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CARDIOVASCULAR ANESTHESIA

The Role of K⁺ Channels in Vasorelaxation Induced by Hypoxia and the Modulator Effects of Lidocaine in the Rat Carotid Artery

Hiroyuki Kinoshita, MD PhD^*, Yoshiki Kimoto, MD, Katsutoshi Nakahata, MD^*, Hiroshi Iranami, MD^*, Mayuko Dojo, MD, and Yoshio Hatano, MD, PhD

*Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, and Department of Anesthesiology, Wakayama Medical University, Japan

Address correspondence and reprint requests to Hiroyuki Kinoshita, MD, PhD, Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, 4-20 Komatsubara-dori, Wakayama, Wakayama 640-8269, Japan. Address e-mail to hkinoshi{at}pd5.so-net.ne.jp

	Abstract

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Hypoxia induces vasodilation, partly via the activation of K⁺ channels. Lidocaine impairs vasorelaxation mediated by a K⁺ channel opener, suggesting that this antiarrhythmic drug may inhibit hypoxia-induced vasodilation mediated by K⁺ channels. We designed the current study to determine whether, in the carotid artery, K⁺ channels contribute to vasorelaxation in response to hypoxia and whether lidocaine modulates vasorelaxation induced by K⁺ channels via pathophysiological and pharmacological stimuli. Rings of rat common carotid artery without endothelium were suspended for isometric force recording. During contraction to phenylephrine, hypoxia-induced vasorelaxation or concentration-response to an adenosine triphosphate-sensitive K⁺ channel opener was obtained changing control gas to hypoxic gas and the cumulative addition of levcromakalim, respectively. Hypoxia-induced vasorelaxation was significantly reduced by glibenclamide (5 µM) but not by iberiotoxin (0.1 µM), apamin (0.1 µM), BaCl₂ (10 µM), or 4-aminopyridine (1 mM). Levcromakalim-induced vasorelaxation was completely abolished by glibenclamide. Lidocaine (10–100 µM) concentration-dependently inhibited this vasodilation, whereas it did not affect hypoxia-induced vasodilation. These results suggest that adenosine triphosphate-sensitive K⁺ channels play a role in hypoxia-induced vasodilation in the rat carotid artery and that lidocaine differentially modulates vasodilation via these channels activated by pathophysiological and pharmacological stimuli.

IMPLICATIONS: In rat carotid artery, levcromakalim produced vasorelaxation mediated by adenosine triphosphate (ATP)-sensitive K⁺ channels, whereas hypoxia induced it partly via these channels. Lidocaine inhibited vasorelaxation induced by an ATP-sensitive K⁺ channel opener but not by hypoxia, indicating the differential mechanisms of modulatory effects of this antiarrhythmic drug on vasodilation via ATP-sensitive K⁺ channels activated by pathophysiological and pharmacological stimuli.

	Introduction

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Adenosine triphosphate (ATP)-sensitive K⁺ channels mediate vasodilation induced by a number of pharmacological and pathophysiological stimuli, suggesting that these channels are crucial in the regulation of cerebral circulation (1,2). Indeed, studies have demonstrated that ATP-sensitive K⁺ channel openers are capable of augmenting cerebral blood flow or cerebral vasodilation (3). Hypoxia reportedly induces vasodilation partly via the activation of ATP-sensitive K⁺ channels in vascular smooth muscle cells, resulting in increased cerebral blood flow (4,5). The carotid artery supplies cerebral blood flow from the systemic circulation, suggesting that this artery can participate as an important regulator of cerebral circulation. However, the involvement of K⁺ channels in vasodilator effects of hypoxia has not been well studied in this artery.

Previous studies have shown that pretreatment with one of the Class Ib antiarrhythmic drugs lidocaine can reduce cerebral infarct sizes after cerebral ischemia, indicating that this drug may protect neuronal tissues by preserving cerebral blood flow (6). However, this beneficial effect of lidocaine has long been controversial because in some studies it failed to ameliorate global ischemic brain damage (7). We have reported that in the rat aorta, lidocaine impairs vasorelaxation induced by an ATP-sensitive K⁺ channel opener (8). These results suggest that, in the carotid artery, lidocaine may impair vasodilator response via the activation of ATP-sensitive K⁺ channels, which is capable of augmenting cerebral blood flow.

Therefore, we designed the present study to determine whether, in the carotid artery, K⁺ channels play a role in vasorelaxation in response to hypoxia and whether lidocaine modulates vasorelaxation induced by K⁺ channels via pathophysiological and pharmacological stimuli.

	Methods

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Our institutional animal care and use committee approved this study. The experiments were performed on 3-mm common carotid arterial rings obtained from male Wistar rats (300–400 g), with inhaled 3% halothane in 100% oxygen (3 L/min). Rings were studied in modified Krebs-Ringer bicarbonate solution (control solution) of the following composition (mM): NaCl 119, KCl 4.7, CaCl₂ 2.5, MgSO₄ 1.17, KH₂PO₄ 1.18, NaHCO₃ 25, and glucose 11. Our previous study demonstrated that vasorelaxation in response to an ATP-sensitive K⁺ channel opener is augmented in the presence of functional endothelium (9). In addition, in the isolated carotid artery, hypoxia to a similar degree used in the present study reportedly produces vasorelaxation in the endothelium-independent fashion (5). Therefore, the endothelium in all rings was removed mechanically. The endothelial removal was confirmed by the absence of relaxation to acetylcholine (10 µM). Several rings cut from the same artery were studied in parallel. Each ring was connected to an isometric force transducer and suspended in an organ chamber filled with 10 mL of control the solution (37°C; pH 7.4) bubbled with 95% O₂–5% CO₂ gas mixture. The artery was gradually stretched to the optimal point of its length-tension curve as determined by the contraction to phenylephrine (0.3 µM). In most of the studied arteries, optimal tension was achieved approximately at 1.0 g. Preparations were equilibrated for 90 min. During submaximal contraction to phenylephrine (0.3 µM), hypoxia-induced vasorelaxation or concentration-response to an ATP-sensitive K⁺ channel opener was obtained by changing the control gas (95% O₂ and 5% CO₂) to hypoxic gas (95% N₂ and 5% CO₂) (Table 1) and the cumulative addition of levcromakalim (0.01–3 µM), respectively. The vasorelaxation was studied in the absence or in the presence of lidocaine (10–100 µM) or K⁺ channel antagonists of large conductance Ca²⁺-dependent (iberiotoxin; 0.1 µM), small conductance Ca²⁺-dependent (apamin; 0.1 µM), inward rectifier (BaCl₂; 10 µM), delayed rectifier (4-aminopyridine; 1 mM), and ATP-sensitive (glibenclamide; 5 µM). Concentration-response curves were obtained in a cumulative fashion. Only one concentration-response curve was made from each ring. Lidocaine, iberiotoxin, apamin, BaCl₂, 4-aminopyridine, or glibenclamide was given 15 min before the addition of phenylephrine. The relaxation was expressed as a percentage of the maximal relaxation in response to papaverine (300 µM), which was added at the end of experiments to produce maximal relaxation (=100%) of the artery.

The data are expressed as mean ± SD; n refers to the number of rats from which the artery was taken. Statistical analysis was performed using repeated-measures of analysis of variance followed by Scheffe’s F test for multiple comparisons. Differences were considered to be significant when P < 0.05.

	Results

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During submaximal contraction in response to phenylephrine (0.3 µM), hypoxia produced initial peak vasorelaxation of the common carotid artery without endothelium, followed by plateau relaxation. The peak or plateau vasorelaxation was reached approximately 15 and 60 min after the beginning of hypoxia, respectively. Both components of vasorelaxation were significantly reduced by a selective ATP-sensitive K⁺ channel antagonist glibenclamide (5 µM) but not by K⁺ channel antagonists of large conductance Ca²⁺-dependent (iberiotoxin; 0.1 µM), small conductance Ca²⁺-dependent (apamin; 0.1 µM), inward rectifier (BaCl₂; 10 µM), or delayed rectifier (4-aminopyridine; 1 mM) (Fig. 1).

View larger version (36K): [in this window] [in a new window]   Figure 1. Hypoxia-induced vasorelaxation in the absence and in the presence of K+ channel antagonists of large conductance Ca2+-dependent (iberiotoxin; 0.1 µM), small conductance Ca2+-dependent (apamin; 0.1 µM), inward rectifier (BaCl2; 10 µM), delayed rectifier (4-aminopyridine; 1 mM), and adenosine triphosphate (ATP)-sensitive (glibenclamide; 5 µM) obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (300 µM; 100% = 1006 ± 298 mg [n = 7], 1063 ± 189 mg [n = 7], and 983 ± 234 mg [n = 7] for control rings and rings treated with glibenclamide or BaCl2 and 100% = 973 ± 313 mg [n = 6], 1060 ± 226 mg [n = 6], 893 ± 332 mg [n = 6], and 953 ± 218 mg [n = 6] for control rings and rings treated with iberiotoxin, apamin, or 4-aminopyridine, respectively). *Difference between rings treated with glibenclamide and control rings was significant (P < 0.05).

View larger version (17K): [in this window] [in a new window]   Figure 2. Concentration-response curves to levcromakalim in the absence or in the presence of glibenclamide (5 µM) obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (300 µM; 100% = 1060 ± 219 mg [n = 6] and 1000 ± 255 mg [n = 6] for control rings and rings treated with glibenclamide, respectively). *Difference between control rings and rings treated with glibenclamide was significant (P < 0.05).

View larger version (22K): [in this window] [in a new window]   Figure 3. Concentration-response curves to levcromakalim in the absence or in the presence of lidocaine (10, 30, and 100 µM) obtained in the rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (300 µM; 100% = 1008 ± 173 mg [n = 5], 872 ± 254 mg [n = 5], 880 ± 240 mg [n = 5], and 1024 ± 269 mg [n = 5] for control rings and rings treated with lidocaine [10 µM], lidocaine [30 µM], or lidocaine [100 µM], respectively). *Difference between control rings and rings treated with lidocaine was significant (P < 0.05).

View larger version (18K): [in this window] [in a new window]   Figure 4. Hypoxia-induced vasorelaxation in the absence and in the presence of lidocaine (100 µM) obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (300 µM; 100% = 612 ± 145 mg [n = 5] and 632 ± 158 mg [n = 5] for control rings and rings treated with lidocaine, respectively).

	Discussion

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In the present study, hypoxia produced vasorelaxation, which is partly reduced by glibenclamide but not by iberiotoxin, apamin, BaCl₂, or 4-aminopyridine. These results suggest that ATP-sensitive K⁺ channels (11), but not inward rectifier (12), delayed rectifier (13), large-conductance Ca²⁺-dependent (14), or small-conductance Ca²⁺-dependent K⁺ channels (15), mediate vasodilator response produced by hypoxia in the carotid artery. In the present study, glibenclamide completely abolished relaxation in response to a selective ATP-sensitive K⁺ channel opener levcromakalim, indicating the selectivity of this compound on ATP-sensitive K⁺ channels (10,11). ATP-sensitive K⁺ channels should be inhibited by intracellular ATP, and the decrease of intracellular levels of ATP will be expected in hypoxia (16). Therefore, these results support the conclusion that hypoxia induces decreased levels of intracellular ATP, leading to the opening of ATP-sensitive K⁺ channels, and this, in turn, can mediate vasorelaxation via hyperpolarization of vascular smooth muscle cells.

One study has demonstrated that in the rabbit carotid artery, most components of hypoxic vasodilation seem to be mediated by means other than the activation of ATP-sensitive K⁺ channels (5). Therefore, we hypothesized that in the rat carotid artery, K⁺ channels other than ATP-sensitive channels may play a role in the vasodilator effect of hypoxia. However, in contrast to our expectation, the role of K⁺ channels in hypoxia-induced vasorelaxation in the rat carotid artery is likely to be rather limited, and the ATP-sensitive K⁺ channel is solely involved in this vasorelaxation. As previous studies have already suggested, the K⁺ channel-unrelated mechanisms of vasodilation produced by hypoxia, including reduced activity of Ca²⁺ channels and impaired electromechanical coupling in the vascular smooth muscle cells, probably mediate the vasodilator effect of hypoxia (17).

Prolonged hypoxia produced initial peak vasorelaxation of the common carotid artery followed by plateau relaxation, and the peak or plateau vasorelaxation was reached approximately 15 and 60 minutes after the beginning of hypoxia, respectively. Because this is the first study demonstrating biphasic vasodilator response to prolonged hypoxia, we do not have a clear explanation of the mechanisms for these components of relaxation. Indeed, most previous studies have only shown the relatively early phase of hypoxic vasodilator response such as a 15-minute exposure of hypoxia (5,18). In the present study, both components of vasorelaxation were similarly inhibited by glibenclamide, indicating that the ATP-sensitive K⁺ channel-involved components were constantly present during the whole period in which we studied the hypoxic vasodilator response. Therefore, the biphasic time course of vasorelaxation induced by prolonged hypoxia is most likely mediated by mechanisms other than the activation of ATP-sensitive K⁺ channels, including changes of intracellular Ca²⁺ levels and electromechanical coupling (17). In the preliminary study, we found that the levels of oxygen tension in the Krebs-Ringer solution are not differ between those at 15 minutes and 60 minutes after the beginning of hypoxia (Kimoto et al., unpublished observation, 2001). This, in turn, suggests that these biphasic components of vasorelaxation induced by prolonged hypoxia are unlikely to be caused by changes of oxygen tension in the perfused solution induced by the prolonged exposure to hypoxic gas.

A previous study on the rabbit demonstrated that the high arterial oxygen tension (PaO₂) more than 500 mm Hg produces an increase in coronary perfusion pressure, indicating that such high oxygen tension itself may induce vasoconstriction of the coronary artery (19). However, this effect of high oxygen tension was abolished by the removal of functional endothelium; therefore, the vasoconstrictor effect of oxygen seems to be completely endothelium-dependent (19). Because, in the present study, the endothelium in all of the rings was removed, it is unlikely that our results regarding the vasodilator effects of hypoxia were modified by the higher oxygen tension seen in the control solution. This conclusion is further supported by a previous study on the carotid artery that hypoxia to a similar degree used in the present study produces vasorelaxation in an endothelium-independent fashion (5).

The threshold for hypoxic cerebral vasodilation in humans is reportedly at a PaO₂ of 60 mm Hg, suggesting that the mild hypoxia (PO₂ of 52 mm Hg) used in the current study is capable of producing an increase in human cerebral blood flow (20). In addition, a dramatic decrease in PaO₂ from 500 to 50 mm Hg seems to be possible in patients with difficulty in tracheal intubation during the induction of anesthesia and those undergoing one-lung ventilation during thoracic surgery (21,22). These results support the idea that mild hypoxia as well as the changes of a partial oxygen tension in the Krebs-Ringer solution in our study may have clinical relevancy regarding the increase in human cerebral blood flow induced by hypoxia during anesthesia.

Previous studies documented that the common carotid artery has more activity of K⁺ channels than large conduit arteries like the aorta, especially in arteries from animals with chronic hypertension (23) (Kinoshita et al., unpublished observations, 1999). These studies suggest that even the common carotid artery is categorized into a small conduit artery, and the pharmacological property of this artery may be close to resistance arteries including intracranial arteries, which are capable of representing myogenic tone (24). However, it is unclear whether vasodilation induced by hypoxia in the common carotid artery similarly contributes to increased cerebral blood flow compared with that seen in intracranial arteries.

In the rat carotid artery, a Class Ib antiarrhythmic drug, lidocaine, inhibited the vasorelaxation induced by levcromakalim, whereas it did not affect vasodilation produced by hypoxia. Our study has demonstrated that, in the rat carotid artery, levcromakalim can selectively activate ATP-sensitive K⁺ channels (10). These results suggest that lidocaine may selectively impair vasorelaxation induced by an ATP-sensitive K⁺ channel opener but not by hypoxia. The ATP-sensitive K⁺ channel is a complex of two proteins: the sulfonylurea receptor and a smaller pore-forming protein, which belongs to the inward rectifier K⁺ channel family (25). The sulfonylurea receptor of ATP-sensitive K⁺ channel is a target of channel openers (26). Therefore, these results suggest that hypoxia probably stimulates the compartment of ATP-sensitive K⁺ channels other than the sulfonylurea receptor, whereas lidocaine may affect the sulfonylurea receptor of the K⁺ channels. Indeed, our studies documented that, in the rat aorta, lidocaine similarly impaired vasorelaxation induced by ATP-sensitive K⁺ channel openers (8). However, further studies will be warranted to clarify these molecular mechanisms.

The therapeutic ranges of plasma concentrations of lidocaine used as an antiarrhythmic drug were reported as 8 to 50 µM (27). Because approximately 50% of lidocaine is bound to plasma proteins, concentrations of lidocaine used in the present study are slightly larger than free plasma concentrations in the clinical setting (28). However, our results suggest that, in the clinical situation, lidocaine may reduce vasodilation via ATP-sensitive K⁺ channels activated by the opener but not by hypoxia. Considering the concept that the carotid artery plays a role in supplying cerebral blood flow from systemic circulation, our results may also support the conclusion that in the clinical setting, lidocaine seems to preserve increased cerebral blood flow during hypoxia. In contrast, it may adversely affect the regulation of cerebral circulation when one administers ATP-sensitive K⁺ channel openers to ameliorate decreased cerebral blood flow during pathophysiological situations such as cerebral vasospasm after subarachnoid hemorrhage (3). However, in the present study, the reported force changes produced by lidocaine were relatively small. Because, in the clinical setting, multiple factors are interacting to regulate vascular smooth muscle tone, it may be difficult to extrapolate the present in vitro findings to the clinical setting.

In conclusion, our results in the rat carotid artery suggest that ATP-sensitive K⁺ channels contribute to vasodilation of the carotid artery during hypoxia and that lidocaine differentially modulates vasodilation via these channels activated by hypoxia and the channel opener.

	Acknowledgments

 
Supported, in part, by Grant-in-Aid, 10470324 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (YH) and 11–7 for Medical Research from Wakayama prefecture (HK).

	Footnotes

 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October 12–16, 2002.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Kinoshita, H. Articles by Hatano, Y. Search for Related Content PubMed PubMed Citation Articles by Kinoshita, H. Articles by Hatano, Y. Related Collections Cardiovascular Mechanisms

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