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(Circulation Research. 1996;78:50-57.)
© 1996 American Heart Association, Inc.

Articles

Acidosis-Induced Coronary Arteriolar Dilation Is Mediated by ATP-Sensitive Potassium Channels in Vascular Smooth Muscle

Hiroshi Ishizaka, Lih Kuo

From the Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station, Tex.

Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station, TX 77843-1114. E-mail lkuo@tamu.edu.

	Abstract

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Abstract Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulation during hypoxia, ischemia, and increased metabolic demand of the heart, its vasomotor control mechanism has not been elucidated. To examine the effect of acidosis on vasomotor tone, porcine coronary arterioles (40 to 110 µm) were isolated, cannulated, and pressurized to 60 cm H₂O intraluminal pressure without flow for in vitro study. Acidosis (pH 7.4 to 7.0) was produced by adding HCl to the extravascular solution. The involvement of potassium channels in the vasomotor response to acidosis was evaluated by using BaCl₂ (100 µmol/L, nonspecific potassium channel inhibitor), glibenclamide (5 µmol/L, ATP-sensitive potassium channel inhibitor), and iberiotoxin (100 nmol/L, calcium-activated potassium channel inhibitor). To determine whether endothelial hyperpolarization contributes to the acidosis-induced dilation, the pH-diameter relation of the vessel was examined under a high intraluminal concentration of KCl (40 mmol/L). The involvement of nitric oxide and prostaglandins was assessed by using N^G-monomethyl-L-arginine (L-NMMA, 10 µmol/L) and indomethacin (10 µmol/L), respectively. To evaluate the role of endothelium in the acidosis-induced dilation, the pH-diameter relation was studied after endothelial removal. All vessels developed a similar level of spontaneous tone (internal diameter, 75±4 µm [69±1% of maximum diameter]) and dilated to HCl in a dose-dependent manner. Glibenclamide completely abolished vasodilation to a mild level of acidosis (pH 7.2 to 7.3) and attenuated the vasodilation by 70% at pH 7.0. Acidosis-induced dilation was also inhibited by BaCl₂ but not by iberiotoxin. L-NMMA, indomethacin, and intraluminal KCl did not alter the pH-diameter relation. Vasodilation to acidosis of the endothelium-denuded vessels was identical to that of the endothelium-intact vessels. In addition, glibenclamide attenuated the acidosis-induced arteriolar dilation of endothelium-denuded vessels in a manner similar to that of endothelium-intact vessels. These results suggest that the opening of ATP-sensitive potassium channels in vascular smooth muscle mediates the coronary arteriolar dilation during acidosis.

Key Words: endothelium • microcirculation • nitric oxide • prostaglandins • vasodilation

	Introduction

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Over one century ago, Gaskell¹ studied the tonicity of blood vessels in frog skeletal muscle and found that arteries dilate significantly during perfusion of acidic solution. Since then, the phenomenon of vasodilation in response to acidosis has been consistently reported in many vascular beds of mammalian tissue, including cerebral,^{2 3} skeletal muscle,⁴ and coronary⁵ circulations. Although a decrease in extravascular pH has been suggested to be involved in coronary flow regulation during hypoxia, ischemia, and increased metabolic demand of the heart,⁶ its vasomotor control mechanism has not been elucidated. In vivo study of canine coronary circulation indicates that acidosis-induced vasodilation is independent of muscarinic, ß-adrenergic, or sympathetic nervous activation.⁵ Interestingly, a recent in vivo study showed that intracoronary administration of L-arginine analogues attenuates coronary vascular dilation in response to hypercapnic acidosis,⁷ suggesting that endogenous release of nitric oxide may be responsible for the acidosis-induced coronary vasodilation. Since nitric oxide has been shown to participate in the regulation of vascular tone during variation of local hemodynamic factors (ie, shear stress) and also to modulate coronary autoregulation,⁸ it is not clear whether the attenuation of vasodilation by L-arginine analogues is due to the inhibition of vascular response to acidosis or due secondarily to the inhibition of nitric oxide–related vasoregulatory mechanisms. Therefore, the role of nitric oxide in the mediation of acidosis-induced dilation is still not clear.

Recently, it has been reported that lowering pH_o causes vascular hyperpolarization.⁹ Since the activation of potassium channels is a major vasodilatory mechanism through membrane hyperpolarization,¹⁰ the goal of the present study was to examine whether any specific potassium channels, such as K_ATP and/or K_Ca channels, are involved in the coronary arteriolar dilation in response to acidosis. In addition, the role of endothelium and the release of nitric oxide and prostaglandins were evaluated. To accomplish this goal, isolated vessel techniques were used to eliminate the confounding influences from neurohumoral and local control mechanisms. Since the majority of coronary resistance (>60%) was observed downstream from arterioles <150 µm in diameter,¹¹ it is important to understand the basic regulatory mechanisms that control resistance in these small arteriolar vessels during acidosis.

	Materials and Methods

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General Preparation
Pigs (8 to 12 weeks old of either sex) were sedated with an intramuscular injection of telazol (4.4 mg/kg) and xylazine (2.25 mg/kg), anesthetized, and then heparinized with an intravenous injection of pentobarbital sodium (20 mg/kg) and heparin (1000 U/kg), respectively, via the marginal ear vein. Pigs were intubated and ventilated with room air. After a left thoracotomy was performed, the heart was electrically fibrillated, excised, and immediately placed in cold (5°C) saline solution.

Isolation and Cannulation of Microvessels
The techniques for isolation of porcine coronary arterioles were described previously.¹² In brief, a mixture of india ink and gelatin in PSS containing (mmol/L) NaCl 145.0, KCl 4.7, CaCl₂ 2.0, MgCl₂ 1.17, NaH₂PO₄ 1.2, glucose 5.0, pyruvate 2.0, EDTA 0.02, and MOPS buffer 3.0 was perfused into the left anterior descending artery and the circumflex artery to enable visualization of the coronary microvessels. The subepicardial coronary arterioles (40 to 110 µm) were carefully dissected from surrounding cardiac tissue under cold (5°C) PSS containing albumin (1 g/100 mL PSS, US Biochemical Corp) at pH 7.4. Each isolated microvessel was then transferred for cannulation to a Lucite vessel chamber containing albumin-PSS (pH 7.4) equilibrated with room air at ambient temperature. One end of the microvessel was cannulated with a glass micropipette filled with filtered albumin-PSS, and the outside of the microvessel was securely tied to the pipette with 11-O ophthalmic suture (Alcon). The ink-gelatin solution inside the vessel was flushed out at a low perfusion pressure (<20 cm H₂O). The other end of the vessel was cannulated with a second micropipette and secured with a suture.

Instrumentation
After a vessel was cannulated, the preparation was transferred to the stage of an inverted microscope (Diaphot 300, Nikon) coupled to a CCD camera (TM-34KC, Pulnix) and video micrometer (Microcirculation Research Institute, Texas A&M University Health Science Center). Internal diameters of the vessel were measured throughout the experiment by using video microscopic techniques incorporated with the MacLab (ADInstruments Inc) data acquisition system.¹³ The micropipettes were connected to independent pressure reservoir systems, and intraluminal pressures were measured through side arms of the two reservoir lines by low-volume displacement strain-gauge transducers (Statham P23 Db, Gould). The isolated vessels were pressurized without flow by setting both reservoirs at the same hydrostatic level. Leaks were detected by closing off the system to the reservoirs and examining for a decline in intraluminal pressure. Preparations with leaks were excluded from further study.

Experimental Protocols
Each cannulated vessel was bathed in albumin-PSS and equilibrated with room air, and the temperature was maintained at 36°C to 37°C by an external heat changer. The vessel was set to its in situ length and allowed to develop spontaneous tone at 60 cm H₂O intraluminal pressure without flow. This pressure is comparable to that in coronary arterioles of this size in vivo.¹¹ After a stabilization period of 60 minutes, acidosis-induced vasodilation was studied by incrementally adding HCl (0.05N) to the vessel bath to reduce extravascular pH. Vessel diameter was measured at pH values of 7.4, 7.3, 7.2, 7.1, and 7.0. After the pH-diameter relation was examined, the arteriole was washed with albumin-PSS and equilibrated for 60 minutes. To evaluate the role of different potassium channels in acidosis-induced vasodilation, the arteriole was then exposed to glibenclamide (5 µmol/L, a specific inhibitor of K_ATP channels^{14 15} ), iberiotoxin (100 nmol/L, a specific inhibitor of K_Ca channels^{10 16} ), or BaCl₂ (100 µmol/L, a nonspecific inhibitor of potassium channels¹⁷ ) for 20 minutes, and the pH-diameter relation of the vessel was reexamined. The extravascular pH was not altered by adding inhibitors (20 µL) to the vessel bath (2 mL). In some control experiments, the pH-diameter relation was studied repeatedly to confirm its reproducibility.

The involvement of nitric oxide and prostaglandins in acidosis-induced vasodilation was determined by using their specific inhibitors, L-NMMA (Calbiochem) and indomethacin, respectively. The pH-diameter relation of the vessel was examined before and after incubation with either L-NMMA (10 µmol/L) or indomethacin (10 µmol/L) for 30 minutes. To examine whether endothelial hyperpolarization contributes to acidosis-induced coronary arteriolar dilation, the intraluminal fluid of the vessel was replaced with a solution containing a high concentration of potassium (40 mmol/L) to inhibit endothelial hyperpolarization. To accomplish this, an isotonic high-potassium albumin-PSS was prepared by substituting 35 mmol/L NaCl with an equimolar amount of KCl. After 10 minutes of incubation, the vasodilation to acidosis was examined. Finally, to assess the role of endothelium in acidosis-induced vasodilation, experiments were performed to evaluate the pH-diameter relation after endothelial denudation. These denuded vessels were also exposed to glibenclamide (5 µmol/L) to evaluate the involvement of smooth muscle K_ATP channels in the mediation of vasodilation to acidosis. To evaluate whether glibenclamide has a nonspecific effect on the vascular function, the dose-dependent dilation of isolated vessels to sodium nitroprusside (10^-9 to 10^-5 mol/L) was examined in the presence of glibenclamide (5 µmol/L). At the end of each experiment, each vessel was relaxed completely with nitroprusside (100 µmol/L) in albumin-PSS to obtain the maximum diameter at 60 cm H₂O intraluminal pressure.

Endothelial Denudation
CHAPS (0.4%), a nonionic detergent, was intraluminally perfused into the vessel for 1 to 2 minutes to remove endothelial cells. After disruption of the endothelium, as verified by the absence of vasodilation in response to the endothelium-dependent vasodilator bradykinin (100 nmol/L), the vessel was perfused with PSS-albumin for 5 minutes to remove CHAPS. To ensure that the vascular smooth muscle function was not compromised by CHAPS, dose-dependent dilation of the denuded vessel to sodium nitroprusside (10^-9 to 10^-5 mol/L) was examined. Only vessels that exhibited normal spontaneous tone, showed no vasodilation to bradykinin, and showed unaltered vasodilation to nitroprusside after endothelial removal were accepted for data analysis.

Chemicals
Drugs were obtained from Sigma Chemical Co, except as specifically stated. Iberiotoxin, BaCl₂, L-NMMA, bradykinin, and sodium nitroprusside were dissolved in PSS. Glibenclamide and indomethacin were dissolved in DMSO and then diluted in PSS to obtain the desired final concentration. The final concentration of DMSO in tissue bath was 0.03%. Vehicle control study indicated that this concentration of DMSO had no effect on the arteriolar responses to acidosis.

Data Analysis
All diameter changes were normalized to the maximum dilation in the presence of sodium nitroprusside (100 µmol/L) and expressed as a percentage of maximum dilation. All data are described as mean±SEM. Statistical comparisons of acidosis-induced vasodilation under different treatments were performed with two-way ANOVA and tested with Fisher's protected least significant difference multiple-range test. Differences in baseline diameter before and after pharmacological interventions and the vascular responses to bradykinin before and after endothelial removal were compared by paired t test. Significance was accepted at P<.05.

	Results

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Acidosis-Induced Coronary Arteriolar Dilation
All isolated arterioles developed a similar level of spontaneous tone (69±1% of their maximum diameter) within 40 minutes at 36°C to 37°C bath temperature and 60 cm H₂O intraluminal pressure without flow. The response of an isolated coronary arteriole (46 µm) to a stepwise reduction of solution pH is shown in Fig 1A. Hydrogen ions increased coronary arteriolar diameter in a concentration-dependent manner. When the tissue bath was replaced with a normal pH solution (pH 7.4), the diameter returned to the control level within 6 minutes (Fig 1A). The extent of vasodilation to pH reduction was reproducible after equilibration of the vessels (n=5) for 60 minutes.

View larger version (17K): [in this window] [in a new window]   Figure 1. Effect of extravascular acidosis on the coronary arteriolar diameter. A, Acidosis-induced coronary arteriolar dilation. Hydrogen ions dilated the coronary arteriole in a concentration-dependent manner. After a normal pH solution (pH 7.4) was restored, the diameter returned to the baseline level. B, Effect of glibenclamide on the acidosis-induced arteriolar dilation. Exposure of the vessel to glibenclamide (5 µmol/L) for 20 minutes did not alter the baseline diameter of the vessel, but the dilation in response to an increase in hydrogen ion concentration (pH 7.2) was abolished.

Effect of Potassium Channel Inhibitors
As shown in Fig 1B, under control conditions, an acute decrease in extravascular pH from 7.4 to 7.2 produced a marked vasodilation (21% increase in diameter from baseline). Exposure of the vessel to glibenclamide (5 µmol/L) for 20 minutes did not alter the baseline diameter, but the vasodilation in response to an acute reduction in pH (7.2) was abolished (Fig 1B). The average response of coronary arterioles to various degrees of acidosis (pH 7.4 to 7.0) is summarized in Fig 2. Glibenclamide (5 µmol/L) completely abolished arteriolar vasodilation at moderate acidosis (pH 7.2 to 7.3) and significantly attenuated the vasodilatory response to the severe reductions in pH (7.0 to 7.1). Acidosis-induced arteriolar dilation was also attenuated by BaCl₂ (100 µmol/L) but not by iberiotoxin (100 nmol/L) (Fig 2).

View larger version (23K): [in this window] [in a new window]   Figure 2. Effect of potassium channel inhibitors on the acidosis-induced arteriolar dilation. The pH-diameter relation was examined in the absence (control; resting diameter, 74±6 µm; maximum diameter, 105±8 µm; n=15) and presence of extraluminal glibenclamide (5 µmol/L; resting diameter, 88±9 µm; maximum diameter, 127±10 µm; n=5), iberiotoxin (100 nmol/L; resting diameter, 64±8 µm; maximum diameter, 93±12 µm; n=5), or BaCl2 (100 µmol/L; resting diameter, 65±13 µm; maximum diameter, 94±15 µm; n=5). Iberiotoxin-treated vessels dilated significantly (P<.05) to acidosis (pH 7.3 to 7.0), and the extent of the dilation was not different from the control value. Glibenclamide and BaCl2 significantly inhibited vasodilation to acidosis compared with the control condition (*P<.05).

Contribution of Nitric Oxide, Prostaglandins, and Endothelial Hyperpolarization
Extravascular administration of L-NMMA (10 µmol/L) slightly but not significantly decreased arteriolar diameter from 74±8 to 67±7 µm. The pH-diameter relation of coronary arterioles was not altered by L-NMMA (Fig 3). Incubation of the vessels with indomethacin (10 µmol/L) did not affect either resting arteriolar diameter or the arteriolar response to acidosis (Fig 3). To examine whether vasodilation during acidosis is due to transduction of a hyperpolarization signal from the endothelium via a gap junction mechanism, the intraluminal fluid was replaced with a solution containing a high concentration of potassium (40 mmol/L) to inhibit the endothelial hyperpolarization. The high intraluminal concentration of potassium did not alter resting vascular tone (87±11 µm [control] versus 86±12 µm [after intraluminal KCl]), and the pH-diameter relation was identical to that in the control condition (Fig 4).

View larger version (19K): [in this window] [in a new window]   Figure 3. Effect of L-NMMA and indomethacin on the acidosis-induced arteriolar dilation. The pH-diameter relation was studied in the absence (control; resting diameter, 74±8 µm; maximum diameter, 112±10 µm; n=10) and presence of extraluminal L-NMMA (10 µmol/L; resting diameter, 67±7 µm; maximum diameter, 114±15 µm; n=5) or indomethacin (10 µmol/L; resting diameter, 71±10 µm; maximum diameter, 109±14 µm; n=5). Neither L-NMMA nor indomethacin altered the acidosis-induced coronary arteriolar dilation.

View larger version (17K): [in this window] [in a new window]   Figure 4. Effect of intraluminal KCl on the acidosis-induced arteriolar dilation. The pH-diameter relation of the vessel was not altered by the administration of a high intraluminal concentration of KCl (40 mmol/L; resting diameter, 86±12 µm; maximum diameter, 119±11 µm; n=3).

Role of Endothelium
Fig 5 summarizes the effect of endothelial removal on vascular dilation to acidosis. Before endothelial denudation, coronary arterioles dilated from a baseline value of 77±13 to 101±20 µm (n=4, P<.05) in response to bradykinin (100 nmol/L). Disruption of endothelium by CHAPS did not significantly alter vascular tone (77±13 µm [before denudation] versus 75±14 µm [after denudation]) but abolished the dilation to bradykinin (75±14 to 76±13 µm, P>.05). In addition, the dose-dependent vasodilation to nitroprusside (10^-9 to 10^-5 mol/L) was not altered after endothelial denudation. In these denuded vessels, the vasodilatory response to acidosis was identical to that of endothelium-intact vessels, but this dilation was attenuated in the presence of glibenclamide (5 µmol/L) (Fig 5).

View larger version (23K): [in this window] [in a new window]   Figure 5. Effect of endothelial denudation on acidosis-induced arteriolar dilation. Vasodilation of the endothelium-denuded vessels (resting diameter, 75±14 µm; maximum diameter, 101±19 µm; n=4) to acidosis was identical to that of the endothelium-intact vessels (resting diameter, 75±4 µm; maximum diameter, 109±6 µm; n=28). In addition, glibenclamide (5 µmol/L) significantly attenuated the vasodilation of these denuded vessels to acidosis (*P<.05).

Effect of Glibenclamide on Vascular Function
Sodium nitroprusside (10^-9 to 10^-5 mol/L), an endothelium-independent vasodilator, produced dose-dependent dilation of isolated coronary arterioles (Fig 6). This dilation was not altered in the presence of glibenclamide (5 µmol/L), indicating that the vasodilatory capacity of these vessels was not affected by glibenclamide.

View larger version (20K): [in this window] [in a new window]   Figure 6. Effect of glibenclamide on sodium nitroprusside–induced arteriolar dilation. Dose-dependent arteriolar dilation in response to sodium nitroprusside was not altered in the presence of glibenclamide (5 µmol/L; resting diameter, 65±7 µm; maximum diameter, 98±5 µm; n=5).

	Discussion

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The major findings of the present study are as follows: (1) Hydrogen ions dilate the coronary arterioles in a concentration-dependent manner. (2) Acidosis-induced arteriolar dilation is attenuated by glibenclamide and BaCl₂ but not by iberiotoxin, L-NMMA, indomethacin, and a high intraluminal concentration of potassium. (3) Endothelial denudation does not alter the coronary arteriolar dilation in response to acidosis, but this dilation is significantly inhibited in the presence of glibenclamide. The present study demonstrates that hydrogen ions dilate coronary arterioles through the opening of K_ATP channels in vascular smooth muscle. In addition, it is noteworthy to emphasize that the endothelium plays, if any, a minimum role in the acidosis-induced arteriolar dilation. To provide a perspective for our observations and conclusion, methodological considerations such as the isolated vessel preparation and specificity of potassium channel inhibition are discussed. In addition, the release of nitric oxide and prostaglandins as well as the role of endothelium in the vascular dilation to acidosis are addressed. Finally, the possible physiological and pathophysiological significance of our findings are discussed.

Considerations of Methodology and Potassium Channel Inhibition
Many in vivo studies have been performed to search for the mechanism(s) responsible for vasodilation during acidosis,^{3 7 18 19} but the results have been inconclusive, possibly because of the confounding influences from neurohumoral and/or local control mechanisms. Under physiological conditions, vascular tone is modulated not only by the local chemical environments (ie, hormonal and metabolic substances)¹⁸ but also by the changes in pressure (myogenic response)¹² and flow (shear-induced response).^{13 20} Since vasodilation initially occurs during acidosis, it is conceivable that the local changes in pressure and flow (thus, local regulation) will influence the acidosis-induced responses. Since local pressure and flow cannot be precisely controlled in vivo, it is difficult to determine from in vivo preparations whether the inhibition of acidosis-induced vasodilation by pharmacological antagonists is due to the direct effect of drugs on this response or is due secondarily to the alteration of local regulatory mechanisms. In the present study, without confounding influences from alterations in flow, pressure, and other regulatory mechanisms, we found that coronary arteriolar dilation to acidosis was specifically inhibited by glibenclamide (5 µmol/L) (Figs 1 and 2).

Another methodological consideration is that the present study was performed on the vessels with pressure-induced myogenic tone. Since the mechanism of pressure-induced and pharmacologically induced constriction may be different in these vessels, it is possible that the acidosis-induced dilation of agonist-preconstricted vessels may be resistant to glibenclamide. To address this issue, acidosis-induced dilation was examined in the vessels, which were preconstricted with a thromboxane analogue (U46619, n=2) or acetylcholine (an endothelium-independent constrictor in porcine coronary arterioles,¹³ n=2) (data not shown). In these agonist-preconstricted vessels, the vasodilation in response to acidosis was also inhibited by glibenclamide, indicating that glibenclamide has a general inhibitory effect on the acidosis-induced vasodilation regardless of the source of vascular tone.

Glibenclamide has been shown to be a selective antagonist of K_ATP channels.^{10 14 15} The inhibition of K_ATP channels by glibenclamide is concentration dependent. We have previously reported that coronary arteriolar dilation (75% to 80% of maximum dilation) induced by pinacidil (10 nmol/L), a specific K_ATP channel agonist, is completely abolished by 1.0 µmol/L glibenclamide.²¹ However, a higher concentration of glibenclamide (5 µmol/L) is required to effectively block vasodilation produced by 100 nmol/L pinacidil. Therefore, in the present study, 5 µmol/L glibenclamide was used. This concentration of glibenclamide inhibited coronary arteriolar dilation to acidosis without altering vasodilation to sodium nitroprusside (10^-9 to 10^-5 mol/L) (Fig 6), indicating that the action of glibenclamide is selective on the acidosis rather than the results of a nonspecific loss of vasodilatory capacity or damage of vascular smooth muscle. Similarly, the inhibitory effect of glibenclamide on hydrogen ion–induced dilation was also found in arterioles isolated from pig hind-limb skeletal muscle (82±14 µm, n=3; data not shown). It appears that the opening of K_ATP channels is a general mechanism, at least in the porcine model, for the dilation of blood vessels in response to acidosis.

The involvement of K_ATP channels in the acidosis-induced dilation is further supported by the inhibitory effect of BaCl₂ (100 µmol/L), although barium also has an inhibitory action on K_Ca channels with a very high dissociation constant (K_d, >10 mmol/L).²² Compared with glibenclamide, barium has less potency in blocking K_ATP channels.²² This is consistent with our finding that an 20-fold higher concentration of barium compared with glibenclamide was required to inhibit vasodilation to acidosis. The K_d for blockade by barium of the K_ATP channels in skeletal muscle¹⁷ and cerebral arteries²³ ranges from 25 to 100 µmol/L, which is in the range of barium concentration required to inhibit acidosis-induced coronary arteriolar dilation in the present study (Fig 2). Since barium might also potentially block K_Ca channel activity, the involvement of K_Ca channels in the acidosis-induced dilation was further examined by using its specific inhibitor, iberiotoxin. As shown in Fig 2, inhibition of the K_Ca channel by iberiotoxin (100 nmol/L) had no effect on acidosis-induced vasodilation. The potency of iberiotoxin in inhibiting arterial vascular smooth muscle K_Ca channels was reported to be <10 nmol/L (for 50% inhibition),¹⁶ and a very low dose of iberiotoxin (1.0 nmol/L) is sufficient to block K_Ca channel–mediated shear-induced dilation in isolated vessel studies.²⁴ Since vasodilation to acidosis was not altered by a relatively high concentration of iberiotoxin (100 nmol/L) in the present study (Fig 2), it is unlikely that K_Ca channels are involved in acidosis-induced coronary arteriolar dilation.

Role of Nitric Oxide and Prostacyclin
It is well documented that vascular endothelium plays a crucial role in modulating vascular tone by releasing vasodilators such as nitric oxide, prostacyclin, and some not-yet-identified hyperpolarizing factors.²⁵ Interestingly, recent studies showed that nitric oxide^{26 27} and prostacyclin^{10 28} can activate vascular K_ATP channels in several different organs. In the present study, we found that the pH-diameter relation of coronary arterioles was not altered by L-NMMA and indomethacin (Fig 3), the specific inhibitors for nitric oxide and prostaglandin synthesis, respectively. The concentration (10 µmol/L) of inhibitors used in the present study has been shown to block nitric oxide and prostaglandin synthesis in our previous isolated vessel preparations.²⁹ Although inhibiting the release of nitric oxide or prostaglandins alone was not sufficient to affect the vasodilation to acidosis, it is still possible that the corelease of nitric oxide and prostaglandins may be responsible for the acidosis-induced vasodilation. To test this possibility, the acidosis-induced dilation was evaluated in the presence of both L-NMMA and indomethacin. The extent of vasodilation in response to acidosis was not altered by coadministration of L-NMMA and indomethacin (n=2, data not shown). Collectively, these results suggest that hydrogen ions did not induce a release of nitric oxide and/or prostaglandins from blood vessels, and the opening of K_ATP channels during acidosis was independent of these two endogenous vasodilators. Since L-NMMA and indomethacin also block the synthesis pathway in vascular smooth muscle, it is unlikely that smooth muscle–derived nitric oxide³⁰ or prostaglandins³¹ are involved in the activation of K_ATP channels during acidosis.

In contrast to the present isolated vessel study, recent in vivo studies in the coronary⁷ and cerebral³ circulation have indicated that vasodilation in response to hypercapnic acidosis is attenuated by inhibiting nitric oxide synthesis. As discussed earlier, the vasodilation in vivo during acidosis may result from the combination of the direct effect of acidosis and the activation of local regulatory mechanisms. It is worth noting that inhibition of endogenous nitric oxide would abolish shear-induced dilation²⁹ but enhance myogenic constriction in the coronary circulation.^{8 29} Therefore, it is possible that the observed attenuation of vasodilation to hypercapnic acidosis by nitric oxide synthesis inhibition in the aforementioned in vivo studies may be due in part to the action of drugs on these local regulatory mechanisms. Another alternative explanation for this discrepancy, in addition to the species variations, may be the different vasodilatory mechanisms elicited by CO₂ versus the hydrogen ion, as recently reported in isolated rat cerebral arteries,³² although it is generally believed that the action of CO₂ on pial vessels is mediated by alterations in pH_o.² Interestingly, a recent study in the cat cerebral microcirculation indicated that L-NA, an L-arginine analogue, has the ability to inhibit K_ATP channel activity in addition to the inhibition of nitric oxide synthesis.¹⁹ In addition, the hypercapnia-induced dilation is significantly attenuated by both L-NA and glibenclamide^{3 19} but not by guanylate cyclase inhibitor.¹⁹ These findings may suggest that the inhibition of vasodilation to hypercapnic acidosis by L-NA is due to the inhibition of K_ATP channels instead of the inhibition of the production of nitric oxide during acidosis.¹⁹

Role of Endothelium in Acidosis-Induced Dilation
In addition to the release of vasoactive substances, endothelial hyperpolarization can also possibly contribute to the smooth muscle relaxation by means of electronic propagation through gap junctions.³³ We tested this possibility by inhibiting endothelial hyperpolarization with high intraluminal concentrations of KCl (40 mmol/L). We have previously shown that intraluminal administration of this concentration of KCl does not significantly alter resting vascular tone and function but that extraluminal application causes significant vasoconstriction.²¹ This indicates that the effect of intraluminal KCl on smooth muscle, if any, is minimal. In addition, this concentration of KCl has been shown to depolarize endothelial cells³⁴ and also to inhibit endothelial hyperpolarization in response to various stimuli in isolated blood vessel preparations.^{21 35} In the present study, the vasodilatory response of coronary arterioles to acidosis was not affected by high intraluminal concentrations of KCl (Fig 4), suggesting that the acidosis-induced dilation is independent of endothelial hyperpolarization. It is also possible that the release of EDHF³⁶ contributes to the vascular dilation during acidosis. To address this issue, the pH-diameter relation of isolated arterioles was examined after endothelial removal. As shown in Fig 5, the vasodilatory response of endothelium-denuded vessels to acidosis was identical to that of endothelium-intact vessels. Glibenclamide also attenuated the acidosis-induced arteriolar dilation of endothelium-denuded vessels in a manner identical to that of endothelium-intact vessels, indicating that coronary arteriolar dilation to acidosis is independent of endothelium, including the release of EDHF.

Mechanistic Speculation and Pathophysiological Considerations
Recent studies have shown that lowering pH_o causes vascular hyperpolarization,^{9 37} an increase in potassium permeability,³⁷ and a decrease in calcium influx.³⁸ It is speculated that the opening of K_ATP channels during acidosis contributes to the hyperpolarization of vascular smooth muscle and thus inhibits calcium influx through the voltage-sensitive calcium channels and subsequently leads to vasodilation. In the present study, it remains undetermined whether K_ATP channels in vascular smooth muscle are activated directly by hydrogen ions or secondarily by the intracellular metabolic mechanisms (ie, reduction of cytosolic ATP or an increase in the production of adenosine). It was reported recently that during cellular acidosis, there was a marked reduction in the inhibitory effect of ATP on the skeletal muscle K_ATP channels.³⁹ Since it is believed that cytosolic ATP concentration is maintained relatively constant even during sustained activity,⁴⁰ the modulation of K_ATP channel kinetics by pH_i may play a major role in the determination of membrane potential and thus vascular relaxation. In vascular strips, changes in pH_o are rapidly transduced in the cell, and smooth muscle tone is regulated by pH_i rather than pH_o.⁴¹ Therefore, it is likely that the enhanced opening kinetics and/or sensitivity of K_ATP channels by cytosolic acidosis may initiate vascular smooth muscle hyperpolarization and thus produce vasodilation. Another possibility related to the release of adenosine during acidosis should also be considered because adenosine has recently been reported to activate K_ATP channels in the coronary resistance vessels.^{21 42} However, we have previously shown that low doses of adenosine (<10^-8 mol/L) primarily act on the endothelial cells to produce nitric oxide–mediated vasodilation in the isolated coronary arterioles.²¹ In the present study, we found that the vasodilation to acidosis is endothelium independent and is not mediated by the release of nitric oxide. If there was a release of adenosine during acidosis, we should have seen the endothelium-dependent and/or L-NMMA–sensitive effect of acidosis-induced vasodilation. However, this is not the case. Therefore, it is unlikely that the release of adenosine occurred during acidosis in the present study.

It has been shown that coronary ischemia induced by a 3-minute period of arterial occlusion causes a decrease in tissue pH by 0.33 units.⁴³ Interestingly, ischemia- and hypoxia-induced coronary dilation in the intact heart⁴² and the systemic hypotension produced by lactic acidosis during hypoxia⁴⁴ are reversed by the inhibition of K_ATP channels. In addition, the coronary vascular dilation in response to metabolic stress is also prevented by the inhibition of K_ATP channels.⁴⁵ Since tissue acidosis occurs under these conditions (ie, ischemia, hypoxia, and increased metabolic activity), our present finding of activation of smooth muscle K_ATP channels during acidosis may explain these observations. It is conceivable that dysfunction of K_ATP channels under pathophysiological conditions such as chronic hypertension,⁴⁶ atherosclerosis,⁴⁷ or diabetes⁴⁸ would attenuate the vasodilatory response of the vessels to acidosis, resulting in an inadequate oxygen supply during intense metabolic demands.

	Selected Abbreviations and Acronyms

 

DMSO = dimethyl sulfoxide EDHF = endothelium-derived hyperpolarizing factor KATP channel = ATP-sensitive potassium channel KCa channel = calcium-activated potassium channel L-NA = NG-nitro-L-arginine L-NMMA = NG-monomethyl-L-arginine

	Acknowledgments

 
This study was supported by National Heart, Lung, and Blood Institute grant HL-48179 to Dr Kuo. We thank Travis W. Hein for his suggestions and review of this manuscript.

Received July 7, 1995; accepted September 28, 1995.

	References

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