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Volatile anesthetics regulate pulmonary vascular tension through different potassium channel subtypes in isolated rabbit lungs

[Les anesthésiques volatils maintiennent la tension vasculaire pulmonaire par différents sous-types de canaux potassiques dans des poumons de lapins isolés]

Renyu Liu, MD PhD^*, Yuichi Ishibe, MD PhD^*, Naoto Okazaki, PhD^*, Mayumi Ueda, MD PhD and Juichi Hirosawa, MD^*

^* From the Department of Anaesthesiology and Reanimatology, Tottori University Faculty of Medicine, Tottori, Yonago, and
the Department of Anaesthesia, Toyooka Hospital, Toyooka, Hyogo, Japan.

Address correspondence to: Dr. Renyu Liu, Department of Anaesthesia, University of Pennsylvania, 3400 Spruce Street, 7th Dulles, Philadelphia, Pennsylvania 19104-4283, USA. E-mail: liu{at}mail.med.upenn.edu

	Abstract

TOP Abstract Introduction Materials and methods Results Discussion References

 
Background: The effects of volatile anesthetics on subtypes of K⁺ channels located on pulmonary vessels remain largely unexplored.

Methods: To investigate whether or not potassium channels play a role in the effect of volatile anesthetic on pulmonary vessels, isolated and perfused rabbit lungs were divided into four groups (n = 7 each): a control group without treatment, a glibenclamide (Glib) group treated with adenosine triphosphate-sensitive K⁺ (K_ATP) channel inhibitor, a 4-aminopyridine (4-AP) group treated with voltage-sensitive K⁺ (K_V) channel inhibitor, and an iberiotoxin (IbTX) group treated with high conductance calcium-activated K⁺ (K_Ca) channel inhibitor. After inhibitor administration and stabilization, two minimum alveolar concentration (MAC) of halothane, enflurane, isoflurane, or 1.8 MAC of sevoflurane were randomly administered for 15 min followed by eight minutes of fresh gas mixture after each agent inhalation.

Results: Isoflurane did not change pulmonary vascular tension in the control group but instead constricted the pulmonary vessels when K_V channels were inhibited with 4-AP; constrictive effects of enflurane and halothane were observed on pulmonary vessels, and were enhanced by K_V channel inhibition with 4-AP, but they were inhibited by K_Ca channel inhibition with IbTX; the dilation effect of sevoflurane was observed on pulmonary vessels but was not significantly affected by any of the K⁺ channel inhibitors.

Conclusion: Halothane, enflurane and isoflurane, but not sevoflurane, regulate pulmonary vascular tension through K_V and/or K_Ca channels in isolated rabbit lungs.

	Introduction

TOP Abstract Introduction Materials and methods Results Discussion References

 
VARIOUS subtypes of K⁺ channels are located on pulmonary vascular smooth muscle cells including voltage-dependent K⁺ (K_V) channels, adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channels and calcium-activated K⁺ (K_Ca) channels.¹ The effects of volatile anesthetics on K_V and K_Ca K⁺ channels located on pulmonary vessels remain largely unexplored. Some K⁺ channel inhibitors have already been used clinically² and the activity of K⁺ channels may change in certain pathophysiological conditions.³ Therefore, it becomes clinically relevant to investigate if volatile anesthetics affect pulmonary vessels through K⁺ channels. We have demonstrated previously that isoflurane (not sevoflurane) modulates pulmonary vascular response through K_V and K_Ca channels during hypoxia.⁴ In the present study, we hypothesized that different inhaled anesthetics may affect pulmonary tension differently in the presence or absence of potassium channel inhibitors under normoxic conditions. The hypothesis was tested in isolated perfused rabbit lungs.

	Materials and methods

TOP Abstract Introduction Materials and methods Results Discussion References

 
Isolated lung preparation
The experimental protocol was approved by the Tottori University Faculty of Medicine Laboratory Animal Care Committee. Twenty-eight female Japanese white rabbits (2.0–2.5 kg) were anesthetized with pentobarbital (20 mg•kg^-1, intravenously) and ketamine (30 mg•kg^-1, intramuscularly). The lungs were isolated and perfused as described previously.^4,5

Experimental protocol
Following commencement of perfusion and ten minutes for stabilization, the lungs were divided into four groups in random order (n = 7, each) according to the K⁺ channel subtype inhibitor added into the perfusate from the reservoir. In the control group, no channel inhibitor was added. In the glibenclamide (Glib) group, the perfusate contained 10 µM Glib, a highly selective K_ATP channel inhibitor. In the iberiotoxin (IbTX) group, the perfusate contained 45 nM of IbTX, a highly selective inhibitor of K_Ca channels. In the 4-aminopyridine (4-AP) group, the perfusate contained 1 mM of 4-AP, a K_V channel inhibitor. Twenty minutes elapsed for stabilization after inhibitor administration, then two minimum alveolar concentrations (MAC) of halothane (2.8%), sevoflurane (7.4%), isoflurane (4.0%), or 1.8 MAC enflurane (5.3%) were randomly administered for 15 min. The lungs were ventilated without volatile agent for eight minutes to wash out the anesthetic after each agent inhalation and to allow the pulmonary vascular tension to return to the pre-inhalation value. Halothane, enflurane, isoflurane, or sevoflurane was administered using an agent specific vaporizer and monitored with an anesthetic gas monitor.

The pulmonary vascular resistance (PVR) was determined before and after each inhibitor or anesthetic administration. Total PVR (Rt), pulmonary arterial resistance (Ra) and pulmonary venous resistance (Rv) were determined as described previously.⁴

Data are presented as mean ± SD. Within-group differences were analyzed using one-way analysis of variance (ANOVA) with repeated measures (Statview 4.5, Abacus Concepts, Berkeley, CA, USA). Pre- and post-agent administration comparison was performed with a t test. Multiple samples at the same time intervals were analyzed using one-way ANOVA. The differences in resistance among groups for each volatile anesthetic were analyzed with post hoc comparisons. Scheffe’s test was used for post hoc comparisons. A P < 0.05 was considered significant.

	Results

TOP Abstract Introduction Materials and methods Results Discussion References

 
Effects of K⁺ channel inhibitors on PVR (Figure 1)
There was no significant difference in PVR among groups before K⁺ channel inhibitor administration. PVR increased after 4-AP and IbTX administration, but did not change significantly after Glib administration.

View larger version (18K): [in this window] [in a new window]   FIGURE 1 Pulmonary vascular resistance (PVR) change before and after inhibitor administration. 4-AP = 4-aminopyridine; IbTX = iberitoxin; Glib = glibenclamide; before = before inhibitor administration; after = after inhibitor administration.

View larger version (23K): [in this window] [in a new window]   FIGURE 2 Total pulmonary vascular resistance (Rt) before and after anesthetic inhalation. See text for details. Data are mean ± SD. n = 7 per group. *P < 0.01 vs control group. Rt difference = resistance after anesthetic administration - (minus) resistance before anesthetic administration.

	Discussion

TOP Abstract Introduction Materials and methods Results Discussion References

The vasodilation of cerebral⁷ and mesenteric vessels⁸ induced by isoflurane and sevoflurane appears to be mediated via the activation of K_ATP channels. In the present study, however, the effect of volatile anesthetics on pulmonary vascular tension was not affected by K_ATP channel inhibition. It is therefore likely that volatile anesthetics did not affect basal vascular tension through K_ATP channels in the pulmonary vessels.

Although K_V channels in mesenteric vessels are not affected by isoflurane,⁸ 4-AP-sensitive K_V channels are suppressed reversibly by clinically relevant concentrations of halothane and isoflurane in canine coronary arteries.⁹ The results of the present study suggest that halothane, enflurane and isoflurane may regulate pulmonary vascular tension through K_V channels. Enflurane and halothane may inhibit K_V channels or strengthen the inhibitory effect of channel inhibitors.

Volatile anesthetics affect K_Ca channels in aortic endothelial cells¹⁰ and small mesenteric arteries.⁸ Our results suggest that halothane may also have significant effects on K_Ca channels in pulmonary vessels. Since the constrictive effect of halothane on pulmonary vessels was attenuated by IbTX, it is likely that halothane may activate K_Ca channels, and consequently hyperpolarize the membrane potential of smooth muscle cells.

In summary, pulmonary vascular effects vary between volatile anesthetics. Halothane constricted pulmonary vessels, and the constrictive effect was potentiated by K_V channel inhibition (4-AP), attenuated by K_Ca channel inhibition (IbTX), but not altered by K_ATP channel inhibition (Glib). Enflurane constricted pulmonary vessels, and the constrictive effect was potentiated by K_V channel inhibition, but not changed by K_Ca or K_ATP channel inhibition. Isoflurane, neither a vasoconstrictor nor dilator, constricted pulmonary vessels when K_V channels were inhibited with 4-AP. Sevoflurane dilated pulmonary vessels, and dilation was not influenced by any K⁺ channel subtype inhibitor in isolated rabbit lungs. The results suggest that halothane, enflurane, and isoflurane (but not sevoflurane) regulate pulmonary vascular tension through K_V and/or K_Ca channels in isolated rabbit lungs.

	Acknowledgments

 
The authors thank Jason Keller for English grammar editing assistance.

	Footnotes

 
Financial support: support was provided from institutional and department sources.

Revision received November 29, 2002. Accepted for publication August 20, 2002.

	References

TOP Abstract Introduction Materials and methods Results Discussion References

 
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