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Anesth Analg 2004;99:904-909
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000133912.54318.0F

NEUROSURGICAL ANESTHESIA

Lidocaine Impairs Vasodilation Mediated by Adenosine Triphosphate-Sensitive K+ Channels but Not by Inward Rectifier K+ Channels in Rat Cerebral Microvessels

Hiroyuki Kinoshita, MD PhD*, Katsutoshi Nakahata, MD{dagger}, Mayuko Dojo, MD*, Yoshiki Kimoto, MD*, and Yoshio Hatano, MD PhD*

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

Address correspondence and reprint requests to Hiroyuki Kinoshita, MD, PhD, Department of Anesthesiology, Wakayama Medical University, 811–1 Kimiidera, Wakayama, Wakayama 641–0012, Japan. Address e-mail to hkinoshi{at}pd5.so-net.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Vasodilator effects of adenosine triphosphate (ATP)-sensitive, as well as inward rectifier, K+ channel openers have not been well demonstrated in cerebral microvessels. Although lidocaine impairs vasorelaxation via ATP-sensitive K+ channels in the rat aorta, the effects of this compound on K+ channels in the cerebral circulation have not been shown. We designed the present study to examine whether ATP-sensitive and inward rectifier K+ channels contribute to vasodilator responses in cerebral microvessels and whether the vasodilation mediated by these channels is inhibited by lidocaine. Rat brain slices were monitored using a computer-assisted videomicroscopy. Cerebral parenchymal arterioles (diameter, 5–10 µm) were contracted with prostaglandin F2{alpha}, and thereafter potassium chloride (KCl), levcromakalim, or sodium nitroprusside was added to the perfusion chamber. Levcromakalim and KCl produced vasodilation of the cerebral parenchymal arterioles, which was abolished by an ATP-sensitive K+ channel antagonist, glibenclamide, or an inward rectifier K+ channel antagonist, barium chloride, respectively. Lidocaine (10–5 to 3 x 10–5 M) inhibited the dilation produced by levcromakalim but not by KCl or sodium nitroprusside. In parenchymal arterioles of the cerebral cortex, lidocaine seems to reduce vasodilation mediated by ATP-sensitive K+ channels but not by inward rectifier K+ channels.

IMPLICATIONS: In parenchymal arterioles of the rat cerebral cortex, lidocaine impairs vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels but not by inward rectifier K+ channels. These results indicate that lidocaine may impair vasodilator responses mediated via ATP-sensitive K+ channels, resulting in decreased cerebral parenchymal perfusion.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Adenosine triphosphate (ATP)-sensitive K+ channels play an important role in cerebral circulation, especially under pathophysiological conditions such as ischemia, because these channels are regulated by intracellular energy status, including intracellular concentrations of ATP (1,2). Neuronal activity and stresses such as cerebral ischemia and hypoglycemia are capable of producing increased concentrations of extracellular K+ in the brain (3,4). Previous studies demonstrated that small increases in extracellular K+ induce cerebral vasorelaxation, primarily through hyperpolarization of smooth muscle cell membranes via the activation of inward rectifier K+ channels (5–7). These results suggest that both ATP-sensitive and inward rectifier K+ channels participate in the regulation of cerebral blood flow coupled to the changes in cerebral metabolic state.

Vascular smooth muscle tone produced by cerebral arterioles, including those in the brain parenchyma, seem to be a crucial determinant of cerebral vascular resistance (8). Although our recent study has shown that the activation of ATP-sensitive K+ channels induces cerebral vasodilation in precapillary arterioles (9), vasodilation mediated by inward rectifier K+ channels has not been demonstrated in cerebral precapillary microvessels.

Previous studies have shown that pretreatment with lidocaine can reduce cerebral infarct size after cerebral ischemia, indicating that this drug may improve postischemic outcomes by preserving cerebral blood flow (10). However, the beneficial effect of lidocaine has long been controversial because in some studies this compound failed to provide amelioration of global ischemic brain damage (11). We reported that in the rat aorta, lidocaine impairs vasorelaxation induced by levcromakalim, indicating that this drug may also impair vasodilator responses via ATP-sensitive K+ channels in cerebral circulation (12). However, the effects of lidocaine on K+ channels have not been shown in the cerebral circulation. The ATP-sensitive K+ channel is a hetero-octameric complex comprising two subunits: the inward rectifier K+ channel, which is a pore-forming subunit, and the sulfonylurea receptor, which is a regulatory subunit (13). Because the ATP-sensitive K+ channel contains the inward rectifier K+ channel family in its molecular structure, lidocaine may also produce inhibition of cerebral vasodilation mediated by inward rectifier K+ channels.

The present study was designed to examine whether ATP-sensitive and inward rectifier K+ channels play a part in vasodilator responses in cerebral microvessels and whether the vasodilation mediated by these channels is inhibited by lidocaine.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The institutional animal care and use committee approved this study. Male Wistar rats (300–400 g) were anesthetized with inhaled 3% halothane in 100% oxygen (3 L/min). A midline thoracotomy was performed, and 50 mL of saline was infused intracardially into the left ventricle while a right atrial incision was made for blood drainage. The rats were then decapitated and the brains rapidly removed and rinsed with artificial cerebrospinal fluid (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. Brains were cut freehand into blocks containing the neocortex, followed by immediate sectioning into slices (200-µm thick) with a mechanical tissue slicer (Vibratomes 1000; Ted Pella Inc, Redding, CA) (9). Three to four slices were obtained from each rat. Throughout the slicing procedure, brain blocks were continuously bathed in the control solution bubbled with 93% O2 + 7% CO2 at 4°C. Individual slices were transferred to a recording chamber filled with control solution, which was mounted on an inverted microscope (Olympus IX70; Olympus, Tokyo, Japan). The recording system consisted of a recording chamber (3 mL) and a tubing compartment (7 mL), including the perfusion chamber (9). The slices were continuously superfused with control solution at the flow rate of 1.5 mL/min and bubbled with 93% O2 + 7% CO2 (PCO2 = 40 mm Hg, pH value of 7.4, and at 37°C). An intraparenchymal arteriole (internal diameter, 5–10 µm) was located within the neuronal tissue, and its internal diameter was continuously monitored by live computerized videomicroscopy (9). The videomicroscopy equipment consisted of an inverted microscope, a 40x objective (Olympus), and a 2.25x video projection lens (Olympus). Arterioles were microscopically identified and differentiated from venules by the presence of the layer of vascular smooth muscle cells, and, in some studies, these were confirmed by hematoxylin-eosin staining of the slice after each experiment (9). The image of a parenchymal arteriole was transmitted to a video camera (C6790–81; Olympus) and displayed on a computer via a media converter (Physio-Tech, Tokyo, Japan). We defined the intraluminal diameter as the length between the internal margins of the arteriolar walls. Changes of intraluminal diameter in cerebral microvessels were recorded on computer image files and then analyzed using image analysis software with a sensitivity to 0.01 µm (Physio-Tech).

Each slice was equilibrated for at least 30 min before the start of the experimental protocols. All experiments were performed during submaximal constriction in response to prostaglandin F2{alpha} (5 x 10–7 M). We have found that this concentration of prostaglandin F2{alpha} produces approximately 70% vasoconstriction compared with maximal contraction induced by prostaglandin F2{alpha} (10–5 M) in cerebral parenchymal arterioles (9). Barium chloride (BaCl2; 10–5 M), glibenclamide (5 x 10–6 M), or lidocaine (10–5–3 x 10–5 M) was applied 10 min before the addition of prostaglandin F2{alpha} (5 x 10–7 M). Concentration-responses to levcromakalim (3 x 10–8 to 3 x 10–7 M), potassium chloride (KCl; 5–10 mM), and sodium nitroprusside (3 x 10–8 to 3 x 10–6 M) were obtained in the absence or presence of BaCl2, glibenclamide, or lidocaine. Concentration-responses were obtained in a cumulative fashion by adding vasoconstrictor or vasodilator substances into the bubbling chamber connected to, but separated from, the recording chamber. Only one concentration-response was made from each slice. The duration of the experiment for each slice was within 3 h because our recent study showed that even 3 h after the preparation of the brain slice, the vasodilator function mediated by endothelial or neuronal nitric oxide synthase seemed to be intact in our experimental condition (9). The amount of dilation of the cerebral arteriole induced by levcromakalim, KCl, or sodium nitroprusside was normalized by using the constriction produced by prostaglandin F2{alpha} (5 x 10–7 M) in each arteriole. Therefore, the percent dilation was calculated by the following equation: % dilation = 100 x (Ddilator – DPGF)/(Dcontrol – DPGF); % constriction to prostaglandin F2{alpha} = 100 x (DPGF – Dcontrol)/Dcontrol. Dcontrol, DPGF, and Ddilator were the arteriolar diameters of control condition, after administration of prostaglandin F2{alpha} (5 x 10–7 M), or the vasodilators, respectively.

The following pharmacological drugs were used: BaCl2, dimethyl sulfoxide (DMSO), glibenclamide, KCl, prostaglandin F2{alpha}, and sodium nitroprusside (Sigma, St Louis, MO). Levcromakalim was a generous gift from GlaxoSmithKline plc (Greenford, United Kingdom). Drugs were dissolved in distilled water such that volumes of <60 µL were added to the perfusion system. Stock solutions of levcromakalim (10–5 M) and glibenclamide (10–5 M) were prepared in DMSO (3 x 10–4 M). The concentrations of drugs are expressed as final molar (M) concentration.

The data are expressed as mean ± SD; n refers to the number of rats from which the brain slice was taken. Statistical analysis was performed using repeated-measures analysis of variance, followed by Scheffé F test. Differences were considered to be statistically significant when P < 0.05.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In Figure 1, a representative example of vasodilator response induced by levcromakalim (3 x 10–7 M) is shown. The control arteriole of rat cerebral cortex was contracted with prostaglandin F2{alpha} (5 x 10–7 M), and levcromakalim (3 x 10–7 M) produced almost full vasodilation of this contracted arteriole (Fig. 1). In arterioles contracted with prostaglandin F2{alpha} (5 x 10–7 M), levcromakalim (3 x 10–8 to 3 x 10–7 M) induced vasodilation in a concentration-dependent fashion (Fig. 2a). This vasodilator effect was completely abolished by the selective ATP-sensitive K+ channel antagonist glibenclamide (5 x 10–6 M) but not by the inward rectifier K+ channel antagonist BaCl2 (10–5 M) (Figs. 2, A and B), whereas BaCl2 (10–5 M) completely inhibited vasodilation produced by KCl (5–10 mM) (Fig. 3).



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  		Figure 1. Representative vasodilator response of the rat cerebral parenchymal arteriole induced by levcromakalim. The arrow indicates the intraluminal diameter defined as the length between the internal margins of the arteriole wall. In the control, parenchymal arteriole (internal diameter 6.2 µm) (A), which was contracted with prostaglandin F2{alpha} (5 x 10–7 M) (internal diameter 5.2 µm) (B), levcromakalim (3 x 10–7 M) produced almost maximal vasodilation (internal diameter, 6.1 µm) (C).

 


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  		Figure 2. (A) Vasodilator responses to levcromakalim (3 x 10–8, 10–7, and 3 x 10–7 M) in the absence or presence of glibenclamide (5 x 10–6 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –19.7% ± 9.6% or –15.0% ± 4.9% for control arterioles and arterioles treated with glibenclamide, respectively. *The difference between control arterioles and arterioles treated with glibenclamide was statistically significant (P < 0.05). (B) Vasodilator responses to levcromakalim in the absence or presence of barium chloride (BaCl2; 10–5 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –17.4% ± 8.1% or –15.7% ± 3.7% for control arterioles and arterioles treated with BaCl2, respectively. Data are shown as mean ± SD.

 


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  		Figure 3. Vasodilator responses to potassium chloride (KCl; 5–10 mM) in the absence or presence of barium chloride (BaCl2; 10–5 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –11.4% ± 3.2% or –13.5% ± 6.5% for control arterioles and arterioles treated with BaCl2, respectively. Data are shown as mean ± SD. *The difference between control arterioles and arterioles treated with BaCl2 was statistically significant (P < 0.05).

 
In Figure 4, a representative example of the inhibitory effect of lidocaine (3 x 10–5 M) on vasodilation produced by levcromakalim is shown. This concentration of lidocaine abolished the dilation provoked by levcromakalim (3 x 10–7 M) (Fig. 4). Lidocaine (10–5 to 3 x 10–5 M) concentration-dependently inhibited the vasodilation produced by this ATP-sensitive K+ channel opener (Fig. 5). In contrast, lidocaine (3 x 10–5 M) did not alter vasodilation induced by KCl (5–10 mM) or sodium nitroprusside (3 x 10–8 to 3 x 10–6 M) (Figs. 6, A and B) and constriction in response to prostaglandin F2{alpha} (5 x 10–7 M) (Figs. 5 and 6).



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  		Figure 4. The representative vasodilator response to levcromakalim in the rat cerebral parenchymal arteriole treated with lidocaine (3 x 10–5 M). In the control, parenchymal arteriole treated with lidocaine (internal diameter, 8.5 µm) (A), which was contracted with prostaglandin F2{alpha} (5 x 10–7 M) (internal diameter, 6.2 µm) (B), levcromakalim (3 x 10–7 M) did not produce vasodilation (internal diameter, 6.2 µm) (C).

 


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  		Figure 5. Vasodilator responses to levcromakalim in the absence or presence of lidocaine (10–5 to 3 x 10–5 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –17.8% ± 11.5%, –16.7% ± 8.8%, or –21.1% ± 5.0% for control arterioles, arterioles treated with lidocaine (10–5 M), and those with lidocaine (3 x 10–5 M), respectively. Data are shown as mean ± SD. *The difference between control arterioles and arterioles treated with lidocaine was statistically significant (P < 0.05).

 


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  		Figure 6. (A) Vasodilator responses to KCl (5–10 mM) in the absence or presence of lidocaine (3 x 10–5 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –12.5% ± 2.6% or –15.2% ± 6.2% for control arterioles and arterioles treated with lidocaine (3 x 10–5 M), respectively. (B) Vasodilator responses to sodium nitroprusside (3 x 10–8, 3 x 10–7, and 3 x 10–6 M) in the absence or presence of lidocaine (3 x 10–5 M) obtained in rat cerebral parenchymal arterioles. Vasoconstrictor responses to prostaglandin F2{alpha} (5 x 10–7 M) were –24.9% ± 7.1% or –26.3% ± 2.6% for control arterioles and arterioles treated with lidocaine (3 x 10–5 M), respectively. Data are shown as mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In parenchymal arterioles of the rat cerebral cortex, levcromakalim induced vasodilation in a concentration-dependent fashion and this vasodilator effect was completely abolished by glibenclamide (5 x 10–6 M), but not by BaCl2 (10–5 M). Because glibenclamide and BaCl2 are ATP-sensitive and inward rectifier K+ channel antagonists in each concentration used in the current study, respectively, these results indicate that vasodilation induced by levcromakalim in this preparation is selectively mediated by ATP-sensitive K+ channels (9,14–16). This conclusion is also supported by our recent findings showing the selectivity of glibenclamide on ATP-sensitive K+ channels in the rat cerebral arteriole (9). Indeed, our results are consistent with a previous in vivo study demonstrating that intraparenchymal injection of an ATP-sensitive K+ channel opener produces an increase in local cerebral blood flow (17). In rat cerebral parenchymal microvessels, 3 x 10–7 M of levcromakalim produced almost maximal vasodilation. A previous study documented, in rat middle cerebral arteries (diameters of 200–300 µm), that this concentration of levcromakalim induced up to 70% vasodilation (18). There do not seem to be regional differences between the response of more proximal cerebral arteries and distal cerebral microvessels to the ATP-sensitive K+ channel opener levcromakalim.

This is the first study demonstrating the vasodilation of cerebral parenchymal arterioles mediated by inward rectifier K+ channels. In the present study, KCl (5–10 mM) produced approximately 30% to 40% of cerebral vasodilation, which was completely abolished by BaCl2, indicating that vasodilation induced by KCl in this preparation is mediated by inward rectifier K+ channels (2,15). The degree of vasodilation induced by KCl in the cerebral parenchymal arteriole is similar to that obtained in the basilar artery in vivo using cranial window models (5,6). Accordingly, there may not be regional differences in the vasodilator effects of potassium ion between proximal cerebral arteries and the distal arterioles in the rat brain.

Lidocaine produced concentration-dependent inhibition of the cerebral parenchymal arteriolar vasodilation induced by levcromakalim, whereas it did not affect dilation produced by KCl. Because, as discussed above, levcromakalim and KCl evoke vasodilator effects mediated by ATP-sensitive and inward rectifier K+ channels, respectively, these results indicate that lidocaine may selectively inhibit vasodilation mediated by ATP-sensitive K+ channels. This conclusion is further supported by the evidence that lidocaine did not affect cerebral parenchymal vasodilation induced by the nitric oxide donor sodium nitroprusside. The therapeutic ranges of plasma concentrations of lidocaine used as an antiarrhythmic drug have been reported as 8 x 10–6 M to 5 x 10–5 M (19). Although some lidocaine is bound to plasma proteins, concentrations of lidocaine used in the present study seem to be within the free plasma concentrations encountered in clinical situations (20,21). Therefore, the results of the present study suggest that, in the clinical situation, lidocaine may impair cerebral parenchymal vasodilation via ATP-sensitive K+ channels but not via inward rectifier K+ channels or increased levels of nitric oxide. Lidocaine-induced inhibition of vasodilation via ATP-sensitive K+ channels seems to be more evident in rat cerebral arterioles than in the rat aorta (12). Although we cannot completely explain this differential inhibitory effect of lidocaine between large conduit and small cerebral arterioles, it is most likely that regional differences of sensitivity or distribution of ATP-sensitive K+ channels to lidocaine contribute to the above differential results. In the present study, lidocaine altered neither baseline diameter nor vasoconstriction induced by prostaglandin F2{alpha}, indicating that in intraparenchymal cerebral arterioles, lidocaine can inhibit vasodilation via ATP-sensitive K+ channels without producing direct vasoconstriction.

The vascular function of parenchymal cerebral arterioles has not been well studied because penetrating microvessels are quite small and difficult to access when embedded within brain parenchyma. However, Sagher et al. (22) introduced a new system that is capable of evaluating microvessels approximately 20 µm in diameter in the brain parenchyma using live videomicroscopy. We have further developed this microscopic system using computer image analysis in which smaller cerebral arterioles <10 µm in internal diameter can be examined (9). In our preparation, parenchymal arterioles responded well to vasoactive substances (9). Because the arterioles of the brain slice are embedded in parenchyma composed of both neuronal and glial cells attached to the arterioles, the circumference, including the resting vascular tone of these arterioles, may be close to that seen in the in vivo condition. However, it may be difficult to directly extrapolate our results into in vivo situations because we cannot exclude the possibility that the absence of intraluminal flow in cerebral arterioles alters the behavior of our preparation. In addition, we evaluated the effects of K+ channel openers and lidocaine on the arterioles treated with a vasoconstrictor drug used in vitro preparations. Therefore, our preparation is different from the physiological condition.

During brain hypoxia, acidosis, or ischemia, ATP-sensitive K+ channels are activated, resulting in arterial dilation and increased tolerance of tissues to ischemia (16,23,24). These findings suggest that ATP-sensitive K+ channels play an important role in the regulation of cerebral circulation during pathophysiological conditions. In addition, one study has demonstrated that systemic administration of cromakalim can recover vasodilation of rabbit basilar arteries during vasospasm after subarachnoid hemorrhage, suggesting that the ATP-sensitive K+ channel openers represent a potential therapeutic effect for the treatment of cerebrovascular pathophysiology after subarachnoid hemorrhage (25). Therefore, our results indicate that lidocaine may impair beneficial vasodilator responses mediated via ATP-sensitive K+ channels, resulting in decreased cerebral parenchymal perfusion in various pathophysiological situations.


   Acknowledgments
 
Supported, in part, by grants-in-aid, 13470327 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, Tokyo, Japan (YH), and 11–7 for Medical Research from Wakayama prefecture, Wakayama, Japan (HK).


   Footnotes
 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October 11–15, 2003.


   References
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 Abstract
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 Discussion
 References
 

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Accepted for publication May 11, 2004.




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K. Nakahata, H. Kinoshita, Y. Tokinaga, Y. Ishida, Y. Kimoto, M. Dojo, K. Mizumoto, K. Ogawa, and Y. Hatano
Vasodilation Mediated by Inward Rectifier K+ Channels in Cerebral Microvessels of Hypertensive and Normotensive Rats
Anesth. Analg., February 1, 2006; 102(2): 571 - 576.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press