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Anesth Analg 2001;93:282-286
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Cibenzoline Has an Inhibitory Effect on Vasorelaxation Mediated by Adenosine Triphosphate-Sensitive K+ Channels in the Rat Carotid Artery

Hiroyuki Kinoshita, MD*, Hiroshi Iranami, MD*, Yoshiki Kimoto, MD{dagger}, Mayuko Dojo, MD{dagger}, and Yoshio Hatano, MD{dagger}

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

Address correspondence and reprint requests to Hiroyuki Kinoshita, MD, 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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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Studies in cardiac myocytes have shown that cibenzoline reduces adenosine triphosphate (ATP)-sensitive K+ currents, suggesting that this class Ia antiarrhythmic drug may modify the activity of ATP-sensitive K+ channels in these preparations. The effects of class Ia antiarrhythmic drugs on vasodilation mediated by ion channels have not been studied. Therefore, we designed this study to examine whether cibenzoline may produce changes in vasorelaxation in response to a selective ATP-sensitive K+ channel opener, levcromakalim, in the isolated rat carotid artery. Rings of rat carotid arteries without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contraction to phenylephrine (3 x 10-7 M), vasorelaxation in response to levcromakalim (10-8 to 10-5 M) or 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10-10 to 10-5 M) was obtained. During contraction to phenylephrine, levcromakalim induced concentration-dependent vasorelaxation. A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10-6 M), completely abolished vasorelaxation in response to levcromakalim, whereas a selective Ca2+-dependent K+ channel antagonist, iberiotoxin (5 x 10-8 M), did not affect the relaxation. Cibenzoline (10-6 to 10-5 M) significantly reduced vasorelaxation to levcromakalim in a concentration-dependent fashion. In contrast, cibenzoline (10-5 M) did not alter vasorelaxation to a nitric oxide donor, NOC-7. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by ATP-sensitive K+ channels.

IMPLICATIONS: In isolated rat carotid artery, cibenzoline (10-6 to 10-5 M) reduced vasorelaxation to levcromakalim in a concentration-dependent fashion. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by adenosine triphosphate-sensitive K+ channels.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Adenosine triphosphate (ATP)-sensitive K+ channels mediate cerebral vasodilation induced by a number of pharmacologic and pathophysiologic stimuli, suggesting that these channels are important in the regulation of cerebral circulation (1,2). Indeed, previous studies, including ones from this laboratory, have shown that, in the cerebral circulation and the central nervous system, ATP-sensitive K+ channels are activated during hypoxia, acidosis, and ischemia, resulting in arterial dilation or increased tolerance of tissues to ischemia, respectively (3–5). Several studies have demonstrated that ATP-sensitive K+ channel openers are capable of augmenting cerebral blood flow or cerebral vasodilation, indicating that the application of ATP-sensitive K+ channel openers may have therapeutic benefit, especially in patients with decreased cerebral blood flow (6,7). 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 role of ATP-sensitive K+ channels in carotid arterial vasodilation is still undefined.

Cibenzoline is a novel class Ia antiarrhythmic drug that acts on cardiac Na+ channels (8). It has a less potent effect on muscarinic receptors in cardiac myocytes and rarely affects the QT interval in electrocardiograms, suggesting that this drug may have lesser anticholinergic and proarrhythmic effects than the other class Ia antiarrhythmic drugs (8,9). However, studies with cardiac myocytes have shown that cibenzoline reduces ATP-sensitive K+ currents, indicating that this class Ia antiarrhythmic drug may modify the activity of ATP-sensitive K+ channels in these preparations (10,11). The effects of class Ia antiarrhythmic drugs on vasodilation mediated by ion channels have not been studied. In addition, the modification of carotid arterial vasodilation induced by antiarrhythmic drugs has not been determined. Therefore, this study was designed to examine whether clinically relevant concentrations of cibenzoline may produce changes in vasorelaxation in response to an ATP-sensitive K+ channel opener, levcromakalim, in isolated rat carotid artery.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experiments were performed on 3-mm common carotid arterial rings obtained from male Wistar rats (300–400 g), with inhalation of 3% halothane in 100% oxygen (3 L/min). The study was approved by the institutional animal care and use committee. 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. In all rings, the endothelium was removed mechanically because our previous study demonstrated that vasorelaxation in response to levcromakalim is augmented in the presence of functional endothelium (12). The endothelial removal was confirmed by the absence of relaxation to acetylcholine (10-5 M). Several rings cut from 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 solution (37°C, pH 7.4) bubbled with a 95% oxygen and 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 (3 x 10-7 M) (Sigma Chemical Co., St. Louis, MO). In most of the studied arteries, optimal tension was achieved at approximately 1.0 g. Preparations were equilibrated for 90 min. During submaximal contractions to phenylephrine (3 x 10-7 M), concentration-response curves to levcromakalim (10-8 to 10-5 M) or 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10-10 to 10-5 M) (Dojindo Laboratories, Kumamoto, Japan) were obtained in the absence or in the presence of cibenzoline (10-6, 3 x 10-6 or 10-5 M), iberiotoxin (5 x 10-8 M), or glibenclamide (5 x 10-6 M). Concentration-response curves were obtained in a cumulative fashion. Only one concentration-response curve was made from each ring. Cibenzoline, iberiotoxin, or glibenclamide was given 15 min before the addition of phenylephrine (3 x 10-7 M). The relaxation was expressed as a percentage of the maximal relaxation in response to papaverine (3 x 10-4 M), which was added at the end of the experiments to produce maximal relaxation (100%) of the artery.

The following pharmacologic agents were used: dimethyl sulfoxide (DMSO), glibenclamide, phenylephrine, and NOC-7. Levcromakalim and cibenzoline were generous gifts from SmithKline Beecham Pharmaceutical Co. (Betchworth, Surrey, Great Britain) and Fujisawa Pharmaceutical Co. (Osaka, Japan), respectively. Drugs were dissolved in distilled water such that volumes of <60 µL were added to the organ chambers. Stock solutions of levcromakalim (10-5 M) and glibenclamide (5 x 10-6 M) were prepared in DMSO (10-4 to 3 x 10-4 M). Stock solutions of NOC-7 (10-5 M) were prepared in 0.01 N NaOH solution. 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 artery was taken. Statistical analysis was performed with repeated-measures of analysis of variance, followed by Scheffé’s F test for multiple comparison. Differences were considered to be significant when P was <0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During submaximal contraction in response to phenylephrine (3 x 10-7 M), levcromakalim (10-8 to 10-5 M) induced concentration-dependent vasorelaxation (Fig. 1). A selective ATP-sensitive K+ channel antagonist, glibenclamide (5 x 10-6 M), completely abolished vasorelaxation in response to levcromakalim, whereas a selective Ca2+-dependent K+ channel antagonist, iberiotoxin (5 x 10-8 M), did not alter the relaxation (Fig. 1). Clinically relevant concentrations of a class Ia antiarrhythmic drug, cibenzoline (10-6 to 10-5 M), significantly reduced vasorelaxation in response to levcromakalim in a concentration-dependent fashion (Fig. 2). In contrast, the largest concentration of cibenzoline (10-5 M) used in this study did not affect vasorelaxation to a nitric oxide donor, NOC-7 (10-10 to 10-5 M) (Fig. 3). Cibenzoline did not produce any effects on baseline tension or contractions to phenylephrine (data not shown). DMSO in the concentration range used in this study did not produce vasodilator effect in arteries contracted with phenylephrine (3 x 10-7 M) (data not shown).



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  		Figure 1. Concentration-response curves to levcromakalim (10-8 to 10-5 M) in the absence and presence of glibenclamide (5 x 10-6 M) or iberiotoxin (5 x 10-8 M), obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 642 ± 229 mg [n = 4], 635 ± 204 mg [n = 4], and 652 ± 199 mg [n = 4] for control rings and rings treated with glibenclamide or iberiotoxin, respectively). *Difference between rings treated with glibenclamide and control rings or rings treated with iberiotoxin is statistically significant (P < 0.05).

 


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  		Figure 2. Concentration-response curves to levcromakalim in the absence or in the presence of cibenzoline (10-6, 3 x 10-6, 10-5 M) obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 810 ± 304 mg [n = 7], 791 ± 183 mg [n = 7], 830 ± 221 mg [n = 7], and 837 ± 98 mg [n = 7] for control rings and rings treated with cibenzoline [10-6 M], cibenzoline [3 x 10-6 M], or cibenzoline [10-5 M], respectively). *Difference between control rings and rings treated with cibenzoline is statistically significant (P < 0.05).

 


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  		Figure 3. Concentration-response curves to 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10-10 to 10-5 M) in the absence and presence of cibenzoline (10-5 M) obtained in rat carotid arterial rings without endothelium. Data are shown as mean ± SD and expressed as percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 687 ± 146 mg [n = 6], 770 ± 176 mg [n = 6] for control rings and rings treated with cibenzoline).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This is the first study demonstrating the effect of a class Ia antiarrhythmic drug on vasorelaxation mediated by ATP-sensitive K+ channels. In this study, cibenzoline (from 10-6 M) reduced vasorelaxation in response to an ATP-sensitive K+ channel opener, levcromakalim, whereas it did not affect vasorelaxation to a nitric oxide donor, NOC-7. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by ATP-sensitive K+ channels.

In this study, glibenclamide, which is a selective antagonist of ATP-sensitive K+ channels, abolished relaxation in response to levcromakalim (13,14). These results are consistent with our study results on the isolated rat aorta, which showed that vasorelaxation to levcromakalim is completely inhibited by glibenclamide (12). Another finding, that a selective large-conductance Ca2+-dependent K+ channel antagonist, iberiotoxin, did not affect vasorelaxation in response to levcromakalim, also supports the selectivity of the opener to ATP-sensitive K+ channels (15). In addition, our previous finding regarding the rat aorta, that glibenclamide does not affect relaxation in response to nitric oxide donors, reinforces the selectivity of glibenclamide on ATP-sensitive K+ channels (16).

In the rat carotid artery without endothelium, cibenzoline significantly reduced vasorelaxation in response to levcromakalim, whereas it did not affect relaxation to a nitric oxide donor, NOC-7. These results suggest that cibenzoline may selectively impair vasorelaxation mediated by ATP-sensitive K+ channels in vascular smooth muscle cells. Previous studies have shown that the carotid artery has the higher activity of K+ channels rather than large conduit arteries such as the aorta, especially in arteries from animals with chronic hypertension (17) (H. Kinoshita, written communication, 1999). These studies suggest that even though the carotid artery is categorized into a small conduit artery, the pharmacologic property of this artery may be close to resistance arteries, including intracranial arteries, which are capable of representing the myogenic tone (18). However, it is unclear whether cibenzoline can modulate the arterial tone in cerebral circulation.

The ATP-sensitive K+ channel is a complex of two proteins: the sulfonylurea receptor (SUR), SUR 1, SUR 2A, or SUR 2B, which is a member of the ATP-binding cassette transporter family; and a smaller pore-forming protein, Kir6.1 or 6.2, which belongs to the inward rectifier K+ channel family (19). A recent study has demonstrated that in NIH3T3 cell lines and cardiac myocytes, up to 10-5 M of cibenzoline can reduce the current via Kir6.1 or 6.2, respectively, and that in cardiac myocytes, the binding of [3H]-labeled cibenzoline is prevented by unlabeled cibenzoline, but not by glibenclamide (11). Because the SUR of the ATP-sensitive K+ channel is a target of glibenclamide, these results suggest that cibenzoline binds the pore-forming subunits of ATP-sensitive K+ channels, Kir6.1 and 6.2, resulting in the impaired activity of these channels (2). Previous studies and this study, including those with vascular smooth muscle, Xenopus oocytes, pancreatic ß cells, and cardiac myocytes, similarly demonstrate the inhibitory effect of cibenzoline on the activity of ATP-sensitive K+ channels, supporting the conclusion that, in a number of preparations, cibenzoline can regulate the activity of ATP-sensitive K+ channels via inhibition of the pore-forming subunits Kir6.1 or 6.2, which are distinct from SUR, in these channels (10,11,20). Indeed, a recent study on African green monkey kidney COS-7 cells has demonstrated that another class Ia antiarrhythmic drug, disopyramide, directly inhibits the activity of Kir6.2 (21).

This study has demonstrated the inhibitory effect of cibenzoline on vasodilation induced by an ATP-sensitive K+ channel opener. Direct functional and biochemical studies have revealed that the SUR of ATP-sensitive K+ channels is a primary target of the openers of this channel (22,23). The structural similarity regarding those imidazoline moieties between cibenzoline and glibenclamide, and the clearly demonstrated inhibitory effect of glibenclamide on SUR, indicate that these compounds may similarly affect the SUR of ATP-sensitive K+ channels (11,14). The subtype of SUR (SUR 2B) in vascular smooth muscle is distinct from that of other subtypes of ATP-sensitive K+ channels existing in other preparations (19). Therefore, although previous studies performed in preparations other than vascular smooth muscle cells strongly suggest the inhibitory effect of cibenzoline on Kir of ATP-sensitive K+ channels, we cannot completely eliminate the possibility that cibenzoline may affect SUR 2B of the ATP-sensitive K+ channel in our preparation, leading to reduced vasodilation mediated by these channels.

Because in this study, cibenzoline did not produce any effects on the baseline tension or contractions to phenylephrine, it is unlikely that the effects of cibenzoline on relaxations to ATP-sensitive K+ channel openers are caused by vasoconstrictor effects of the compound. This conclusion is supported by previous clinical studies documenting that the effects of cibenzoline on blood pressure are minimal (8).

Cibenzoline is currently used in some European and Asian countries. The therapeutic ranges of plasma concentrations of cibenzoline used as antiarrhythmic drugs are 10-6 to 5 x 10-6 M (24). Even though this antiarrhythmic drug is bound to plasma proteins (approximately 50%), some concentrations of cibenzoline used in this study are within the free plasma concentrations in the clinical situations (8,25). Therefore, our results regarding the effects of antiarrhythmic drugs on vasorelaxation in response to an ATP-sensitive K+ channel opener suggest that in clinical situations, cibenzoline may impair carotid arterial dilation mediated by ATP-sensitive K+ channels.

Previous studies, including some from this laboratory, suggest that ATP-sensitive K+ channels are important in the regulation of cerebral circulation during the variable cerebral vascular disorders (3–5). Indeed, one study has demonstrated that the systemic administration of cromakalim can recover vasodilation of rabbit basilar arteries during vasospasm after subarachnoid hemorrhage, suggesting that the ATP-sensitive K+ channel openers are a potential therapeutic tool for treating the impaired cerebral blood flow after subarachnoid hemorrhage (7). Cardiovascular disorders, including ischemic heart disease and arrhythmias, seem to coexist in these patients, because long-lasting hypertension is usually seen in patients with subarachnoid hemorrhage (26). Therefore, it is possible that cibenzoline, administered in patients with cerebral vascular disorders, leads to the aggravation of already decreased cerebral blood flow. Our results suggest that cibenzoline may modulate pathophysiologically and pharmacologically induced beneficial carotid arterial vasodilator responses via ATP-sensitive K+ channels.


   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).


   References
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 Introduction
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 References
 

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Accepted for publication April 2, 2001.




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H. Kinoshita, Y. Kimoto, K. Nakahata, H. Iranami, M. Dojo, and Y. Hatano
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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