Anesth Analg 2003;96:673-679
© 2003 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Mexiletine Differentially Modulates Vasorelaxation Mediated by Adenosine Triphosphate-Sensitive K+ Channels in Aortas from Normotensive and Hypertensive Rats
Yoshiki Kimoto, MD*,
Hiroyuki Kinoshita, MD
,
Katsutoshi Nakahata, MD,
Mayuko Dojo, MD*,
Hiroshi Iranami, MD, and
Yoshio Hatano, MD*
*Department of Anesthesiology, Wakayama Medical College; and
Department of Anesthesia, Japanese Red Cross Society, Wakayama Medical Center, 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 640-8269, Japan. Address e-mail to hkinoshi{at}pd5.so-net.ne.jp
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Abstract
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The modification of vasodilation through adenosine triphosphate (ATP)-sensitive K+ channels induced by antiarrhythmic drugs has not been studied in chronic hypertension. We designed the present study to examine whether mexiletine modulates vasorelaxation via these channels in hypertensive rat aortas. Normotensive and hypertensive rat aortas without endothelium were suspended for isometric force recording. Mexiletine (3 x 10-5 M) increased vasorelaxation induced by levcromakalim (10-8–10-5 M) in normotensive, but not hypertensive, rat aortas. Mexiletine (10-5 to 3 x 10-5 M) also augmented vasorelaxation to sodium nitroprusside (10-10–10-5 M) only in normotensive rat aortas, whereas mexiletine (3 x 10-5 M) did not affect this vasodilation in aortas treated with an ATP-sensitive K+ channel antagonist glibenclamide (10-5 M). A nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; 10-3 M) abolished augmented vasorelaxation to sodium nitroprusside induced by mexiletine (3 x 10-5 M) in normotensive rat aortas, whereas a soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; 10-5 M) failed to alter this augmentation of vasorelaxation. These results suggest that mexiletine induces augmentation of vasodilation via ATP-sensitive K+ channels activated by the opener as well as a nitric oxide donor only in normotensive rat aortas. The vasodilator effects of mexiletine are partly caused by the soluble guanylate cyclase-independent action of nitric oxide on these channels.
IMPLICATIONS: Mexiletine induces augmentation of vasodilation mediated by adenosine triphosphate (ATP)-sensitive K+ channels activated by the opener as well as a nitric oxide donor in normotensive, but not hypertensive, rat aortas, partly by the soluble guanylate cyclase-independent action of nitric oxide on ATP-sensitive K+ channels of vascular smooth muscle cells.
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Introduction
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Our recent study on the rat aorta has demonstrated that a Class Ib antiarrhythmic drug, mexiletine, is capable of increasing vasorelaxation induced by adenosine triphosphate (ATP)-sensitive K+ channel openers (1,2). In the aorta, mexiletine also produces the enhancement of sodium nitroprusside-induced vasorelaxation, which is abolished by an ATP-sensitive K+ channel antagonist (3). These results suggest that mexiletine augments vasodilation via ATP-sensitive K+ channels regardless of the type of stimuli acting on these channels. In addition, this effect of mexiletine seems to be distinct from those of other Class Ib antiarrhythmic drugs because lidocaine clearly causes the inhibition of vasorelaxation through ATP-sensitive K+ channels in the same preparation (1,2). Vasorelaxation in response to ATP-sensitive K+ channel openers is reportedly augmented in the aortas from hypertensive rats, indicating that ATP-sensitive K+ channels expressed in conduit blood vessels are more sensitive to the openers in chronic hypertension (4,5). Taken together, it seems to be reasonable to hypothesize that the effects of mexiletine on vasorelaxation by ATP-sensitive K+ channels may be enhanced in chronic hypertension. However, the modification of vasodilation by ATP-sensitive K+ channels induced by antiarrhythmic drugs has not been studied in hypertensive status. Because antiarrhythmic drugs and vasodilator substances, including ATP-sensitive K+ channel openers and nitric oxide donors, may be administered to patients with hypertension, it seems to be clinically relevant to determine the effects of mexiletine on vasodilation via ATP-sensitive K+ channels in arteries taken from hypertensive animals.
Therefore, we designed the present study to examine whether mexiletine differentially modulates vasorelaxation mediated by ATP-sensitive K+ channels in the aortas from normotensive and hypertensive rats and to clarify the mechanisms of vasodilator effects of mexiletine on these arteries. The results obtained in the current study document unexpectedly negative effects of mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels in the aorta from spontaneously hypertensive rats.
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Materials and Methods
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The institutional animal care and use committee approved this study. Male age-matched Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) (16–18 wk) were obtained from Charles River Japan Inc (Yokohama, Japan). Rats were anesthetized with inhaled 1% halothane, and systemic blood pressure at the abdominal aorta was measured by cannulation from the femoral artery with the 24-gauge Teflon catheter, connecting it to the pressure transducer and this in turn to a recorder (RMC-1100, Nihon Kohden Inc, Tokyo, Japan). Mean arterial blood pressure was greater in SHR compared with WKY rats (135.8 ± 6.3 versus 87.6 ± 9.9 mm Hg; P < 0.05), whereas heart rate did not significantly differ (287.3 ± 17.0 versus 279.3 ± 22.1 bpm, respectively; not significant). After these measurements, the rats were killed by exsanguination, and thoracic aortas were harvested. Thoracic aortic rings of 2 mm in length were studied in modified Krebs-Ringer bicarbonate solution (control solution) of the following composition (mM): NaCl 119, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25, and glucose 11. In each ring, the endothelium was mechanically removed, and the endothelial removal was confirmed by the absence of the relaxation to acetylcholine (10-5 M). Several rings cut from same aorta 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 value of 7.4) bubbled with 95% O2 and 5% CO2. The artery was gradually stretched to the optimal point of its length-tension curve as determined by the contraction in response to phenylephrine (3 x 10-7 M). In most studied arteries, optimal tension was achieved approximately at 1.5 g. Preparations were equilibrated for 90 min. During submaximal contraction to phenylephrine, concentration-response curves to levcromakalim (10-8–10-5 M) or sodium nitroprusside (10-10–10-5 M) were obtained in the absence or in the presence of mexiletine, glibenclamide, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), and carboxy-2-phenyl-4,4,5,5-tetramethyl- imidazoline-1-oxyl 3-oxide (carboxy-PTIO), which were given 15 min before the addition of phenylephrine (3 x 10-7 M). The vasorelaxation was expressed as a percentage of the maximal relaxation to papaverine (3 x 10-4 M), which was added at the end of the experiments to produce the maximal relaxation (100%) of the aorta.
The following pharmacological drugs were used: dimethyl sulfoxide, glibenclamide, phenylephrine, mexiletine hydrochloride, sodium nitroprusside (Sigma, St Louis, MO), ODQ, and carboxy-PTIO (Dojindo Lab, Kumamoto, Japan). 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 organ chambers. Stock solutions of levcromakalim (10-5 M), glibenclamide (10-5 M), and ODQ (10-5 M) were prepared in dimethyl sulfoxide (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 aorta was taken. Statistical analysis was performed using two-way analysis of variance, followed by Scheffé F test for multiple comparisons. Differences were considered to be statistically significant when P was <0.05.
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Results
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During submaximal contraction in response to phenylephrine (3 x 10-7 M), levcromakalim (10-8–10-5 M) induced vasorelaxation, which is completely abolished by the selective ATP-sensitive K+ channel antagonist glibenclamide (10-5 M) in the aortas from both normotensive and hypertensive rats (Fig. 1). However, vasorelaxation induced by levcromakalim was significantly augmented in hypertensive rat aortas (Fig. 1). Mexiletine (3 x 10-5 M) increased this vasodilator response only in the normotensive rat aortas (Fig. 2), whereas, as noted in our recent study, vasorelaxation in response to levcromakalim in the presence of mexiletine (3 x 10-5 M) was completely abolished by glibenclamide (10-5 M).
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Figure 1. Concentration-response curves to levcromakalim (10-8 to 10-5 M) in the absence and in the presence of glibenclamide (10-5 M) obtained in thoracic aortas without endothelium from normotensive Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1184 ± 54 mg [n = 5] and 1140 ± 123 mg [n = 5] for control rings and rings treated with glibenclamide from WKY; 100% = 868 ± 104 mg [n = 5] and 692 ± 132 mg [n = 5] for control rings and rings treated with glibenclamide from SHR, respectively). *Difference between control rings and rings treated with glibenclamide and the #difference between rings treated with glibenclamide from WKY and SHR are both statistically significant (P < 0.05).
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Figure 2. Concentration-response curves to levcromakalim in the absence or in the presence of mexiletine (10-5 or 3 x 10-5 M) obtained in thoracic aortas without endothelium from Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1180 ± 49 mg [n = 6], 1170 ± 171 mg [n = 6], and 1133 ± 117 mg [n = 6] for control rings and rings treated with mexiletine (10-5 M) or mexiletine (3 x 10-5 M) from WKY, respectively; 100% = 923 ± 143 mg [n = 6], 913 ± 105 mg [n = 6], and 947 ± 153 mg [n = 6] for control rings and rings treated with mexiletine (10-5 M) or mexiletine (3 x 10-5 M) from SHR, respectively). *Difference between control rings and rings treated with mexiletine from WKY is statistically significant (P < 0.05).
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During contraction in response to phenylephrine (3 x 10-7 M), the nitric oxide donor sodium nitroprusside (10-10–10-5 M) induced vasodilator responses, which were similarly obtained in aortas from both normotensive and hypertensive rats (Fig. 3). Mexiletine (10-5 to 3 x 10-5 M) augmented vasorelaxation in response to sodium nitroprusside in the aortas from normotensive but not those from hypertensive rats (Fig. 4). Glibenclamide (10-5 M) did not affect vasorelaxation induced by sodium nitroprusside in these aortas (Fig. 5). In the aortas treated with glibenclamide (10-5 M) from normotensive and hypertensive rats, mexiletine (3 x 10-5 M) did not affect vasorelaxation in response to sodium nitroprusside (Fig. 5). Vasorelaxation in response to sodium nitroprusside was abolished by a soluble guanylate cyclase inhibitor ODQ (10-5 M) in aortas from normotensive and hypertensive rats, whereas the relaxation was augmented by mexiletine (3 x 10-5 M) even in the presence of ODQ (10-5 M) in normotensive rat aortas (Fig. 6A). However, an increase in vasorelaxation of sodium nitroprusside induced by mexiletine (3 x 10-5 M) was completely abolished by ODQ (10-5 M) in combination with glibenclamide (10-5 M) in normotensive rat aortas (Fig. 6B). In the aortas from normotensive as well as hypertensive rats treated with the selective nitric oxide scavenger carboxy-PTIO (10-3 M), vasorelaxation in response to sodium nitroprusside was reduced, whereas mexiletine (3 x 10-5 M) did not alter this vasorelaxation in aortas treated with carboxy-PTIO (10-3 M) (Fig. 6C).
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Figure 3. Concentration-response curves to sodium nitroprusside (10-10 to 10-5 M) obtained in thoracic aortas without endothelium from Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 980 ± 174 mg [n = 5] and 1470 ± 387 mg [n = 6] for control rings from WKY and SHR, respectively).
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Figure 4. Concentration-response curves to sodium nitroprusside in the absence or in the presence of mexiletine (3 x 10-6, 10-5, or 3 x 10-5 M) obtained in thoracic aortas without endothelium from Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1480 ± 418 mg [n = 5], 1252 ± 346 mg [n = 5], 1296 ± 268 mg [n = 5], and 1248 ± 205 mg [n = 5] for control rings and rings treated with mexiletine [3 x 10-6 M], mexiletine [10-5 M], or mexiletine [3 x 10-5 M] from WKY, respectively; 100% = 1100 ± 149 mg [n = 6], 1037 ± 339 mg [n = 6], 1147 ± 1241 mg [n = 6], and 1240 ± 180 mg [n = 6] for control rings and rings treated with mexiletine [3 x 10-6 M], mexiletine [10-5 M], or mexiletine [3 x 10-5 M] from SHR, respectively). *Difference between control rings and rings treated with mexiletine from WKY are statistically significant (P < 0.05).
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Figure 5. Concentration-response curves to sodium nitroprusside in the absence and in the presence of glibenclamide (10-5 M) or glibenclamide (10-5 M) plus mexiletine (3 x 10-5 M) obtained in thoracic aortas without endothelium from Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1407 ± 387 mg [n = 6], 1273 ± 311 mg [n = 6], and 1247 ± 370 mg [n = 6] for control rings and rings treated with glibenclamide or glibenclamide plus mexiletine from WKY, respectively; 100% = 980 ± 174 mg [n = 5], 1164 ± 161 mg [n = 5], and 920 ± 261 mg [n = 5] for control rings and rings treated with glibenclamide or glibenclamide plus mexiletine from SHR, respectively).
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Figure 6. (A) Concentration-response curves to sodium nitroprusside in the absence or presence of 1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one (ODQ; 10-5 M) or ODQ and mexiletine (3 x 10-5 M) obtained in thoracic aortas without endothelium from Wistar-Kyoto rats (WKY) or spontaneously hypertensive rats (SHR). Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1376 ± 335 mg [n = 5], 1576 ± 275 mg [n = 5], and 1384 ± 207 mg [n = 5] for control rings, rings treated with ODQ, or rings treated with ODQ plus mexiletine from WKY, respectively; 100% = 1420 ± 251 mg [n = 6], 1313 ± 122 mg [n = 6], and 1247 ± 59 mg [n = 6] for control rings, rings treated with ODQ, or rings treated with ODQ plus mexiletine from SHR, respectively). *Differences between control rings and rings treated with ODQ or rings treated with ODQ plus mexiletine from WKY and SHR and #difference between rings treated with ODQ and rings treated with ODQ plus mexiletine from WKY are both statistically significant (P < 0.05). (B) Concentration-response curves to sodium nitroprusside in the absence or presence of ODQ (10-5 M) in combination with glibenclamide (10-5 M) or with the addition of mexiletine (3 x 10-5 M) obtained in thoracic aortas without endothelium from WKY or SHR. Data are shown as mean ± SD and expressed as a percent of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1387 ± 335 mg [n = 9], 1511 ± 426 mg [n = 9], and 1422 ± 585 mg [n = 9] for control rings, rings treated with ODQ plus glibenclamide, or rings treated with ODQ in combination with glibenclamide and mexiletine from WKY, respectively; 100% = 1420 ± 251 mg [n = 6], 1208 ± 209 mg [n = 5], and 1113 ± 291 mg [n = 6] for control rings, rings treated with ODQ plus glibenclamide, or rings treated with ODQ in combination with glibenclamide and mexiletine from SHR, respectively). *Differences between control rings and rings treated with ODQ plus glibenclamide or rings treated with ODQ in combination with glibenclamide and mexiletine from WKY and SHR are both statistically significant (P < 0.05). (C) Concentration-response curves to sodium nitroprusside in the absence or in the presence of carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (c-PTIO; 10-3 M) or c-PTIO plus mexiletine (3 x 10-5 M) obtained in thoracic aortas without endothelium from WKY or SHR. Data are shown as mean ± SD and expressed as a percentage of maximal relaxation induced by papaverine (3 x 10-4 M; 100% = 1387 ± 335 mg [n = 9], 1520 ± 268 mg [n = 9], and 1440 ± 357 mg [n = 9] for control rings, rings treated with c-PTIO, or rings treated with c-PTIO plus mexiletine from WKY, respectively; 100% = 1400 ± 306 mg [n = 6], 1553 ± 405 mg [n = 6], and 1427 ± 551 mg [n = 6] for control rings, rings treated with c-PTIO, or rings treated with c-PTIO plus mexiletine from SHR, respectively). *Differences between control rings and rings treated with c-PTIO or rings treated with c-PTIO plus mexiletine from WKY and SHR are both statistically significant (P < 0.05).
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Discussion
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This is the first study to determine the effects of an antiarrhythmic drug on vasorelaxation mediated by ATP-sensitive K+ channels in chronic hypertension. The current results suggest that mexiletine induces augmentation of vasorelaxation mediated by ATP-sensitive K+ channels only in the normotensive arteries. This vasodilator effect of mexiletine is probably caused by the soluble guanylate cyclase-independent action of nitric oxide on ATP-sensitive K+ channels in vascular smooth muscle cells.
The present study demonstrated that mexiletine augments vasorelaxation induced by an ATP-sensitive K+ channel opener in the aorta from normotensive, but not hypertensive, rats. This Class Ib antiarrhythmic drug also increased vasorelaxation produced by a nitric oxide donor only in normotensive rat aortas. In addition, these augmented vasodilator responses were completely abolished by glibenclamide, which is a well known selective ATP-sensitive K+ channel antagonist (6). Therefore, our results suggest that mexiletine can enhance the vasodilator responses via the components activated by ATP-sensitive K+ channels only in the normotensive status. Indeed, our recent studies have documented this augmentation of vasorelaxation via ATP-sensitive K+ channels induced by mexiletine in the normotensive conduit arteries (1–3).
We hypothesized that the effects of mexiletine on vasorelaxation through ATP-sensitive K+ channels may be enhanced in chronic hypertension because vasorelaxation in response to ATP-sensitive K+ channel openers is reportedly augmented in the aortas from hypertensive rats (4,5). However, the results obtained in the current study document unexpectedly negative effects of mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels in the aorta from SHRs. The most likely explanation for the negative effects of mexiletine on vasodilator responses induced by ATP-sensitive K+ channel openers in hypertensive rat aortas is that this vasodilator component modified by mexiletine seems to be fully activated by chronic hypertension without the application of this antiarrhythmic drug. However, in hypertensive rat aortas, mexiletine failed to augment vasodilator responses to sodium nitroprusside, and the vasorelaxation to this nitric oxide donor in the absence of mexiletine was not altered. Therefore, we cannot explain the negative effects of mexiletine on vasorelaxation to nitric oxide donors in hypertensive rat aortas by the augmentation of basal activity of ATP-sensitive K+ channels on vascular smooth muscle cells. Vasorelaxation in response to a nitric oxide donor activated by mexiletine only in the normotensive aortas is likely to be a rather insensitive vasodilator component via ATP-sensitive K+ channels, particularly in the hypertensive state. Our results strongly suggest that each mechanism contributing to the insensitive vasodilator effects of mexiletine in chronic hypertension is dependent on substances activating ATP-sensitive K+ channels, although the vasodilator components seem to be similarly insensitive to mexiletine in the hypertensive state. The ATP-sensitive K+ channel is a complex of two proteins: the sulfonylurea receptor, which is a member of the ATP-binding cassette transporter family, and a smaller pore-forming protein, which belongs to the inward rectifier K+ channel family (7). The sulfonylurea receptor of the ATP-sensitive K+ channel is a target of openers of these channels, indicating that mexiletine may affect vasodilator responses induced by ATP-sensitive K+ channel openers through the sulfonylurea receptors (8). However, we do not have a clear explanation of the molecular mechanisms of another vasodilator component activated by mexiletine during vasorelaxation in response to a nitric oxide donor.
In contrast to the findings in the conduit arteries, previous studies suggest that vasodilation in response to an ATP-sensitive K+ channel opener is impaired in the cerebral artery from stroke-prone hypertensive rats when compared with that of normotensive rats (9). Therefore, one should be careful when extrapolating the current results on the conduit arteries to those of resistant blood vessels.
We have demonstrated that in normotensive rat aortas, mexiletine augments vasorelaxation in response to sodium nitroprusside in an ODQ-insensitive manner, suggesting that this Class Ib antiarrhythmic drug causes an increase in vasodilation to a nitric oxide donor via soluble guanylate cyclase-independent mechanisms (3,10,11). However, in this previous study, we could not determine the action of mexiletine in detail on the soluble guanylate cyclase-independent component of vasodilator responses. In the current study, an increase in vasorelaxation in response to sodium nitroprusside induced by mexiletine was completely abolished by ODQ in combination with glibenclamide in normotensive rat aortas. The inhibitory effect of ODQ on increased levels of cyclic GMP induced by sodium nitroprusside have been reported by many studies, including those on blood vessels, and the concentration of ODQ used in our study has proven to be effective in abolishing the increased production of cyclic GMP induced by this nitric oxide donor (10,11). Therefore, our current results suggest that mexiletine can produce the augmentation of vasorelaxation in response to a nitric oxide donor through ATP-sensitive K+ channels, even in the situation where the activity of soluble guanylate cyclase is abolished. This, in turn, indicates that the vasodilator effect of mexiletine is mediated by the direct effect of nitric oxide on these channels in the normotensive status. This conclusion is supported by our results that in normotensive rat aortas treated with the selective nitric oxide scavenger carboxy-PTIO, vasorelaxation in response to sodium nitroprusside was not altered by mexiletine (12). In the current study, carboxy-PTIO did not abolish vasorelaxation in response to sodium nitroprusside. Previous studies suggested that this nitric oxide scavenger has the only limited access to the intracellular site of vascular smooth muscle cells (13). In addition, findings on blood vessels indicated that sodium nitroprusside is capable of producing extracellular as well as intracellular nitric oxide (14). Therefore, these results indicate that the augmenting effect of mexiletine on sodium nitroprusside-induced vasorelaxation is represented by the action of this compound on ATP-sensitive K+ channels activated by extracellular nitric oxide. Our results regarding the direct effects of nitric oxide on ATP-sensitive K+ channels in vascular smooth muscle cells are consistent with many previous studies, indicating that nitric oxide can cause vasodilation mediated by K+ channels, including ATP-sensitive K+ channels, in vascular smooth muscle via cyclic GMP-independent mechanism (8). Therefore, it can be concluded that the compounds acting on ATP-sensitive K+ channels modify that vasodilation induced by nitric oxide.
The therapeutic ranges of plasma concentrations of mexiletine used as an antiarrhythmic drug have been reported as 8 x 10-7 to 10-5 M (15). The concentrations of mexiletine used in the present study seem to be slightly larger than the plasma-free concentrations in clinical situations. However, at least in normotensive patients, this Class Ib antiarrhythmic drug may be capable of producing the enhancement of vasodilator effects of nitric oxide donors, although this combination of drugs is rarely administered in normotensive patients during anesthesia. In contrast, antiarrhythmic drugs and vasodilator substances, including ATP-sensitive K+ channel openers and nitric oxide donors, have many chances to be administered to patients with hypertension. Our negative results of mexiletine on vasodilator responses mediated by ATP-sensitive K+ channels, including a nitric oxide donor and the channel opener, suggest one of the reasons why this antiarrhythmic drug can be safely used in clinical situations for patients with chronic hypertension.
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Acknowledgments
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Supported, in part, by grant-in-aid, 10470324 for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, Tokyo, Japan (Y.H.), and 11–7 for Medical Research from Wakayama prefecture, Wakayama, Japan (H.K.).
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References
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Accepted for publication November 15, 2002.
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Abstract
Introduction
