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ANESTHETIC PHARMACOLOGY

The Influence of Hemorrhagic Shock on the Minimum Alveolar Anesthetic Concentration of Isoflurane in a Swine Model

From the Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Address correspondence and reprint requests to Tadayoshi Kurita, MD, Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Address e-mail to tadkur{at}hama-med.ac.jp.

	Abstract

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BACKGROUND: Although hemorrhagic shock decreases the minimum alveolar concentration (MAC) of inhaled anesthetics, it minimally alters the electroencephalographic (EEG) effect. Hemorrhagic shock also induces the release of endorphins, which are naturally occurring opioids. We tested whether the release of such opioids might explain the decrease in MAC.

METHODS: Using the dew claw-clamp technique in 11 swine, we determined the isoflurane MAC before hemorrhage, after removal of 30% of the estimated blood volume (21 mL/kg of blood over 30 min), after fluid resuscitation using a volume of hydroxyethylstarch equivalent to the blood withdrawn, and after IV administration of 0.1 mg/kg of the µ-opioid antagonist naloxone.

RESULTS: Hemorrhagic shock decreased the isoflurane MAC from 2.05% ± 0.28% to 1.50% ± 0.51% (P = 0.0007). Fluid resuscitation did not reverse MAC (1.59% ± 0.53%), but additional administration of naloxone restored it to control levels (1.96% ± 0.26%). The MAC values decreased depending on the severity of the shock, but the alterations in hemodynamic variables and metabolic changes accompanying fluid resuscitation or naloxone administration did not explain the changes in MAC.

CONCLUSIONS: Consistent with previous reports, we found that hemorrhagic shock decreases MAC. In addition, we found that naloxone administration reversed the effect on MAC, and we propose that activation of the endogenous opioid system accounts for the decrease in MAC during hemorrhagic shock. Such an activation would not be expected to materially alter the EEG, an expectation consistent with our previous finding that hemorrhagic shock minimally alters the EEG.

	Introduction

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Hemorrhagic shock increases the effect of several classes of IV anesthetics because of pharmacokinetic and pharmacodynamic changes (1–5), and such changes sometimes complicate the management of patients who have significant blood loss before or during surgery (6). We previously examined the influence of hemorrhagic shock on the electrolencephalogram (EEG) effect of isoflurane using a stepwise hemorrhagic model in swine, and concluded that hemorrhage, even at a level at which hemorrhagic shock progresses to a decompensated state, minimally alters the EEG effect of isoflurane (7,8). These results suggest that the use of an inhaled anesthetic, rather than an IV anesthetic, may allow for easier control of the hypnotic state in patients who have significant perioperative blood loss. However, the EEG only reflects the influence of hemorrhagic shock on hypnosis, not on immobility in response to noxious stimuli, which is also of importance for the definition of the potency of an inhaled anesthetic. The motor response to a noxious stimulus may be mediated primarily by subcortical structures, especially those in the spinal cord (9–11), and EEG parameters do not directly reflect the activity of these structures. In fact, it has been demonstrated that hemorrhagic shock decreases the minimum alveolar concentration (MAC) of inhaled anesthetics (12,13), in contrast to our previous finding that hemorrhagic shock minimally alters the EEG.

We conducted the present study to clarify the influence of hemorrhagic shock on the MAC and to examine the associated mechanism, using a study protocol similar to that in our previous investigations into the influence of hemorrhagic shock on the hypnotic effect of isoflurane, because this allowed a comparison of differences between hypnotic and antinociceptive effects. First, MAC was assessed in a swine model in the hemorrhagic shock state to determine if MAC would decrease, as shown in previous reports (12,13). Subsequently, MAC was determined again after hydroxyethylstarch infusion to determine if an improvement in hemodynamics reversed the change in MAC. Finally, naloxone (a µ-opioid antagonist) was injected IV and MAC was assessed to determine if the induced changes could be reversed. Our rationale for testing the effect of naloxone was based on the demonstration by Molina that endogenous opioid activation during hemorrhagic shock produces analgesia in conscious and unrestrained rats, as measured using the tail-flick response to a noxious stimulus, and that this analgesia is not observed in hemorrhagic shock animals pretreated with naltrexone (a µ-opioid antagonist) (14). Therefore, we hypothesized that hemorrhagic shock would decrease the MAC of isoflurane, and fluid resuscitation would not reverse this change, but that additional administration of naloxone would restore MAC close to the baseline value.

	METHODS

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Animal Preparation
This study was approved by the Committee on Animal Research, Hamamatsu University School of Medicine, Hamamatsu, Japan. Eleven pigs (body-weight range: 23.1–40.7 kg, mean ± sd = 30.6 ± 5.7 kg) were used in the study. General anesthesia was induced by isoflurane inhalation (5%) in oxygen at 6 L/min using a standard animal mask. After tracheostomy, the lungs of the pigs were mechanically ventilated and anesthesia was maintained with a 2% end-tidal concentration of isoflurane in an oxygen–air mixture (oxygen:air = 3 L/min:3 L/min). The tidal volume was initially set to approximately 10 mL/kg and the ventilation rate 25 breaths per min. Expiratory gases were analyzed using a Capnomac Ultima (ULT-V-31-04, Datex-Ohmeda, Helsinki, Finland) throughout the study. The ventilator was adjusted to keep the end-tidal carbon dioxide between 35 mm Hg and 45 mm Hg during the preparation period, and this setting was maintained throughout the study. Lead II of an electrocardiogram was monitored using three cutaneous electrodes. A pulmonary artery catheter (5F, 4 lumen, Nihon Kohden, Tokyo, Japan) and a central venous catheter (16-gauge) were inserted via the right jugular vein, and another catheter (16-gauge) was placed in the right femoral artery. The blood temperature of the pigs was maintained between 39.0°C and 40.0°C.

Experimental Protocol
Baseline measurements were taken 30 min after completion of animal preparation and then MAC was assessed, beginning at 2% end-tidal concentration (baseline conditions). After determination of MAC under baseline conditions and return of the end-tidal isoflurane concentration to 2%, hemorrhagic shock was induced by removing 30% of the initial blood volume (the total volume was assumed to be 70 mL/kg) from the femoral artery over 30 min. After a further period of 30 min, and after confirming hemodynamic stability, MAC (30% bleeding conditions) was again assessed. After determination of MAC under 30% bleeding conditions and return of the end-tidal isoflurane concentration to 2%, a volume of hydroxyethylstarch (6% hydroxyethylstarch, with a mean molecular weight of 70,000 and a degree of substitution of 0.5–0.55) equivalent to the blood withdrawn was administered via the central venous catheter over 30 min. After a further 30 min, MAC was assessed again (30% bleeding + fluid infusion conditions). After determination of MAC under these conditions and return of the end-tidal isoflurane concentration to 2%, 0.1 mg/kg of naloxone was administered via the central venous catheter. Pilot studies were performed to determine the appropriate dose of naloxone. After a 30-min stabilization period, MAC was again assessed (30% bleeding + fluid infusion + naloxone conditions). Hematocrit, lactate, and arterial blood gases were measured and heart rate (HR), mean arterial blood pressure (MAP), central venous pressure (CVP), and cardiac output (CO) were recorded at 2% end-tidal isoflurane concentration under all conditions. CO was determined with a thermodilution computer (Cardiac Output Computer, MTC6210, Nihon Kohden) using 5 mL cold 5% glucose injected into the right atrium. For each condition, CO measurements were made four times and the mean of the last three values was recorded as the CO.

Determination of MAC
MAC was assessed under each of the four conditions in each pig, starting from a 2% end-tidal concentration of isoflurane. The starting value was determined with reference to the MAC value reported by Eger et al. (15). A supramaximal pain stimulus was created by application of a clamp to the dew claw for 60 s, and the presence or absence of a withdrawal reaction during the 60-s period was recorded. A positive reaction was defined as either a withdrawal of the clamped foot or as a gross movement of another leg or the head. If a positive response occurred, the end-tidal concentration was increased by 0.2%. In exceptional cases in which a positive response occurred but hemodynamic changes were minimal, the end-tidal concentration was increased by 0.1%. After another equilibration period of 20 min, a second noxious stimulus was applied and this protocol was repeated until no motor reaction occurred. If no motor response was elicited by the noxious stimulus, the end-tidal concentration was decreased by 0.2%. In exceptional cases in which no motor response was elicited, but hemodynamic changes were large, the end-tidal concentration was decreased by 0.1%, and the protocol was repeated until a movement response occurred. The study protocol was considered complete after a change in movement response from positive to negative or vice versa. MAC was calculated as the average of the highest isoflurane concentration at which movement occurred and the lowest concentration at which movement was suppressed.

Statistical Analysis
Data are expressed as mean values ± sd. Hematocrit, lactate, arterial blood gas analysis, HR, MAP, CVP, CO, and MAC for each state were analyzed using a repeated-measures one-way analysis of variance (ANOVA). If the ANOVA indicated significance, Scheffé F-test for multiple comparisons was performed. P values <0.05 were considered to be statistically significant.

	RESULTS

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Averaged metabolic and hemodynamic variables for each state are shown in Table 1. After removing 30% of the initial blood volume, base excess decreased and lactate increased, and both values significantly changed after fluid infusion because of temporary washout after peripheral hypoperfusion. Hematocrit increased after 30% bleeding and decreased after fluid infusion. Hemorrhage increased HR and decreased CVP and CO, but there was no significant change in MAP. Fluid infusion partially reversed the increase in HR and the decrease in CVP, and increased CO to more than the value observed under baseline conditions. This volume-expanding effect was attenuated after naloxone administration.

Hemorrhage decreased MAC to various extents in all except one animal. These values are shown for each condition in Figure 1. The mean MAC value after 30% bleeding differed significantly from those at baseline (P = 0.0007) and after 30% bleeding + fluid infusion + naloxone (P = 0.0043), and the mean MAC value after 30% bleeding + fluid infusion was also significantly different from those at baseline (P = 0.0043) and after 30% bleeding + fluid infusion + naloxone (P = 0.0235). MAC values decreased significantly after 30% bleeding and did not reverse after fluid infusion; however, administration of 0.1 mg/kg naloxone reversed the decrease in MAC, independently of the extent of the decrease.

View larger version (18K): [in this window] [in a new window]   Figure 1. Minimum alveolar anesthetic concentration (MAC) of isoflurane under different conditions. *Significant difference versus baseline and 30% bleeding + fluid infusion + naloxone.

The severity of hemorrhagic shock after 30% bleeding influenced the extent of the decrease in MAC. The percentage decrease in MAC (100 x [MAC at baseline – MAC after 30% bleeding]/MAC at baseline) significantly correlated with the percentage decrease in CO (100 x [CO at baseline – CO after 30% bleeding]/CO at baseline) (P < 0.0001, r² = 0.824), and linear regression gave the following relationship: (percentage decrease in MAC) = 0.806 x (percentage decrease in CO). The percentage decrease in MAC also correlated significantly with the percentage increase in lactate (100 x [lactate after 30% bleeding – lactate at baseline]/lactate at baseline) (P = 0.0004, r² = 0.736), and linear regression gave the following relationship: (percentage decrease in MAC) = 0.247 x (percentage increase in lactate). Although the MAC values decreased depending on the severity of the shock, alterations in hemodynamic variables and metabolic changes accompanying fluid resuscitation or naloxone administration did not explain the changes in MAC.

	DISCUSSION

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We investigated the influence of hemorrhagic shock, subsequent fluid resuscitation, and additional administration of naloxone on the MAC of isoflurane. Although there were some differences among animals, our results indicate that hemorrhage, to a level of 30% of the initial blood volume, decreases the MAC of isoflurane in most animals, consistent with previous reports (12,13). This is in contrast to results obtained in our previous studies in which hemorrhagic shock minimally altered the EEG effect of isoflurane, even in a decompensated state (7,8). The clinical implication of our results is that hemorrhagic shock increases the threshold for movement in response to noxious stimuli and that it is straightforward to obtain immobility using inhaled anesthetics; however, hypnotic potency does not alter in a comparable manner, suggesting that the concentration of an inhaled anesthetic should be decreased with care in patients with hemorrhagic shock during maintenance of hemodynamic stability.

CO decreased by approximately 35% after 30% bleeding, but MAP did not decrease significantly. We observed compensatory increases of systemic vascular resistance and HR after 30% bleeding, as in our previous studies (7,16). Hence, hemorrhagic shock induced by 30% bleeding was considered to be a compensated state. However, because the degrees of hemodynamic and metabolic changes varied among animals (Table 1), the severity of hemorrhagic shock in response to 30% bleeding was apparently variable. The percentage decrease in MAC significantly correlated with the percentage decrease in CO and with the percentage increase in lactate. MAC decreased by <5% in two animals after 30% bleeding (including one pig in which MAC did not change), and these two animals did not show an increase in lactate throughout the study. Therefore, our results indicate that, even under conditions of compensated hemorrhagic shock, alteration of the MAC of isoflurane depends on the severity of the shock. Previous reports have demonstrated that hypotension (MAP decreased more than 50%) induced by several hypotensive drugs (17) or trimethaphan in combination with hemorrhage and a head-up tilt (12) decrease MAC; however, our results indicate that a hemorrhage-induced decrease in MAC is not necessarily accompanied by marked hypotension.

Hydroxyethylstarch infusion equivalent to the volume of withdrawn blood increased CO more than observed under baseline conditions, and partially reversed the increase in HR and the decrease in CVP caused by hemorrhagic shock (Table 1). However, fluid resuscitation did not reverse the decrease in MAC. This is consistent with our previous report, in which we showed that a slight increase in the hypnotic effect of isoflurane induced by decompensated hemorrhagic shock (withdrawal of 40% of the blood volume) cannot be reversed by fluid resuscitation (8), although the alteration of the hypnotic effect is minimal. Therefore, at least over a relatively short duration, fluid resuscitation does not reverse the increase in potency of isoflurane for production of hypnosis and immobility. Cullen and Eger (18) have shown that MAC of halothane remains normal in acute isovolemic anemia in dogs, despite reduction of hematocrit to 10%. In their study, isovolemic anemia was induced by stepwise hemorrhage and an equal volume of dextran infusion to keep the decrease in MAP within 10%; CO increased by approximately 53%, but pH and base excess did not change significantly throughout the study. Therefore, fluid infusion before the appearance of tissue hypoxia and acidosis due to hemorrhage might be effective in preventing a decrease in MAC.

Administration of naloxone after fluid resuscitation reversed the decrease in MAC, but did not reverse the metabolic changes. Although shock-induced metabolic changes might mediate activation of endogenous opioid pathways, the effect of naloxone suggests that the decrease in MAC during hemorrhagic shock is not directly caused by metabolic changes but by activation of endogenous opioid pathways. In fact several studies have reported that naloxone has no effect on the MAC of inhaled anesthetics under normal conditions (19–22). To our knowledge, this is the first report showing that opioid receptors mediate a portion of the decrease in MAC. Hemorrhagic shock produces immediate activation of the autonomic nervous system and endogenous opioid pathways (23–25). In an isobaric hemorrhagic model in rats, Molina (25) has demonstrated that hemorrhage increases the plasma levels of corticosterone (30%), adrenocorticotrophic hormone (three-fold), β-endorphin (four-fold), and epinephrine and norepinephrine (20–50-fold). Furthermore, in conscious and unrestrained rats, endogenous opioid activation during hemorrhagic shock produces analgesia, as measured using the tail-flick response to a noxious stimulus, and this analgesia is not observed in hemorrhagic shock animals pretreated with naltrexone (a µ-opioid antagonist) (14). These findings are consistent with the results of the present study. In our previous studies, we have demonstrated that 30% bleeding does not alter the EEG effect of isoflurane, but 40% bleeding (decompensated hemorrhagic state) slightly alters this effect, causing an approximately 12% decrease in effect-site concentration that produces 50% of the maximal spectral edge effect (7,8). Taken together with the present findings, it appears that endogenous opioids induced by hemorrhagic shock may contribute to these pharmacodynamic changes. Evaluation of these changes using an EEG suggests a minimal alteration in anesthetic potency; however, evaluation of the pharmacodynamic effect using movement in response to a noxious stimulus suggests a larger effect, because this method is more sensitive to opioid-related events. In fact, MAC and MAC-bar (minimum alveolar concentration to block adrenergic response to surgical incision in 50% patients) are decreased markedly compared to MAC-awake (minimum alveolar concentration to prevent response to a verbal command in 50% of patients) in the presence of opioids, and the mechanisms underlying the decreases in these values are not comparable (26). Although we did not measure the plasma concentration of β-endorphin in the present study, we speculate that this level would differ depending on the severity of hemorrhagic shock, leading to different decreases in MAC. Molina (27) has demonstrated in animals that a marked increase of the plasma β- endorphin level occurs after soft tissue trauma and lipopolysaccharide administration, similarly to the effects of hemorrhage; therefore we speculate that alteration of MAC values might be observed under several different stress conditions.

Several limitations of the present study need to be addressed. Although the study was performed using withdrawal of an exact amount of blood, according to our series of previous studies (7,8,16), animals varied in their degree of metabolic compromise or compensation capacity in response to hemorrhagic shock. Hence, use of an isobaric hemorrhage model (4,14) might have been more appropriate to obtain an equivalent degree of metabolic compromise among animals; under these conditions, a clearer and more consistent decrease in MAC might have been observed at the same shock level. In addition, the time-dependence of the observed changes in MAC was not investigated, and it is possible that the duration of the hemorrhagic shock state and/or the period after fluid resuscitation might have influenced MAC. Furthermore, a time-control study of MAC in the absence of hemorrhage was not performed, and it is possible that repetitive noxious stimuli during MAC assessment might have influenced subsequent determinations of MAC. Finally, because naloxone was administered after fluid infusion, the reversal in MAC might not have been solely due to the effect of naloxone. The interpretation of the data would be more reliable if a naloxone group without fluid infusion after 30% bleeding had been included.

In summary, hemorrhagic shock decreased the MAC of isoflurane depending on the severity of the shock. Subsequent fluid resuscitation did not reverse the decrease in MAC, but additional administration of a µ-opioid antagonist reversed the change in MAC. Our results suggest that activation of the endogenous opioid system explains the decrease in MAC during hemorrhagic shock, and further indicate that alterations in anesthetic potency in response to hemorrhage differ at anesthetic sites of action for production of hypnosis and immobility.

	Footnotes

 
Accepted for publication July 24, 2007.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. De Paepe P, Belpaire FM, Rosseel MT, Buylaert WA. The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat. Fundam Clin Pharmacol 1998;12:624–30[Web of Science][Medline]
2. Johnson KB, Kern SE, Hamber EA, McJames SW, Kohnstamm KM, Egan TD. Influence of hemorrhagic shock on remifentanil: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 2001;94:322–32[Web of Science][Medline]
3. De Paepe P, Belpaire FM, Van Hoey G, Boon PA, Buylaert WA. Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of etomidate in the rat. J Pharmacol Exp Ther 1999;290:1048–53[Abstract/Free Full Text]
4. Johnson KB, Egan TD, Kern SE, McJames SW, Cluff ML, Pace NL. Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology 2004;101:647–59[Web of Science][Medline]
5. Weiskopf RB, Bogertz MS. Haemorrhage decreases the anaesthetic requirement for ketamine and thiopentone in the pig. Br J Anaesh 1985;57:1022–5
6. Shafer SL. Shock values. Anesthesiology 2004;101:567–8[Web of Science][Medline]
7. Kurita T, Morita K, Fukuda K, Uraoka M, Takata K, Sanjo Y, Sato S. Influence of hypovolemia on the electroencephalographic effect of isoflurane in a swine model. Anesthesiology 2005;102:948–53[Web of Science][Medline]
8. Kurita T, Morita K, Fukuda K, Uraoka M, Takata K, Sanjo Y, Sato S. Influence of hemorrhagic shock and subsequent fluid resuscitation on the electroencephalographic effect of isoflurane in a swine model. Anesthesiology 2005;103:1189–94[Web of Science][Medline]
9. Rampil IJ, Mason P, Singh H. Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology 1993;78:707–12[Web of Science][Medline]
10. Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993;79:1244–9[Web of Science][Medline]
11. Borges M, Antognini JF. Does the brain influence somatic responses to noxious stimuli during isoflurane anesthesia? Anesthesiology 1994;81:1511–5[Web of Science][Medline]
12. Tanifuji Y, Eger EI II. Effect of arterial hypotension on anaesthetic requirement in dogs. Br J Anaesth 1976;48:947–52[Abstract/Free Full Text]
13. Mattson SF, Kerr CL, Dyson DH, Mirakhur KK. The effect of hypovolemia due to hemorrhage on the minimum alveolar concentration of isoflurane in the dog. Vet Anaesth Analg 2006;33:296–301[Web of Science][Medline]
14. Molina P. Endogenous opioid analgesia in hemorrhagic shock. J Trauma 2003;54:S126–32[Web of Science][Medline]
15. Eger EI II, Johnson BH, Weiskopf RB, Holmes MA, Yasuda N, Targ A, Rampil IJ. Minimum alveolar concentration of I-653 and isoflurane in pigs: definition of a supramaximal stimulus. Anesth Analg 1988;67:1174–6[Abstract/Free Full Text]
16. Kazama T, Kurita T, Morita K, Nakata J, Sato S. Influence of hemorrhage on propofol pseudo-steady state concentration. Anesthesiology 2002;97:1156–61[Web of Science][Medline]
17. Rao TL, Jacobs K, Salem MR, Santos P. Deliberate hypotension and anesthetic requirement of halothane. Anesth Analg 1981;60:513–6[Abstract/Free Full Text]
18. Cullen DJ, Eger EI II. The effects of hypoxia and isovolemic anemia on the halothane requirement (MAC) of dogs. III. The effects of acute isovolemic anemia. Anesthesiology 1970;32:46–50[Web of Science][Medline]
19. Harper MH, Winter PM, Johnson BH, Eger EI II. Naloxone does not antagonize general anesthesia in the rat. Anesthesiology 1978;49:3–5[Web of Science][Medline]
20. Pace NL, Wong KC. Failure of naloxone and naltrexone to antagonize halothane anesthesia in the dog. Anesth Analg 1979;58:36–9[Abstract/Free Full Text]
21. Levine LL, Winter PM, Nemoto EM, Uram M, Lin MR. Naloxone does not antagonize the analgesic effects of inhalational anesthetics. Anesth Analg 1986;65:330–2[Abstract/Free Full Text]
22. Liao M, Laster MJ, Eger EI II, Tang M, Sonner JM. Naloxone does not increase the minimum alveolar anesthetic concentration of sevoflurane in mice. Anesth Analg 2006;102:1452–5[Abstract/Free Full Text]
23. McIntosh TK, Palter M, Grasberger R, Vezina R, Gerstein L, Yeston N, Egdahl RH. Endorphins in primate hemorrhagic shock: beneficial action of opiate antagonists. J Surg Res 1986;40:265–75[Web of Science][Medline]
24. Tuggle D, Horton J. beta-Endorphin in canine hemorrhagic shock. Surg Gynecol Obstet 1986;163:137–44[Web of Science][Medline]
25. Molina P. Opiate modulation of hemodynamic, hormonal, and cytokine response to hemorrhage. Shock 2001;15:471–8[Web of Science][Medline]
26. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998;88:18–24[Web of Science][Medline]
27. Molina P. Stress-specific opioid modulation of haemodynamic counter-regulation. Clin Exp Pharmacol Physiol 2002;29:248–53[Web of Science][Medline]

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