action. The present study is the first work 480 μM.3） in which the faciltatory effect of anabasine on the CA secretion from the perfused model of rat adren- al gland was demonstrated. MATERIALS AND METHODS Experimental procedure Male Sprague-Dawley rats, weighing 180 to Fig. 1 Chemical structure of anabasine 300g, were intraperitoneally anesthetized with thiopental sodium（40mg/kg）. The adrenal gland was isolated by the methods described previously.8） In human granulosa cells, cigarette alkaloids The abdomen was opened by a midline incision, （nicotine, cotinine and anabasine）may inhibit cel- and the left adrenal gland and surrounding area lular progesterone synthesis both by inhibiting were exposed by the placement of three-hook progesterone synthesis and by causing less specific retractors. The stomach, intestine and portion of the toxic effects to the cell. In contrast, cigarette smoke liver were not removed, but pushed over to the right alkaloids slightly stimulated or had no effect on side and covered by saline-soaked gauge pads. The estradiol production.4）These concomitant actions urine in the bladder was removed to obtain enough of cigarette alkaloids partly explain the higher inci- working space for tying blood vessels and cannula- dence of early abortion in pregnant women who tion. smoke. Chronic treatment of mice with（－）-nico- A cannula, used for perfusion of the adrenal tine and anabasine increased the number of nico- gland, was inserted into the distal end of the renal tinic binding sites, whereas lobeline did not affect vein after all branches of adrenal vein（if any）, vena the density of nicotinic acetylcholine（ACh）recep- cava and aorta were ligated. Heparin（400 IU/ml） tors.5）Anabasine attenuated MK-801-elicited pop- was injected into vena cava to prevent blood coagu- ping at a dose that did not cause clonic seizures.6） lation before ligating vessels and cannulation. A Behaviors elicited by MK-801 in mice reflect a small slit was made into the adrenal cortex just pharmacologically induced state of N-methyl-D- opposite entrance of adrenal vein. Perfusion of the aspartate receptor hypofunction, which may be pre- gland was started, making sure that no leakage was sent in schizophrenia. Although the maximum cur- present, and the perfusion fluid escaped only from rents generated by anabaseine and anabasine at the the slit made in adrenal cortex. Then the adrenal α7 receptors are equivalent to that of ACh, the gland, along with ligated blood vessels and the can- maximum response to nicotine was only about nula, was carefully removed from the animal and 65% of the ACh response. At α4 β2 receptors, the placed on a platform of a leucite chamber. The affinities and apparent efficacies of anabaseine and chamber was filled with water continuously circu- anabasine are much less than that of nicotine. lated at 37±1°C. Animal care followed the criteria Anabaseine, nicotine and anabasine were nearly of the Animal Care Committee of the Chosun equipotent on sympathetic（PC12）receptors, University for the care and use of laboratory ani- although parasympathetic（myenteric plexus）recep- mals in research. tors are much more sensitive to anabaseine and nicotine but less sensitive to anabasine.7）The influ- ence of anabasine on the release of catecholamines Perfusion of adrenal gland （CA）has not been previously reported. The adrenal glands were perfused using an ISCO J Cardiol 2007 Dec; 50（6）:351–362 Effect of Anabasine on Catecholamine Secretion 353 pump（WIZ Co.）at 0.31ml/min. The perfusion was ground sample. The adrenal gland perfusate was carried out with Krebs-bicarbonate solution of the collected in chilled tubes. following composition（mM）:NaCl, 118.4 ; KCl, 4.7 ; CaCl2, 2.5 ; MgCl2, 1.18 ; NaHCO3, 25 ; Measurement of catecholamines KH2PO4, 1.2; glucose, 11.7. The solution was con- CA content of perfusate was measured directly 9） stantly bubbled with 95% O2 ＋ 5% CO2 and the by the fluorometric method of Anton and Sayre final pH of the solution was maintained at 7.4－7.5. without the intermediate purification with alumina The solution contained disodium ethylenediamine for the reasons described earlier8）using a fluo- tetraacetic acid（EDTA）（10 μg/ml）and ascorbic rospectrophotometer（Kontron Co.）. A volume of acid（100 μg/ml）to prevent oxidation of CAs. 0.2ml of the perfusate was used for the reaction. The CA content in the perfusate of glands stimulat- Drug administration ed by secretagogues used in the present work was Anabasine（10－4 M）and nicotine（3 × 10－5 M） high enough to obtain
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