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(Circulation. 2002;105:1323.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Barium Reduces Resting Blood Flow and Inhibits Potassium-Induced Vasodilation in the Human Forearm

Matthew Dawes, PhD, MRCP; Christine Sieniawska, BSc, MPhil; Trevor Delves, PhD, CChem, EurClinChem, FRSC; Rahul Dwivedi, MRCP; Philip J. Chowienczyk, FRCP; James M. Ritter, MA, DPhil, FRCP

From the Department of Clinical Pharmacology and Centre for Cardiovascular Biology and Medicine, King’s College, London, UK (M.D., R.D., P.J.C., J.M.R.), and SAS Trace Element Unit, Chemical Pathology, Southampton University Hospitals NHS Trust, Southampton, UK (C.S., T.D.).

Correspondence to Prof J.M. Ritter, Department of Clinical Pharmacology, Block 5, South Wing, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail james.ritter{at}kcl.ac.uk

	Abstract

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Background— Increasing extracellular K⁺ concentration within and just above the physiological range hyperpolarizes and relaxes vascular smooth muscle in vitro. These actions involve inwardly rectifying potassium channels (K_IR) and Na⁺/K⁺ ATPase, which are inhibited, respectively, by Ba²⁺ and ouabain. The role (if any) of K_IR in controlling human resistance vessel tone is unknown, and we investigated this in the forearm.

Methods and Results— Blood flow was measured by plethysmography in healthy men. Drugs and electrolytes were infused through the brachial artery. BaCl₂ (4 µmol/min, also used in subsequent experiments) increased Ba²⁺ plasma concentration in the infused forearm to 50±0.8 µmol/L (mean±SEM) and reduced blood flow by 24±4% (n=8, P<0.001) without causing systemic effects. Ouabain (2.7 nmol/min), alone and with BaCl₂, reduced flow by 10±2% and 28±3%, respectively (n=10). Incremental infusions of KCl (0.05, 0.1, and 0.2 mmol/min) increased flow from baseline by 1.0±0.2, 2.0±0.4, and 4.2±0.5 mL/min per deciliter forearm, respectively. Responses to KCl (0.2 mmol/min) were inhibited by BaCl₂, alone and plus ouabain, by 60±9% and 88±6%, respectively (both P0.01). In control experiments, norepinephrine (240 pmol/min) reduced blood flow by 24±2% but had no significant effect on K⁺-induced vasodilation. BaCl₂, alone or with ouabain, did not significantly influence responses to verapamil or nitroprusside.

Conclusions— Ba²⁺ increases forearm vascular resistance. K⁺-induced vasodilation is selectively inhibited by Ba²⁺ and almost abolished by Ba²⁺ plus ouabain, suggesting a role for K_IR and Na⁺/K⁺ ATPase in controlling basal tone and in K⁺-induced vasorelaxation in human forearm resistance vessels.

Key Words: potassium • vasodilation • endothelium-derived factors • muscle, smooth • vasculature

	Introduction

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Strong inwardly rectifying potassium channels (a family of channels termed K_IR) influence the membrane potential and contractile state of several kinds of vascular smooth muscle and contribute to vasodilator responses to modestly increased extracellular potassium ion concentrations ([K⁺]_o <15 mmol/L) in vitro.^1–4 Such responses could be physiologically or pathologically important because elevated [K⁺]_o occurs in exercising muscle and during myocardial or cerebral ischemia. K⁺ has also been implicated as an endothelium-derived hyperpolarizing factor (EDHF) in some⁵ but not all⁶ blood vessels. Electrophysiological, molecular biological, and gene knockout experiments have shown that one member of the K_IR channel family, K_IR2.1, is needed for K_IR currents and for K⁺-induced vasodilation in rat cerebral arteries in vitro, effects that are blocked by Ba²⁺ concentrations <100 µmol/L.^7,8 It is not known, however, whether K_IR channels control human resistance vasculature under physiological conditions in vivo, and the present study addresses this.

Ba²⁺ has been proposed as a probe of the functional role of K_IR channels,² and concentrations of Ba²⁺ <100 µmol/L are relatively specific for these channels.⁹ Higher concentrations of Ba²⁺ (100 to >1000 µmol/L) are needed to block non-K_IR potassium channels, including HERG (an inwardly rectifying potassium channel present in human hippocampus and distinct from K_IR2.1),¹⁰ ATP-sensitive K-channels,¹¹ Ca²⁺-activated K-channels,¹² and K_V channels.¹³ Soluble barium salts are rapidly absorbed from the intestinal tract, and Ba²⁺ is toxic in systemically active doses. Acute toxic effects of Ba²⁺, which include hypertension, are consistent with block of K_IR.¹⁴ Human studies identified a no-observed adverse-effect dose of 0.21 mg barium/kg body wt per day.^15,16 These data were used by the US Environmental Protection Agency to calculate a chronic oral reference dose of 0.07 mg/kg per day.^17,18 In one study, human volunteers were given up to 10 mg/L in drinking water daily for up to 10 weeks. There were no clinically significant adverse events.¹⁶ We calculated that brachial artery infusion of BaCl₂ could achieve a local Ba²⁺ concentration of 30 to 50 µmol/L in plasma of the infused forearm without causing systemic toxicity.

We measured effects of Ba²⁺ on K⁺-induced vasodilation as well as on basal blood flow. Increasing [K⁺]_o displaces K_IR channel–bound polyamines¹⁹; in the relevant concentration range, this increases outward K⁺ current, hyperpolarizing the membrane.⁴ Increasing [K⁺]_o also hyperpolarizes vascular smooth muscle by activating the electrogenic Na⁺/K⁺ pump.³ Brachial artery infusion of ouabain was therefore used in some experiments to produce unilateral regional block of Na⁺/K⁺ ATPase.^20–22 Experiments with vasodilators (verapamil and nitroprusside) and vasoconstrictors (norepinephrine) that act by mechanisms distinct from K_IR and the Na⁺/K⁺ pump were used to control for possible nonspecific effects.

	Methods

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Human Studies
The St Thomas’ Hospital Research Ethics Committee approved all the studies, and subjects gave written informed consent. Studies were performed in healthy normotensive (arterial pressure, 116±4/70±2 mm Hg; mean±SEM), normocholesterolemic (mean serum cholesterol, 3.6±0.2 mmol/L) men (mean age, 33±2 years) who were taking no medication. Studies were performed in the morning in a temperature-controlled room (24±1°C). The left brachial artery was cannulated with a 27-gauge stainless steel needle (Cooper’s Needleworks) after local anesthesia (<1 mL 1% lidocaine). Isotonic saline (140 mmol/L sodium chloride ) with or without dissolved drugs was infused at 1 mL/min. BaCl₂ was administered through a syringe filter (Acrodisc, 0.2 µm, Pall Corporation). Subjects rested supine for 30 minutes, and saline was infused for 12 minutes before measuring baseline flow. Blood flow (milliliter per minute per deciliter of forearm volume) was measured simultaneously in both arms by venous occlusion plethysmography²³ with the use of electrically calibrated strain gauges.²⁴ During measurements, the hands were excluded from the circulation by inflation of wrist cuffs to 180 mm Hg. Upper arm cuffs were intermittently inflated to 40 mm Hg, and the mean of the last 5 readings of each infusion period was used for analysis.

Plasma Ba²⁺Analysis
In preliminary dose-ranging studies, 19-gauge plastic cannulas were inserted into the medial antecubital veins draining each forearm. Venous blood (10 mL) was sampled at baseline, during the final 30 seconds of the infusion of BaCl₂, and 1 hour after infusion for determination of plasma Ba²⁺ concentration. Samples were immediately centrifuged (1600g for 5 minutes), and plasma was stored at -18°C in Ba²⁺-free tubes. Samples were analyzed in duplicate in the Trace Element Unit, Southampton Hospital, with the use of inductively coupled plasma (ICP) mass spectrometry (Perkin Elmer–Sciex Elan 5000 ICP mass spectrometer), detection limit of 10 nmol/L, with a 0.5-mL plasma sample. Routine serum chemistries including creatinine, electrolytes, and liver function tests, in addition to Ba²⁺ concentration, were measured at baseline and 1 week after BaCl₂ infusion.

In preliminary dose-finding experiments, cumulative infusions of intra-arterial BaCl₂ (0.25 to 2.0 µmol/min, each for 4 minutes) were administered. From these pilot studies, a dose of BaCl₂ of 4 µmol/min for up to 6 minutes was chosen for the following protocols.

Effects of BaCl₂ and Ouabain on Basal Forearm Blood Flow
After measuring basal forearm blood flow as above, BaCl₂ (4 µmol/min) was infused into the brachial artery for 6 minutes and blood flow was measured in both arms (n=8). In 6 of these subjects, plasma Ba²⁺ determinations were made as above. In 10 separate experiments, ouabain (2.7 nmol/min) was infused for 15 minutes and blood flows were measured as described elsewhere.²¹ Ouabain was continued for a further 3 minutes, coinfused with BaCl₂ (4 µmol/min).

Effects of Ba²⁺ (With or Without Ouabain) on Forearm Responses to K⁺ or Verapamil
After measuring basal forearm blood flow, cumulative doses (0.05, 0.1, 0.2 mmol/min, n=8) of KCl were infused into the brachial artery, each dose for 3 minutes. Venous blood samples (10 mL) were taken from both arms during the final 30 seconds for determination of plasma K⁺ concentration.

In separate experiments (n=8), KCl (0.2 mmol/min) was infused for 3 minutes followed by saline for 15 minutes, during which blood flow returned to baseline. BaCl₂ (4 µmol/min) was then infused for 6 minutes: alone for 3 minutes and during a second 3-minute infusion of KCl (0.2 mmol/min). In control experiments, after blood flow was measured at baseline, verapamil (80 nmol/min) was infused with saline followed sequentially by saline alone, BaCl₂ alone, and verapamil with BaCl₂ (n=7).

In further separate experiments (n=6), blood flow was measured as before at baseline and during KCl (0.2 mmol/min), followed by a 15-minute saline recovery period. Ouabain and BaCl₂ were infused as described above and continued during a final 3-minute KCl infusion (0.2 mmol/min).

Lack of Effect of Norepinephrine on Forearm Blood Flow Response to KCl
Baseline blood flow was measured, followed by KCl infusion for 3 minutes (0.2 mmol/min, n=5). Saline was then infused alone for a 15-minute recovery period, followed by norepinephrine (240 pmol/min),initially alone for 3 minutes, and then continued throughout a second 3-minute KCl infusion.

Lack of Effect of BaC1₂ Plus Ouabain on Forearm Blood Flow Response to Nitroprusside
Baseline blood flow was measured during saline, followed by nitroprusside (3.3 nmol/min or 33 nmol/min for 3 minutes, n=4). Saline was then infused for a 15-minute recovery period, followed by sequential cumulative additions of ouabain (2.7 nmol/min), BaCl₂ (4 µmol/min), and nitroprusside (3.3 or 33 nmol/min), with the same timings used as above.

Materials and Drugs
Drugs were obtained from Baxter Healthcare (saline); David Bull Laboratories (sodium nitroprusside); Antigen Pharmaceuticals (KCl, lidocaine); Abbott Laboratories (norepinephrine); BDH Laboratories (BaCl₂ 10% wt/vol); Jenapharm (ouabain); and Baker Norton (verapamil).

Statistical Analysis
Data are presented as mean±SEM. Vasodilator responses were calculated as increases of blood flow (mL/min per deciliter of forearm tissue) above the immediately preceding baseline.^25,26 Vasoconstrictor responses were calculated as percentage decrease of blood flow ratio of the infused to noninfused arm.^27,28 Differences between means were evaluated for statistical significance by means of Student’s paired t test (2-sided) or repeated-measures ANOVA, as appropriate. Differences were considered significant at a level of P<0.05.

	Results

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Neither arterial blood pressure nor forearm blood flow in the noninfused arm changed significantly during any study, consistent with lack of systemic hemodynamic effects of the infused agents at the doses used. BaCl₂ caused no acute ECG changes and had no significant effect on serum electrolytes and liver function tests measured 1 week after the infusion.

Effects of Ba²⁺ and Ouabain on Basal Flow
In pilot experiments, cumulative, rising doses of BaCl₂ (0.25, 0.5, 1.0, and 2.0 µmol/min, n=6), each infused through the brachial artery for 4 minutes, had no significant effect on baseline flow (percent change in baseline flow, -10±10%, -9±7%, -2±14%, and 1±15%, respectively, P=NS). Plasma Ba²⁺ concentration at baseline (ie, before BaCl₂ infusion) was 0.28±0.04 µmol/L and during the final 30 seconds of infusion (at 2.0 µmol/min) was 22±3.4 µmol/L and 1.7±0.9 µmol/L, in the infused and noninfused arms respectively.

BaCl₂ (4 µmol/min for 6 minutes) reduced baseline blood flow by 24±4% (n=8, P<0.001, Figure 1). Plasma Ba²⁺ concentration in venous blood draining the infused arm was 50±8 µmol/L during the final 30 seconds of the infusion (Table 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. Effects of ouabain and Ba2+ on forearm blood flow. Percentage change in resting forearm blood flow (mean±SEM) during brachial artery infusion of ouabain (2.7 nmol/min for 15 min; n=10), barium chloride (4 µmol/min for 6 min; n=8), and ouabain and barium chloride coinfusion (n=10).

View this table: [in this window] [in a new window]   Table 1. Plasma Barium Concentrations

Ouabain (2.7 nmol/min) reduced baseline blood flow by 10±2% (n=10, P<0.05) and coinfusion of BaCl₂ with ouabain reduced baseline flow by 28±3% (n=10, P<0.0005 compared with the effect of ouabain alone, Figure 1).

Effect of K⁺ on Forearm Blood Flow
All subjects reported warmth and tingling in the infused arm during KCl infusion, and in preliminary experiments discomfort limited the maximum dose that was consistently tolerated to 0.2 mmol/min. KCl (0.05, 0.1, and 0.2 mmol/min) increased blood flow by 1.03±0.24, 1.99±0.4, and 4.21±0.46 mL/min per deciliter forearm over baseline (n=8, P<0.0001, ANOVA; Figure 2). The concentration of K⁺ in plasma from venous blood from the infused arm at the end of the infusion of KCl was 6.3±0.2 mmol/L, whereas the concentration in plasma from venous blood draining the noninfused arm was 4.0±0.2 mmol/L (n=6, P<0.0001).

View larger version (13K): [in this window] [in a new window]   Figure 2. Effect of potassium on forearm blood flow. Increases in blood flow above baseline (FBF, mL · min-1 · dL forearm-1; mean±SEM) during cumulative rising-dose infusions of potassium chloride are shown. P<0.0001 ANOVA; n=8.

Effects of Ba²⁺(With or Without Ouabain) on Forearm Response to K⁺ or Verapamil
KCl (0.2 mmol/min) alone increased forearm blood flow by 3.53±0.56 mL/min per deciliter forearm over baseline (n=8, Table 2) and by 1.43±0.28 mL/min per deciliter forearm when coinfused with BaCl₂ (60±9% reduction; P=0.01, Figure 3A). Verapamil (80 nmol/min) increased forearm blood flow by 4.50±0.84 mL/min per deciliter forearm when infused with saline and by 4.46±0.86 mL/min per deciliter forearm when infused with BaCl₂ (n=7, Table 3 P=NS). In separate experiments, KCl (0.2 mmol/min) increased forearm blood flow by 4.49±0.68 mL/min per deciliter forearm over baseline when infused alone and by 0.57±0.23 mL/min per deciliter forearm when coinfused with BaCl₂ and ouabain (88±6% reduction, n=6, P<0.005; Figure 3B and Table 4).

View this table: [in this window] [in a new window]   Table 2. Effects of Ba2+±K+ on Forearm Blood Flow

View larger version (19K): [in this window] [in a new window]   Figure 3. Specificity of inhibition of K+-induced vasodilation by Ba2+±ouabain. Each panel shows the increase above baseline in forearm blood flow (FBF, mL · min-1 · dL forearm-1; mean±SEM) during brachial artery infusion of vasodilators (KCl or nitroprusside) alone (solid bars) and with (open bars) vasoconstrictor (Ba2+±ouabain or norepinephrine). Doses used were: KCl (0.2 mmol/min); BaCl2 (4 µmol/min); ouabain (2.7 nmol/min); norepinephrine (240 pmol/min); nitroprusside (3.6 nmol/min). a, Responses to KCl±BaCl2 (n=8; *P=0.01). b, Responses to KCl±BaCl2 with ouabain (n=6; **P<0.005. c, Responses to KCl±norepinephrine (n=5). d, Effects of nitroprusside±BaCl2 with ouabain (n=4).

View this table: [in this window] [in a new window]   Table 3. Effects of Ba2+±Verapamil on Forearm Blood Flow

View this table: [in this window] [in a new window]   Table 4. Comparison of Effects of Barium+Ouabain on Vasodilator Responses to Potassium Versus Nitroprusside

Responses to KCl were measured before and during vasoconstriction with norepinephrine. Norepinephrine (240 pmol/min) reduced baseline blood flow by 24±2% (n=5, P<0.05). KCl (0.2 mmol/min) increased forearm blood flow by 3.01±0.45 mL/min per deciliter forearm over baseline when infused alone and by 3.79±0.64 mL/min per deciliter of forearm when coinfused with norepinephrine (P=NS, Figure 3C).

Vasodilator responses to nitroprusside were measured in the presence and absence of Ba²⁺ and ouabain (Table 4). Nitroprusside (3.3 and 33 nmol/min) increased forearm blood flow, respectively, by 4.13±0.95 and 8.55±1.1.4 mL/min per deciliter of forearm when infused with saline alone and by 4.19±0.39 and 9.30±2.06 mL/min per deciliter of forearm when coinfused simultaneously with ouabain and BaCl₂ (P=NS; Figure 3D).

	Discussion

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Ba²⁺ as a Probe of K_IR Function in Human Forearm Resistance Vasculature
Electrophysiological and molecular studies have established the presence of K_IR2.1 channels in isolated vascular smooth muscle.^7,8,23 However, K_IR channels are blocked by Ca²⁺ and Mg^2+,9 each present in millimolar concentrations in extracellular fluid, and other signal transduction mechanisms could overwhelm any contribution to basal tone from K_IR in vivo. Ba²⁺ can be used to probe the functional role of K_IR channels.² We investigated the possible role of K_IR channels in human resistance vasculature in vivo by using brachial artery administration of BaCl₂ with bilateral measurement of forearm blood flow. Doses were selected to produce concentrations that are pharmacologically active locally in the infused forearm but not systemically, and no significant effects on blood pressure or on blood flow in the contralateral (noninfused) forearm were observed. The dose of Ba²⁺ administered during each study was less than the daily reference dose, and no adverse effects were observed. The mean concentration of Ba²⁺ measured in plasma from the infused arm was 50±0.8 µmol/L, sufficient to block K_IR channels.^2–4,7–9 Ouabain and other drugs were similarly administered through the brachial artery in doses that are not active systemically^20–22 and produced no change in blood flow in the noninfused arm.

A major concern with this approach is the possibility that Ba²⁺ and ouabain, in the doses studied, could have effects in addition to those on K_IR and Na⁺/K⁺ ATPase. Bilateral measurement of forearm blood flow coupled with brachial artery administration of subsystemically active doses circumvents confounding from drug actions on the central nervous system or heart, which cause bilateral changes in forearm blood flow.²⁶ Thus, central effects of ouabain resulting in increased vascular resistance cannot explain its unilateral effects on the infused forearm. Similarly, actions of Ba²⁺ on the heart or central nervous system cannot explain its unilateral effects in the infused arm. Concentrations of Ba²⁺ in the range of 100 to >1000 µmol/L are needed to block other potassium channels,^10–13 which have not been implicated in K⁺-induced vasodilation and are unlikely to underlie the effect of Ba²⁺ described here. However, it is not possible to exclude completely some other property of Ba²⁺ in the physiological milieu of the human forearm. In particular, physicochemical properties shared with Ca²⁺ raise the theoretical possibility that Ba²⁺ could exert some of the effects we observed by influencing [Ca²⁺]_i signaling. We sought effects of Ba²⁺ on responses to verapamil, an antagonist of L-type voltage-dependent Ca²⁺-channels, which are active under physiological conditions, to address this possibility. The lack of effect of Ba²⁺, in a dose that inhibited K⁺-responses, on responses to verapamil argues against an action of Ba²⁺ on [Ca²⁺]_i signaling under the experimental conditions in our studies. Furthermore, doses of Ba²⁺ and ouabain that almost abolished K⁺-induced vasodilation had no significant effect on vasodilator responses to nitroprusside, ruling out effects of these antagonists on cGMP-mediated vasodilation. Finally, we considered the possibility that the effects of these antagonists on K⁺-induced vasodilatation were simply the result of vasoconstriction. However, a dose of norepinephrine that caused a similar reduction in baseline blood flow as did Ba²⁺ plus ouabain had no significant effect on K⁺-induced vasodilation. The main new positive findings of the present study, namely that Ba²⁺ constricts forearm resistance vasculature under basal physiological conditions, selectively inhibits K⁺-induced vasodilation, and virtually abolishes K⁺ responses when combined with ouabain, can thus best be explained by selective actions of Ba²⁺ and ouabain, in the doses used, on, respectively, K_IR and Na⁺/K⁺ ATPase in the infused forearm.

Implications of Tonic K_IR and Na⁺/K⁺ ATPase Activity in Resistance Vasculature In Vivo
Physiological conditions that influence K_IR-channel activity include membrane potential and K⁺, Ca²⁺, and Mg²⁺ concentrations.^2,4 Consequently, unequivocal evidence of the presence and function of K_IR2.1 channels in arterial smooth muscle in vitro^4,7,8 does not, of itself, prove the functional importance of these channels under in vivo conditions. The modest vasoconstriction caused in the forearm by ouabain (10±2% reduction in basal blood flow, consistent with previous work^20–22) and greater effect of Ba²⁺, demonstrated here for the first time, are consistent with tonic activity of K⁺ on Na⁺/K⁺ ATPase and, more effectively, on K_IR-channels in vascular smooth muscle in forearm resistance vessels in vivo. Tonic K⁺-related vasodilation could have been underestimated by the inhibition observed (24±4% by Ba²⁺ alone, 28±3% by Ba²⁺ plus ouabain) because, due to concerns related to toxicity, we did not perform prolonged infusions. Vasoconstriction caused by Ba²⁺ may therefore not have reached a plateau. Even so, Ba²⁺-induced vasoconstriction was substantial and compares with a maximum vasoconstrictor effect of L-N^G-monomethyl-L-arginine (which blocks basal endothelium-derived nitric oxide synthesis in this vascular bed) of 50% reduction of basal blood flow.²⁹ Another limitation of the study is that it was not practicable to investigate the effect of Ba²⁺ on K⁺-induced responses throughout a dose range of KCl infusions because responses to lower doses of KCl were small and variable and larger doses could not be used as these caused forearm discomfort.

Tonic vasodilator activity of K⁺ within the physiological range could influence arterial blood pressure. Dietary supplementation with potassium salts has been reported to lower blood pressure in patients with essential hypertension.^30,31 Conversely, elevated blood pressure has been described in association with low dietary K⁺.³² The ability of a small increase in [K⁺]_o to hyperpolarize vascular smooth muscle could contribute to the hypotensive effect of potassium salts. Local plasma K⁺ concentrations (mean, 6.3±0.2 mmol/L) achieved in venous blood draining the infused arm are in the range observed in voluntary muscle during exercise,⁴ supporting a role for K_IR and for Na⁺/K⁺ ATPase activation in regional blood flow responses during exercise.⁴ It is likely that mechanisms similar to those we have observed in forearm vasculature also operate in vivo in cerebral and coronary vessels (which are perfused by plasma of the same composition as are forearm vessels) and in which K_IR-channels have been detected in vitro.^2,3 If so, K⁺-induced vasodilation could be important in pathological conditions such as myocardial or cerebral infarction, in which local elevations of [K⁺]_o could reduce resistance vessel tone in and around the infarct.⁴ Furthermore, hyperpolarization-induced vasorelaxation by activation of Na⁺/K⁺ ATPase is reported to be upregulated when nitric oxide bioavailability is impaired,^33,34 so K⁺-induced vasodilation could provide a compensatory mechanism in diseases in which the L-arginine/nitric oxide mechanism is impaired, especially if the K_IR mechanism also proves to be upregulated in such disorders.

In conclusion, Ba²⁺ constricts forearm resistance vessels, and K⁺-induced vasodilation is selectively inhibited by Ba²⁺ and almost abolished by Ba²⁺ plus ouabain. These findings support a role for K_IR and Na⁺/K⁺ ATPase in controlling basal tone and in K⁺-induced vasorelaxation in human forearm resistance vessels in vivo. Such a role has important implications for the (patho-) physiological regulation of resistance vessel tone in humans.

	Acknowledgments

 
This work was supported by the British Heart Foundation. We thank Dr Alison Jones (Guy’s Poisons Unit) for advice on the toxicity of barium salts.

Received January 9, 2002; accepted January 11, 2002.

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