(Stroke. 1997;28:433-438.)
© 1997 American Heart Association, Inc.
Articles |
Role of Potassium Channels in Relaxations of Isolated Canine Basilar Arteries to Acidosis
the Departments of Anesthesiology and Pharmacology, Mayo Clinic and Mayo Foundation, Rochester, Minn.
Correspondence to Zvonimir S. Katusic, MD, PhD, Departments of Anesthesiology and Pharmacology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail Katusic.Zvonimir@mayo.edu.
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Background and Purpose Concentration of hydrogen ions is an important regulator of cerebral arterial tone under physiological and pathological conditions. Previous studies demonstrated that in cerebral arteries, relaxations to hypercapnia are due to decrease in extracellular pH. The present study was designed to determine the role of potassium channels in mediation of cerebral arterial relaxations induced by extracellular acidosis.
Methods Rings of canine basilar arteries without endothelium were suspended for isometric force recording. Acidosis (pH 7.3 to 7.0) was produced by incremental addition of hydrochloric acid (1.0N). The concentration of hydrogen ions was continuously monitored with a pH meter.
Results During contractions to UTP, acidosis (pH 7.3 to 7.0) induced pH-dependent relaxations. These relaxations were abolished in arteries contracted by potassium chloride (20 mmol/L). A nonselective potassium channel inhibitor, BaCl2 (10-3 and 10-4 mol/L), and an ATP-sensitive potassium channel inhibitor, glyburide (5x10-6 mol/L), significantly reduced relaxations to acidosis. Furthermore, BaCl2 (10-3 mol/L) and glyburide (5x10-6 mol/L) abolished relaxations to an ATP-sensitive potassium channel opener, cromakalim (10-8 to 3x10-5 mol/L). However, these potassium channel inhibitors did not affect relaxations to a voltage-dependent calcium channel inhibitor, diltiazem (10-8 to 10-4 mol/L), and glyburide (5x10-6 mol/L) did not alter relaxations to a nitric oxide donor, SIN-1 (10-9 to 10-4 mol/L). A calcium-activated potassium channel inhibitor, charybdotoxin (10-7 mol/L), and a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10-3 mol/L), did not affect relaxations to acidosis.
Conclusions These results suggest that extracellular acidosis causes relaxations of cerebral arteries in part by activation of potassium channels. ATP-sensitive potassium channels appear to contribute to acidosis-induced decrease in cerebral arterial tone.
Key Words: acidosis • cerebral arteries • potassium channels • vasodilation • dogs
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Previous studies demonstrated that reduction of pH is an important regulator in cerebral arterial dilation to carbon dioxide.1 2 3 4 5 6 A recent study in rat cerebral arteries demonstrated that decreased extracellular pH is responsible for vasodilation to hypercapnic acidosis.7 Furthermore, in cat cerebral arterial smooth muscle, lowering of extracellular pH causes hyperpolarization.8 Activation of potassium channels produces vasodilation by membrane hyperpolarization.9 10 Indeed, in voltage-clamped cat cerebral arterial smooth muscle cells, lowering of extracellular pH causes increase in outward potassium current.11 In addition, open probability of ATP-sensitive potassium channels can be augmented by reduction of pH.12 A recent in vivo study in rabbit pial arteries suggested that activation of ATP-sensitive potassium channels may contribute to dilation of cerebral arterioles during hypercapnia.13 In coronary arteries, opening of ATP-sensitive potassium channels on smooth muscle cells can induce arteriolar dilation during acidosis.14 The role of potassium channels in mediation of cerebral arterial relaxations to acidosis has not been studied. The present study was designed to determine whether potassium channels may play a role in relaxation of large cerebral arteries exposed to extracellular acidosis.
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Materials and Methods |
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The experiments were performed on 4-mm basilar artery rings taken from mongrel dogs (weight, 15 to 20 kg) of either sex, anesthetized with 30 mg/kg IV sodium pentobarbital. All procedures were conducted in accordance with institutional guidelines. Rings were studied in modified Krebs-Ringer bicarbonate solution (control solution) of the following composition (mmol/L): NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0, calcium EDTA 0.026, and glucose 11.1. In all rings the endothelium was removed mechanically, and the endothelial removal was confirmed by the absence of relaxation to vasopressin (10-7 mol/L).15 Experiments were performed on arteries without endothelium because several previous studies demonstrated that relaxations of canine, monkey, and rat cerebral arteries in response to hypercapnia or acidosis are not dependent on the presence of intact endothelial cells.4 5 6 Each ring was connected to an isometric force transducer (model FT03, Grass Instrument Co) and suspended in an organ chamber filled with 25 mL control solution (37°C, pH 7.4) bubbled with 94% O2/6% CO2 gas mixture. Arteries were gradually stretched to the optimal point of the length-tension curve as determined by the contraction to UTP (10-5 mol/L). In most of the studied arteries optimal tension was achieved at approximately 3 g. After an equilibration period of 90 minutes, acidosis-induced vasodilation was studied by incrementally adding hydrochloric acid (1.0N, total volume <300 µL) to the organ chamber to reduce extravascular pH.14 The pH of the bathing solution was continuously monitored with a pH meter (model 307, pH/Temperature Meter, Corning Inc).
Drugs
The following pharmacological agents were used: arginine vasopressin, BaCl2, charybdotoxin, cromakalim, diltiazem hydrochloride, dimethyl sulfoxide (DMSO), papaverine hydrochloride, UTP (Sigma), glyburide (BIOMOL Research Laboratories Inc), 4-aminopyridine (Research Biochemicals International), hydrochloric acid (Curtin Matheson Scientific, Inc), 3-morpholinosydnonimine (SIN-1; Molecular Probes), and KCl (EM SCIENCE). Drugs were dissolved in distilled water such that volumes of less than 0.2 mL were added to the organ chambers. Stock solutions of charybdotoxin (10-7 mol/L), cromakalim (3x10-5 mol/L), and glyburide (5x10-6 mol/L) were prepared in DMSO (0.5x10-4 to 1.6x10-4 mol/L). The concentrations of drugs are expressed as final molar concentration.
Concentration-response curves were obtained in a cumulative fashion. Responses to acidosis, cromakalim, diltiazem, and SIN-1 were obtained during submaximal contractions to UTP (10-5 or 3x10-5 mol/L). Because 4-aminopyridine, BaCl2, charybdotoxin, and KCl increased resting tension, care was taken to match the contractions induced by UTP in control and treated rings. The relaxations were expressed as a percentage of the maximal relaxations to papaverine (3x10-4 mol/L). The incubation periods were 15 minutes for 4-aminopyridine, BaCl2, charybdotoxin, glyburide, and KCl.
Statistical Analysis
The data are expressed as mean±SEM; n refers to the number of dogs from which the basilar artery was taken. Statistical analysis was performed with the use of a one-way ANOVA, followed by Scheffe's F test. Differences were considered statistically significant at P<.05.
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During contractions to UTP (10-5 or 3x10-5 mol/L), acidosis (pH 7.3 to 7.0) induced pH-dependent relaxations (Fig 1
). In arteries contracted by KCl (20 mmol/L), relaxations to acidosis were abolished (Fig 1). A nonselective potassium channel inhibitor, BaCl2 (10-3 and 10-4 mol/L), significantly inhibited relaxations to acidosis in a concentration-dependent fashion (Fig 2). An ATP-sensitive potassium channel inhibitor, glyburide (5x10-6 mol/L), significantly reduced relaxations induced by pH of 7.3 and 7.2 (Fig 3). BaCl2 (10-3 mol/L) and glyburide (5x10-6 mol/L) abolished relaxations to an ATP-sensitive potassium channel opener, cromakalim (10-8 to 3x10-5 mol/L) (Fig 4). In contrast, these potassium channel inhibitors did not affect relaxations to a voltage-dependent calcium channel inhibitor, diltiazem (10-8 to 10-4 mol/L) (Table 1), and glyburide (5x10-6 mol/L) did not alter relaxations to a nitric oxide donor, SIN-1 (10-9 to 10-4 mol/L, -log EC50=7.2±0.0 [n=5] and 7.1±0.1 [n=5] for control rings and rings treated with glyburide, and maximal relaxation=-99.5±0.5% [n=5] and -100.0±0.0% [n=5] for control rings and rings treated with glyburide, respectively). A calcium-activated potassium channel inhibitor, charybdotoxin (10-7 mol/L), and a delayed rectifier potassium channel inhibitor, 4-aminopyridine (10-3 mol/L) did not affect relaxations to acidosis (Table 2). Vascular sensitivity to cromakalim (10-8 to 3x10-5 mol/L) was similar between rings obtained from proximal and distal portions of basilar arteries (Fig 5).
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The results of the present study suggest that in canine basilar arteries, extracellular acidosis (pH 7.3 to 7.0) causes smooth muscle relaxations by activation of potassium channels. A significant component of this effect appears to be mediated by activation of ATP-sensitive potassium channels.
Potassium chloride is a well-established depolarizing agent that can inhibit activity of potassium channels.5 9 16 Abolition of relaxations to acidosis in arteries contracted by extracellular potassium indicates that potassium channels are involved in the pH-induced change in vascular tone. This conclusion is further supported by the results observed in arteries treated with BaCl2. Elevation of extracellular Ba2+ can depress potassium conductance,17 and BaCl2 is a nonselective potassium channel inhibitor.9 18 19 Thus, our observation that BaCl2 markedly reduced arterial smooth muscle relaxations to acidosis (pH 7.3 to 7.0) is best explained by the involvement of potassium channels in acidosis-induced cerebral arterial dilation. Moreover, BaCl2 (10-3 mol/L) did not affect relaxations to the voltage-dependent calcium channel inhibitor diltiazem, suggesting that this effect of BaCl2 is selective for potassium channels.
Glyburide has been shown to be a selective antagonist of ATP-sensitive potassium channels, and it does not affect activity of calcium channels, inward rectifier, delayed rectifier, and calcium-activated potassium channels.9 18 20 21 These results are in agreement with our observations that glyburide (5x10-6 mol/L) did not affect relaxations to diltiazem or SIN-1 and that it abolished relaxations to an ATP-sensitive potassium channel opener, cromakalim.10 Our findings that glyburide (5x10-6 mol/L) significantly reduced the effect of acidosis suggest that ATP-sensitive potassium channels contribute to these relaxations. This conclusion is consistent with results of a recent study on coronary arteries, demonstrating the role of ATP-sensitive potassium channels in arteriolar dilation to acidosis.14 Since ATP-sensitive potassium channels in smooth muscle are also inhibited by Ba2+,9 our results with BaCl2 and cromakalim reinforce the conclusion regarding the important role of ATP-sensitive potassium channels in acidosis-induced cerebroarterial dilation.
Nagao and colleagues22 reported that in rabbits, sensitivity to an ATP-sensitive potassium channel opener, levcromakalim, decreases in the distal portion of basilar arteries. In contrast, the results of our study demonstrate that in dogs, relaxations to another ATP-sensitive potassium channel opener, cromakalim, are identical in rings obtained from proximal and distal segments of basilar arteries. Thus, it is very unlikely that our results were influenced by the ATP-sensitive potassium channel heterogeneity in basilar arteries.
Calcium-activated potassium channels are blocked by the scorpion venom, including charybdotoxin.23 24 25 26 Inability of charybdotoxin (10-7 mol/L) to affect relaxations to acidosis suggests that calcium-activated potassium channels do not mediate acidosis-induced cerebral arterial dilation.
4-Aminopyridine is a selective inhibitor of delayed rectifier potassium channels.9 19 27 28 29 In cerebral arteries, inhibitors of ATP-sensitive, calcium-activated, and inward rectifier potassium channels did not affect changes in membrane potential induced by 4-aminopyridine,30 demonstrating selectivity of this compound for delayed rectifier potassium channels. In our experiments, 4-aminopyridine (10-3 mol/L) did not affect relaxations to acidosis, indicating that in cerebral arteries, delayed rectifier potassium channels are not involved in smooth muscle relaxations to reduced pH. A previous study demonstrated that in cat cerebral vascular smooth muscle cells, 4-aminopyridine inhibits potassium currents induced by lowering of extracellular pH.11 We do not have an explanation for the differential effect of extracellular acidosis on 4-aminopyridine-sensitive potassium channels between canine and cat cerebral arterial smooth muscle cells. However, species difference may be the most likely reason for this discrepancy.
It is important to note that BaCl2 (10-3 mol/L), which can inhibit ATP-sensitive, delayed rectifier, and inward rectifier potassium channels, markedly impaired relaxations to acidosis, whereas BaCl2 (10-4 mol/L), which probably inhibits ATP-sensitive and inward rectifier potassium channels, caused an inhibitory effect similar to the effect of high concentrations of glyburide.9 18 19 Higher concentrations of BaCl2 (10-3 mol/L) may inhibit glyburide-insensitive, ATP-sensitive potassium channels. Indeed, Gopalakrishnan et al31 demonstrated that in the brain, the potassium channel openers cromakalim, nicorandil, pinacidil, and minoxidil were not effective as inhibitors of [3H]glyburide binding, suggesting that several different ATP-sensitive potassium channels with differential pharmacological sensitivity to the sulphonylureas and the potassium channel openers may exist in the central nervous system. Thus, it is likely that glyburide-insensitive, BaCl2 (10-3 mol/L)-sensitive potassium channels may be in part responsible for acidosis-induced relaxations.
Recent findings demonstrated the presence of pH-sensitive potassium channels in rabbit cerebral arterial smooth muscle.32 33 These channels are characterized by an inward rectifier current.32 33 Inward rectifier potassium channels are inhibited by low concentrations of extracellular barium.34 Since BaCl2 inhibited relaxations to acidosis, we cannot rule out the involvement of inward rectifier potassium channels in these relaxations. However, BaCl2 (10-4 mol/L), which can inhibit ATP-sensitive and inward rectifier potassium channels, caused inhibition of relaxations to acidosis similar to those induced by high concentrations of glyburide,9 18 19 suggesting that this inhibition of relaxations by BaCl2 (10-4 mol/L) is mainly due to blockade of ATP-sensitive potassium channels.
In vivo, increase in cerebral blood flow in response to hypercapnia or extracellular acidosis is abolished or partly reduced by nitric oxide synthase inhibitors.13 35 36 37 38 39 In contrast, in vitro studies demonstrated that in isolated canine, monkey, and rat cerebral arteries, removal of endothelium or inhibition of nitric oxide synthase does not affect relaxations to hypercapnia or extracellular acidosis.4 5 6 These findings suggest that under in vivo conditions, nitric oxide may play a role in reactivity of cerebral arteries to acidosis. However, the results obtained on the isolated blood vessels strongly suggest that the source of nitric oxide is not in vascular wall. It is apparent from the results of the present study that the vasodilator effect of acidosis is not entirely dependent on nitric oxide production. More recent preliminary findings demonstrated that L-arginine analogues used to inhibit nitric oxide synthase in vivo may have a nonselective effect and inactivate potassium channels,40 suggesting that the role of nitric oxide in acidosis-induced vasodilation in vivo may have been overestimated. Further studies are certainly needed to determine relative contribution of nitric oxide–dependent and nitric oxide–independent mechanisms in mediation of vasodilator effect of acidosis.
ATP-sensitive potassium channels are involved in the metabolic regulation of blood flow and are activated by low pH.9 12 14 41 Indeed, lactic acidosis also leads to a glyburide-sensitive decrease in blood pressure,42 suggesting a possible role of these channels in circulatory shock. In cerebral arteries, during hypoxia and ischemia, ATP-sensitive potassium channels are activated, resulting in arterial dilation and/or increased tolerance of cerebral tissues to ischemia.43 44 These studies suggest that activation of potassium channels plays an important role in regulation of cerebral circulation during acidosis. Our results demonstrated that potassium channels on cerebral arterial smooth muscle cells mediate vasodilation induced by decreased pH.
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Acknowledgments |
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This study was supported in part by National Heart, Lung, and Blood Institute grant HL-53524 and the Mayo Foundation. We thank Leslie Smith for technical assistance and Janet Beckman for typing the manuscript.
Received July 12, 1996; revision received November 6, 1996; accepted November 6, 1996.
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Editorial Comment
Department of Internal MedicineMedical College of VirginiaRichmond, Va
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It is generally accepted that the primary mechanism of the vasodilator effect of hypercapnia on cerebral blood vessels is a local action involving a decrease in the extracellular fluid pH. Although this evidence was first reported (see Reference 2 in the accompanying article) almost two decades ago, the mechanism by which H+ relaxes cerebral vascular smooth muscle and thereby dilates cerebral vessels has remained elusive. In recent years one particular potent vasodilator, nitric oxide, has attracted much attention as the likely mediator for the hypercapnia-induced dilation. This evidence of nitric oxide involvement is based primarily on pharmacological experiments in which high doses of arginine analogues were used. However, in vitro studies, the present study included, demonstrated that isolated cerebral blood vessels in the absence of endothelial cells or neuronal elements continued to dilate normally in response to hypercapnic acidosis, suggesting that the response is a direct action on vascular smooth muscle and independent of the production of nitric oxide from endothelial or neuronal nitric oxide synthase.
More recently it was found that hypercapnic acidosis opens potassium channels (see article Reference 13). A recent study1R showed that high-dose arginine analogues inhibit the hypercapnia-induced dilation by blocking ATP-sensitive potassium channels.
In the present study the authors systematically examined the role of potassium channels in mediating vascular relaxation from acidosis. To my knowledge, this is the first evidence from isolated cerebral blood vessels showing that cerebral vasodilation to acidosis can be explained in part by activation of ATP-sensitive potassium channels. It is of interest that glyburide did not completely inhibit relaxations at lower pH values in the present study. This is similar to observations made in in vivo studies in which residual dilation to severe hypercapnic acidosis persisted in the presence of glyburide or high-dose arginine analogues. In the present study the authors attributed this residual dilation at low pH values to other types of ATP-sensitive potassium channels that are glyburide-insensitive yet BaCl2-sensitive. It remained to be clarified in animal studies whether other mechanisms, in addition to ATP-sensitive potassium channels, are involved in cerebral vasodilator response induced by severe hypercapnic acidosis.
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1R. Kontos HA, Wei EP. Arginine analogues inhibit responses mediated by ATP-sensitive K+ channels. Am J Physiol.. 1996;271:H1498-H1506.
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H. Kinoshita, H. Iranami, Y. Kimoto, M. Dojo, and Y. Hatano Cibenzoline Has an Inhibitory Effect on Vasorelaxation Mediated by Adenosine Triphosphate-Sensitive K+ Channels in the Rat Carotid Artery Anesth. Analg., August 1, 2001; 93(2): 282 - 286. [Abstract] [Full Text] [PDF]
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T. Pfefferkorn, S. von Stuckrad-Barre, J. Herzog, T. Gasser, G. F. Hamann, and M. Dichgans Reduced Cerebrovascular CO2 Reactivity in CADASIL : A Transcranial Doppler Sonography Study Stroke, January 1, 2001; 32(1): 17 - 21. [Abstract] [Full Text] [PDF]
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 T. Najarian, A. M. Marrache, I. Dumont, P. Hardy, M. H. Beauchamp, X. Hou, K. Peri, F. Gobeil Jr, D. R. Varma, and S. Chemtob Prolonged Hypercapnia-Evoked Cerebral Hyperemia via K+ Channel- and Prostaglandin E2-Dependent Endothelial Nitric Oxide Synthase Induction Circ. Res., December 8, 2000; 87(12): 1149 - 1156. [Abstract] [Full Text] [PDF]
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M. Bayerle-Eder, M. Wolzt, E. Polska, H. Langenberger, J. Pleiner, D. Teherani, G. Rainer, K. Polak, H.-G. Eichler, and L. Schmetterer Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1667 - R1673. [Abstract] [Full Text] [PDF]
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C. Austin and S. Wray Interactions Between Ca2+ and H+ and Functional Consequences in Vascular Smooth Muscle Circ. Res., February 18, 2000; 86(3): 355 - 363. [Abstract] [Full Text] [PDF]
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D. A. Pelligrino, R. A. Santizo, and Q. Wang Miconazole represses CO2-induced pial arteriolar dilation only under selected circumstances Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1484 - H1490. [Abstract] [Full Text] [PDF]
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E. P. Wei, H. A. Kontos, and F. M. Faraci Blockade of ATP-Sensitive Potassium Channels in Cerebral Arterioles Inhibits Vasoconstriction From Hypocapnic Alkalosis in Cats • Editorial Comment Stroke, April 1, 1999; 30(4): 851 - 854. [Abstract] [Full Text] [PDF]
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M. D. S. Frame Conducted signals within arteriolar networks initiated by bioactive amino acids Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H1012 - H1021. [Abstract] [Full Text] [PDF]
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 F. M. FARACI and D. D. HEISTAD Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels Physiol Rev, January 1, 1998; 78(1): 53 - 97. [Abstract] [Full Text] [PDF]
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