JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Uryu, K.
Right arrow Articles by Shigematsu, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Uryu, K.
Right arrow Articles by Shigematsu, A.
Anesth Analg 2000;91:546-551
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Inhibition by Neuromuscular Blocking Drugs of Norepinephrine Transporter in Cultured Bovine Adrenal Medullary Cells

Kayo Uryu, MD*, Kouichiro Minami, MD, PhD*, Nobuyuki Yanagihara, PhD{dagger}, Koji Hara, MD, PhD*, Yumiko Toyohira, PhD{dagger}, Futoshi Izumi, MD, PhD{dagger}, and Akio Shigematsu, MD, PhD*

Departments of *Anesthesiology and {dagger}Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

Address correspondence and reprint requests to Kouichiro Minami, the Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan. Address e-mail to kminami{at}med.uoeh-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Pancuronium stimulates the cardiovascular system, whereas vecuronium, a derivative of pancuronium, has far fewer effects. The inhibition of norepinephrine transporter (NET) in the sympathetic nervous system may partly account for the stimulatory actions of pancuronium. To investigate the mechanism of action of pancuronium on NET, we examined the effects of pancuronium on NET activity by using cultured bovine adrenal medullary cells and compared pancuronium with other neuromuscular blocking drugs. Pancuronium (1–300 µM) inhibited desipramine-sensitive [3H]norepinephrine (NE) uptake in a concentration-dependent manner. Vecuronium (100–300 µM) and d-tubocurarine (300 µM) also decreased [3H]NE uptake but were less potent than pancuronium at clinical concentrations. Succinylcholine had little effect on [3H]NE uptake. Saturation analysis showed that pancuronium and vecuronium reduced an apparent maximum velocity (Vmax) of [3H]NE uptake without altering Michaelis-Menten constant, indicating noncompetitive inhibition. Pancuronium did not inhibit the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. A protein kinase C inhibitor, GF109203X, did not affect the inhibition of [3H]NE uptake by pancuronium. Pancuronium enhanced the inhibition of NET induced by ketamine. These results suggest that pancuronium, with clinically relevant concentrations, inhibits NET activity by interacting with a site distinct from the recognition site for NE and the desipramine binding site on the transporter.

Implications: In this study, pancuronium inhibited norepinephrine uptake and was the most potent of the neuromuscular blocking drugs we tested, including pancuronium, vecuronium, d-tubocurarine, and succinylcholine. Pancuronium may affect the sympathetic nervous system by inhibiting the activity of the presynaptic norepinephrine transporter at clinically relevant concentrations.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Pancuronium has well known effects on the autonomic nervous system (1). It induces hypertension and tachycardia in anesthetized patients and experimental animals (2–4). However, vecuronium, which is derived from pancuronium, has fewer effects on the cardiovascular system than pancuronium (5). Several mechanisms have been proposed for the cardiovascular effects of pancuronium by using animal models. These include: 1) vagolytic properties (6); 2) stimulation of catecholamine release by inhibiting presynaptic muscarinic receptors (7); 3) indirect sympathomimetic stimulation (8); and 4) inhibition of norepinephrine (NE) uptake (9). However, the precise mechanisms of these effects are still not clear.

Adrenal medullary cells arise from the neural crest, share many physiological and pharmacological properties with postganglionic sympathetic neurons, and abundantly express the norepinephrine transporter (NET) (10), which is a member of the superfamily of structurally related sodium- and chloride-dependent neurotransmitter transporters (11). Lingen et al. (12) cloned the cDNA of the bovine NET, and its deduced amino acid sequence shows a very high degree of identity with the sequence of the human NET (13). The NET of the adrenal medullary cells have been pharmacologically well characterized. Therefore, adrenal medullary cells provide a convenient model system for studying the effects of anesthetics, such as ketamine on this transport system (14).

Although the mechanisms responsible for the inhibition by pancuronium of NE uptake are not available, there are the following assumptions: 1) direct interaction with NET on a site of desipramine binding or NE translocation; and 2) indirect effect on NET via cellular signal transductions, such as protein kinase C (PKC) which plays an important role in the regulation of NET (15). To address these issues, we studied the effects of pancuronium and other neuromuscular blocking drugs on [3H]NE uptake by using a kinetic analysis. We also examined the effects of pancuronium on the specific binding of [3H]desipramine and on NET function in the presence or absence of a selective PKC inhibitor in bovine adrenal medullary cells.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We used the following chemicals: Eagle’s minimum essential medium; fetal calf serum; (-)NE; pargyline hydrochloride; (-)-ascorbic acid; 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES); collagenase; desipramine hydrochloride; succinylcholine chloride; d-tubocurarine chloride; (±)-ketamine hydrochloride; nisoxetine hydrochloride; a protein kinase C inhibitor (GF109203X); (-)-[7, 8- 3H]-norepinephrine (33.0 Ci/mmol); [benzene ring, 10, 11- 3H]-desmethylimipramine hydrochloride ([3H]desipramine) (73.0 Ci/mmol); pancuronium bromide; and vecuronium bromide. (-)-NE was dissolved with 0.1 M HCl and diluted with distilled water before use.

Adrenal medullary cells were isolated by collagenase digestion of slices of bovine adrenal medulla as previously described (16). The cells were plated at a density of 4 x106 cells/dish (Falcon, 35 mm) in Eagle’s minimum essential medium containing 10% fetal calf serum and several antibiotics (14). The cells were cultured in 5% CO2/95% air in an incubator at 37°C and used for experiments after 2 to 4 days of culture.

Cultured cells (4 x106 per dish) were incubated at 37°C for 15 min in Krebs-Ringer HEPES (KRH) buffer containing 10 µM pargyline, 100 µM ascorbic acid, and 500 nM [3H]NE in the presence or absence of neuromuscular blocking drugs. KRH buffer consisted of 154 mM NaCl, 5.6 mM KCl, 1.1 mM MgSO4, 2.2 mM CaCl2, 10 mM HEPES, and 10 mM glucose, adjusted to pH 7.4. After incubation, the cells were rapidly washed four times with 1 mL of ice-cold KRH buffer and solubilized in 1 mL of 10% Triton X-100. The radioactivity in the solubilized cells was counted by a liquid scintillation counter (LSC-3500E, Aloka, Tokyo, Japan). Nonspecific uptake was determined in the presence of 10 µM desipramine and specific uptake was obtained by subtracting the nonspecific uptake from the total uptake.

Plasma membranes isolated from bovine adrenal medulla were prepared as previously described (10). The binding of [3H]desipramine was determined by incubating membranes (10 µg protein) suspended in buffer B (135 mM NaCl, 10 mM Tris-HCl, pH 7.4, 5 mM KCl, and 1 mM MgSO4) for 30 min at 4°C. The incubation medium (final volume, 250 µL) contained [3H]desipramine (2–24 nM) in the presence or absence of 30 µM pancuronium. After incubation, binding was terminated by the addition of 2 mL of ice-cold buffer B and rapid filtration of the membrane suspension under vacuum through Whatman GF/C (Maidstone, England) glass fiber filters. The filters were rapidly washed twice with 2 mL of ice-cold buffer B and its radioactivity was counted. Specific binding of [3H]desipramine was defined as the binding inhibited by the selective NET inhibitor, 10 µM of nisoxetine.

All values are expressed as mean ± SD. Comparison of several means was performed by using analysis of variance and Scheffé’s test. A P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Pancuronium (1–300 µM) inhibited [3H]NE uptake by adrenal medullary cells in a concentration-dependent manner with 50% inhibitory concentration (IC50) of 27 ± 5 µM (Fig. 1). Vecuronium and d-tubocurarine significantly inhibited the [3H]NE uptake to 65 ± 6% and 80 ± 8% of control at 100 µM and 300 µM, respectively, whereas succinylcholine had little effect on [3H]NE uptake, regardless of concentration (0.1–300 µM).



View larger version (21K):
[in this window]
[in a new window]
  		Figure 1. Effects of neuromuscular blocking drugs on desipramine-sensitive [3H] norepinephrine (NE) uptake. Cultured adrenal medullary cells were incubated at 37°C for 15 min with 500 nM [3H]NE in the presence or absence of pancuronium (0.1–300 µM) (•), vecuronium (0.1–300 µM) ({triangleup}), d-tubocurarine (0.1–300 µM) ({blacksquare}) and succinylcholine (0.1–300 µM) ({diamond}). Desipramine-sensitive [3H]NE uptake by cells was measured. Data were expressed as a percentage of control values (20 ± 3 pmol/4x106 cells/15 min). Data are mean ± SD of six separate experiments carried out in duplicate (n = 6). *P < 0.05 compared with control.

 
When the effects of pancuronium were compared with those of vecuronium and d-tubocurarine at the concentration required to produce 95% muscle paralysis (17), 0.6 µM of pancuronium, 0.3 µM of vecuronium, and 1.7 µM of d-tubocurarine inhibited [3H]NE uptake to 88 ± 4% (P < 0.05), 97 ± 4%, and 96 ± 5% of control, respectively.

Incubation of the cells with increasing concentrations of [3H]NE (1–30 µM) showed that [3H]NE uptake was saturable (Fig. 2A). Eadie-Hofstee analysis showed the maximal velocity (Vmax) was 185 ± 8 pmol/4x106 cells/15 min and an apparent Michaelis-Menten constant (Km) was 5.1 ± 0.8 µM in control cells. In the presence of 30 µM of pancuronium and 100 µM of vecuronium, Vmax changed to 154 ± 6 and 143 ± 8 pmol/4x106 cells/15 min with no significant change in Km to 6.5 ± 0.3 and 6.0 ± 0.9 µM, respectively. These results indicate a noncompetitive inhibition (Fig. 2B).



View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Saturation curve of desipramine-sensitive [3H] norepinephrine (NE) uptake (A) and Eadie-Hofstee analysis of [3H]NE uptake (B). A, Cells were incubated without and with 30 µM of pancuronium (•) or 100 µM of vecuronium ({triangleup}) in the presence of concentrations varying from 1 to 30 µM of [3H]NE at 37°C for 15 min. Data are mean ± SD of six separate experiments carried out in duplicate (n = 6). B, Eadie-Hofstee analysis of [3H]NE uptake. V = velocity; V/S = velocity/substrate.

 
To eliminate the possibility that NET was down-regulated by pancuronium via activation of PKC, we next examined the effects of pancuronium on [3H]NE uptake in the presence of a PKC inhibitor, GF109203X (200 nM) (Ki = 2.4 nM) (18). GF109203X did not affect the inhibitory effects of pancuronium on [3H]NE uptake (Fig. 3).



View larger version (54K):
[in this window]
[in a new window]
  		Figure 3. Effect of GF109203X on [3H] norepinephrine (NE) uptake inhibited by pancuronium. Cells were incubated with 500 nM [3H]NE in the presence or absence of 200 nM of GF109203X and 30 µM of pancuronium at 37°C for 30 min. PCB = pancuronium, GF = GF109203X. Data are expressed as a percentage of control values (47 ± 6 pmol/4x106 cells/30 min). Data are mean ± SD of six separate experiments carried out in duplicate (n = 6).

 
To study the site of action of pancuronium on NET, we examined the effects of pancuronium on [3H]desipramine binding to plasma membranes isolated from bovine adrenal medulla. Specific binding of [3H]desipramine was saturable with an increasing concentration of 2–24 nM [3H]desipramine (Fig. 4A). Scatchard analysis showed a single population of binding sites with an apparent dissociation constant (Kd) of 13.1 ± 3.7 nM and maximal binding (Bmax) of 3.3 ± 0.2 pmol/mg protein in control membranes (Fig. 4B). Pancuronium (30 µM) did not change either the Kd (11.0 ± 2.7 nM) or Bmax (2.8 ± 0.3 pmol/mg protein) of [3H]desipramine binding.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 4. The effects of pancuronium on specific binding of [3H]desipramine to plasma membranes of bovine adrenal medulla (A) and Scatchard plot analysis of [3H]desipramine binding (B). A, Plasma membranes (10 µg protein) isolated from bovine adrenal medulla were incubated at 4°C for 30 min with (•) or without ({circ}) 30 µM of pancuronium in the presence of increasing concentrations of 2–24 nM [3H]desipramine. Data are mean ± SD of six separate experiments carried out in duplicate (n = 6). B, Scatchard plot analysis of [3H]desipramine binding. B/F = bound/free, B = bound.

 
We determined if ketamine affects the pancuronium-induced inhibition of [3H]NE uptake (Fig. 5) to examine the additive effects of ketamine and pancuronium on NET function. Ketamine (30 µM) enhanced the 10 µM of pancuronium-induced inhibition of [3H]NE uptake to 37 ± 6% from 25 ± 3% of control (P < 0.05).



View larger version (34K):
[in this window]
[in a new window]
  		Figure 5. The effect of ketamine on pancuronium-induced inhibition of [3H]norepinephrine (NE) uptake. Cells were incubated with 500 nM [3H]NE in the presence or absence of 10 µM and 30 µM of ketamine and 10 µM of pancuronium at 37°C for 15 min. Data are mean ± SD of six separate experiments carried out in duplicate (n = 6) and expressed as a percentage inhibition of control values (18 ± 2 pmol/4x106 cells/15 min). PCB = pancuronium, K 10 = ketamine 10 µM, K 30 = ketamine 30 µM. *P < 0.05 compared with [3H]NE uptake inhibited by pancuronium.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we demonstrated that pancuronium, vecuronium, and d-tubocurarine, but not succinylcholine, inhibited [3H]NE uptake by cultured bovine adrenal medullary cells. These results are consistent with previous reports that pancuronium inhibits [3H]NE uptake in several tissues, including rat heart (9), rat anococcygeus and rat vas deferens (19). The rank order of potency of these neuromuscular blocking drugs was pancuronium > vecuronium > d-tubocurarine. The plasma concentrations of pancuronium, vecuronium, and d-tubocurarine that produce 95% muscle paralysis are reported to be 0.6 µM, 0.3 µM, and 1.7 µM, respectively (17). The administration of a single dose of 4 mg IV pancuronium to humans is reported to produce a plasma concentration of approximately 100–500 ng/mL (0.14–0.7 µM) during the first three hours (20). Of the neuromuscular blocking drugs tested, only pancuronium appears to cause a small, but significant, inhibition of [3H]NE uptake at clinically relevant concentrations. The structures of pancuronium and vecuronium are very similar. The only difference in structures between these two drugs is a 2-methyl quaternizing group present in pancuronium, but not in vecuronium, and important in the inhibition of NET function.

There has been controversy over the in vivo effect of pancuronium on the plasma NE concentration. Some studies reported no change (21) or a decrease (22), whereas Nana et al. (23) showed an increase in the plasma NE concentration with in vivo administration of pancuronium. The plasma concentration of NE is the result of a balance between the rate of spillover into the circulation and the rate of clearance from the circulation (24). The balance between the release and uptake of NE determines the spillover into the circulation. In our previous studies (25,26), pancuronium and vecuronium inhibited nicotinic acetylcholine receptor-mediated secretion of catecholamines from bovine adrenal medulla. Therefore, these two neuromuscular blocking drugs inhibited not only catecholamine secretion induced by nicotinic stimulation, but also uptake of NE with the same potency. Under some resting or anesthetic conditions, in which the basal release of NE is not influenced by pancuronium, it may increase the concentration of plasma NE, as previously reported (23). In the sympathetic nervous system, the termination of synaptic transmission is mainly regulated by the reuptake of NE from the synaptic cleft (11,27). Even a slight inhibition of NET function by pancuronium may have a pronounced influence on the activity of the sympathetic nervous system, stimulating the cardiovascular system. Furthermore, in some cases, pancuronium and ketamine are used at the same time clinically. In our study, ketamine enhanced the inhibitory effects of pancuronium on NET function, suggesting that pancuronium may potentiate the stimulatory effects of ketamine on the sympathetic nervous system under ketamine anesthesia.

To investigate the inhibitory mechanism of pancuronium and vecuronium, their influence on the kinetic variables of NE transport was studied at various concentrations of [3H]NE. The Eadie-Hofstee analysis of [3H]NE uptake showed that pancuronium and vecuronium reduced the Vmax values of [3H]NE uptake without altering the Km values for NE, indicating noncompetitive inhibition. One possible reason for the noncompetitive interaction with [3H]NE uptake can be studied. Several investigators have reported that NET possesses consensus sequences for phosphorylation by PKC and the phosphorylation of the transporter by PKC down-regulates the transporter. Bönisch et al. (15) demonstrated that NET was reduced relatively quickly by PKC-activating phorbol esters in COS-7 cells transiently expressing the human or bovine NET. In our study, GF109203X, a selective inhibitor of PKC, did not affect the inhibitory effect of pancuronium on [3H]NE uptake, suggesting that PKC is not involved in the pancuronium-induced inhibition of [3H]NE uptake.

In our study, Scatchard plot analysis of [3H]desipramine binding revealed that pancuronium did not change either the Kd or Bmax of [3H]desipramine binding, suggesting that the site of action of pancuronium on NET is distinct from the desipramine binding site. A series of studies on recombinant and chimeric dopamine/NE transporters (28,29) reported that distinct regions of the transporter determine substrate uptake and tricyclic antidepressant binding, which partially overlapped with each other (30). In a previous study, we reported that ketamine inhibited [3H]NE uptake and [3H]desipramine binding in noncompetitive and competitive manners, respectively (14). This suggests that ketamine may interact with NET at a site partly overlapping the desipramine binding site, leading to a conformational change in the transporter, which inhibits NET function (14). Combined with our previous evidence, our results suggest that pancuronium interacts with a unique site on NET, which is different from the sites of NE recognition, desipramine binding, and probably ketamine binding. To provide more information concerning the inhibitory mechanism of pancuronium on NET function requires further studies using recombinant transporter chimeras or NET mutants in which certain amino acids within the assumed pancuronium binding area have been changed.

In conclusion, pancuronium, but not other neuromuscular blocking drugs, inhibits the function of NET at clinically relevant concentrations. Pancuronium inhibits NET activity by interacting with a site distinct from the recognition site for NE and the desipramine binding site on the transporter. Our findings may be related to the stimulatory effects of pancuronium on the sympathetic nervous system.


   Acknowledgments
 
Supported, in part, by Grants 09671595, 09671596, 10770539, 11671532, 10770778, 11770878, 12770849 from the Ministry of Education, Science, and Culture of Japan, the Japanese Foundation for Cardiovascular Research, the Sasakawa Scientific Research Grant, and the Kanehara-Ichiro Memorial Medical Foundation.

The authors would like to thank Organon Teknika for the generous gift of pancuronium bromide and vecuronium bromide.


   Footnotes
 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Dallas, TX, October 1999.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Stoelting RK. Neuromuscular blocking drugs. In: Stoelting RK, ed. Pharmacology and physiology in anesthetic practice. Philadelphia: JB Lippincott, 1987: 172–225.
  2. Loh L. The cardiovascular effects of pancuronium bromide. Anaesthesia 1970; 25: 356–63.[Web of Science][Medline]
  3. Smith G, Proctor DW, Spence AA. A comparison of some cardiovascular effects of tubocurarine and pancuronium in dogs. Br J Anaesth 1970; 42: 923–7.[Abstract/Free Full Text]
  4. Stoelting RK. The hemodynamic effects of pancuronium and d-tubocurarine in anesthetized patients. Anesthesiology 1972; 36: 612–5.[Web of Science][Medline]
  5. Marshall IG, Agoston S, Booij LHDJ, et al. Pharmacology of ORG NC 45 compared with other nondepolarizing neuromuscular blocking drugs. Br J Anaesth 1980; 52: 11S–19S.
  6. Saxena PR, Bonta IL. Mechanism of selective cardiac vagolytic action of pancuronium bromide: specific blockade of cardiac muscarinic receptors. Eur J Pharmacol 1970; 11: 332–41.[Web of Science][Medline]
  7. Muscholl E. Peripheral muscarinic control of norepinephrine release in the cardiovascular system. Am J Physiol 1980; 239: H713–20.
  8. Domenech JS, Garcia RC, Sasiain JMR, et al. Pancuronium bromide: an indirect sympathomimetic agent. Br J Anaesth 1976; 48: 1143–8.[Abstract/Free Full Text]
  9. Salt PJ, Barnes PK, Conway CM. Inhibition of neuronal uptake of noradrenaline in the isolated perfused rat heart by pancuronium and its homologues, ORG. 6368, ORG. 7268 and NC 45. Br J Anaesth 1980; 52: 313–7.[Abstract/Free Full Text]
  10. Michael-Hepp J, Blum B, Bönisch H. Characterization of the [3H]-desipramine binding site of the bovine adrenomedullary plasma membrane. Naunyn-Schmiedeberg’s Arch Pharmacol 1992; 346: 203–7.[Web of Science][Medline]
  11. Amara SG, Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci 1993; 16: 73–93.[Web of Science][Medline]
  12. Lingen B, Brüss M, Bönisch H. Cloning and expression of the bovine sodium- and chloride-dependent noradrenaline transporter. FEBS Lett 1994; 342: 235–8.[Web of Science][Medline]
  13. Pacholczyk T, Blakely RD, Amara SG. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 1991; 350: 350–4.[Medline]
  14. Hara K, Yanagihara N, Minami K, et al. Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site [published erratum appears in Naunyn-Schmiedeberg’s Arch Pharmacol 1998;358:600]. Naunyn-Schmiedeberg’s Arch Pharmacol 1998; 358: 328–33.[Web of Science][Medline]
  15. Bönisch H, Hammermann R, Brüss M. Role of protein kinase C and second messengers in regulation of the norepinephrine transporter. Adv Pharmacol 1998; 42: 183–6.
  16. Yanagihara N, Isosaki M, Ohuchi T, Oka M. Muscarinic receptor-mediated increase in cyclic GMP level in isolated bovine adrenal medullary cells. FEBS Lett 1979; 105: 296–8.[Web of Science][Medline]
  17. Shanks CA. Pharmacokinetics of the nondepolarizing neuromuscular relaxants applied to calculation of bolus and infusion dosage regimens. Anesthesiology 1986; 64: 72–86.[Web of Science][Medline]
  18. Toullec D, Pianetti P, Coste H, et al. The bisindolylmaleimide GF109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 1991; 266: 15771–81.[Abstract/Free Full Text]
  19. Docherty JR, McGrath JC. A comparison of the effects of pancuronium bromide and its monoquaternary analogue, ORG NC 45, on autonomic and somatic neurotransmission in the rat. Br J Pharmacol 1980; 71: 225–33.[Web of Science][Medline]
  20. McLeod K, Watson MJ, Rawlins MD. Pharmacokinetics of pancuronium in patients with normal and impaired renal function. Br J Anaesth 1976; 48: 341–5.[Abstract/Free Full Text]
  21. Zsigmond EK, Matsuki A, Kothary SP, et al. The effect of pancuronium bromide on plasma norepinephrine and cortisol concentrations during thiamylal induction. Can Anaesth Soc J 1974; 21: 147–52.[Web of Science][Medline]
  22. Roizen MF, Forbes AR, Miller RD, et al. Similarity between effects of pancuronium and atropine on plasma norepinephrine levels in man. J Pharmacol Exp Ther 1979; 211: 419–22.[Free Full Text]
  23. Nana A, Cardan E, Domokos M. Blood catecholamine changes after pancuronium. Acta Anaesthesiol Scand 1973; 17: 83–7.[Web of Science][Medline]
  24. Deegan R, He HB, Wood AJJ, Wood M. Effects of anesthesia on norepinephrine kinetics: comparison of propofol and halothane anesthesia in dogs. Anesthesiology 1991; 75: 481–8.[Web of Science][Medline]
  25. Sumikawa K, Kashimoto T, Izumi F, et al. Effects of muscle relaxants on catecholamine release from adrenal medulla. Res Commun Chem Pathol Pharmacol 1979; 25: 205–14.[Web of Science][Medline]
  26. Wada A, Arita M, Takara H, et al. Inhibition by vecuronium of carbachol-induced influx of 22Na +, 45Ca2+ and secretion of catecholamines in cultured bovine adrenal medullary cells. Naunyn-Schmiedeberg’s Arch Pharmacol 1989; 340: 605–9.[Web of Science][Medline]
  27. Iversen LL. Uptake processes of biogenic amines. In: Iversen LL, Iversen SD, Snyder SH, eds. Handbook of psychopharmacology. New York: Plenum, 1975: 381–442.
  28. Buck KJ, Amara SG. Chimeric dopamine-norepinephrine transporters delineate structural domains influencing selectivity for catecholamines and 1-methyl-4-phenylpyridinium. Proc Natl Acad Sci USA 1994; 91: 12584–8.[Abstract/Free Full Text]
  29. Giros B, Wang YM, Suter S, et al. Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J Biol Chem 1994; 269: 15985–8.[Abstract/Free Full Text]
  30. Buck KJ, Amara SG. Structural domains of catecholamine transporter chimeras involved in selective inhibition by antidepressants and psychomotor stimulants. Mol Pharmacol 1995; 48: 1030–7.[Abstract]
Accepted for publication May 17, 2000.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Uryu, K.
Right arrow Articles by Shigematsu, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Uryu, K.
Right arrow Articles by Shigematsu, A.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press