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Hypertension. 2004;43:891-896
Published online before print March 1, 2004, doi: 10.1161/01.HYP.0000121882.42731.6b
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(Hypertension. 2004;43:891.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Nitric Oxide Donor Sodium Nitroprusside Dilates Rat Small Arteries by Activation of Inward Rectifier Potassium Channels

Rudolf Schubert; Ulrike Krien; Iris Wulfsen; Dorrit Schiemann; Gernot Lehmann; Norbert Ulfig; Ruediger W. Veh; Jürgen R. Schwarz; Hristo Gago

From Institute of Physiology (R.S., U.K., G.L.), University Rostock, Germany; Institute of Physiology (I.W., D.S., J.R.S.), University Hamburg, Germany; Institute of Anatomy (N.U.), RG Neuroembryology, University Rostock, Germany; Institute of Anatomy (R.W.V.), Charite, Humboldt-University, Berlin, Germany; Institute of Biophysics (H.G.), Bulgarian Academy of Sciences, Sofia, Bulgaria.

Correspondence to Dr R. Schubert, Institute of Physiology, University Rostock, PSF 100888, 18055 Rostock, Germany. E-mail rudolf.schubert{at}medizin.uni-rostock.de


*    Abstract
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 *Abstract
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 down arrowResults
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The role of vascular smooth muscle inward rectifier K+ (KIR) channels in the mechanisms underlying vasodilation is still unclear. The hypothesis that KIR channels are involved in sodium nitroprusside (SNP)-induced dilation of rat-tail small arteries was tested. SNP relaxed tail small arteries with an EC50 of 2.6x10-8 mol/L. Endothelium removal did not attenuate this effect. Vessel pretreatment with hydroxocobalamin, a nitric oxide (NO) scavenger, but not with rhodanese and sodium thiosulfate, inactivators of cyanide (CN), abolished the SNP effect. Vessel pretreatment with 10-5 mol/L Ba2+, a specific blocker of KIR channels at micromolar concentrations, reduced the SNP effect. Low concentrations of K+ dilated the vessels; this effect was attenuated largely after pretreatment with 3x10-5 mol/L Ba2+. In freshly isolated smooth muscle cells, a barium-sensitive current was observed at potentials negative to the potassium equilibrium potential. Application of 10-4 mol/L SNP increased the barium-sensitive current 1.79±0.23-fold at -100 mV and hyperpolarized the membrane potential by 8.6±0.5 mV. In tissue from freshly dissected vessels, transcripts for KIR 2.1 and 2.2, but not for KIR 2.3 and 2.4, were found. However, only KIR 2.1 antibodies immunostained the tunica media of the vessel. These data suggest that vascular smooth muscle KIR 2.1 channels are involved in the SNP-induced dilation of rat-tail small arteries.


Key Words: arteries • ions • nitric oxide • potassium channels • vasodilation


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowDiscussion
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Small arteries and arterioles play an important role for the regulation of blood pressure and blood flow distribution to different organs. An important factor regulating the contractile state of these vessels is the membrane potential of their smooth muscle cells.1 The latter depends, to a large extent, on the activity of various types of K+ channels, eg, delayed rectifier, ATP-sensitive, Ca2+-activated, and inward rectifier K+ (KIR) channels.2 Whereas the properties and the functional role of most of these K+ channels have been studied for a long time,2,3 the KIR channel in arterial smooth muscle cells has been investigated only recently. First information about the existence of KIR channels in small artery preparations was reported by Edwards.4,5 Thereafter, direct measurements of ion currents in vascular smooth muscle cells demonstrated the existence of KIR currents in cerebral,6,7 coronary,8–10 and renal11 small arteries and in the hepatic artery.12 Recently, it has been demonstrated by electrophysiological and molecular biological techniques that KIR 2.1 channels underlie the KIR currents in coronary, cerebral, and mesenteric small artery smooth muscle cells.13,14 Further, it has been shown that the vessel dilation or hyperpolarization induced by small increases of the extracellular potassium concentration in cerebral, coronary, and hepatic arteries in vitro4,12,15,16 as well as in cerebral arteries17 and human forearm18 in vivo is mediated by KIR channels, most probably KIR 2.1.14 KIR channels may also play a role in the transmission of signals causing remote vasodilation.19 In contrast, the involvement of KIR channels in vessel reactions to vasodilating substances is less well known. Therefore, the hypothesis that KIR channels are involved in the sodium nitroprusside (SNP)-induced vasodilation of small arteries was tested.


*    Methods
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 up arrowIntroduction
 *Methods
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The methods used in this study are described only briefly, because they have been presented in detail previously.20,21 An expanded Methods section is available in an online supplement at http://www.hypertensionaha.org.

The investigation conforms with the Guide for the Care and Use of Laboratory Animals by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Small tail arteries, first-order branches of the main ventral tail artery, were obtained from male Wistar-Kyoto rats grown at the central animal facility, University of Rostock. They were mounted in an experimental chamber placed on a microscope stage. The microscope image of the vessel was viewed with a CCD camera, digitized by a frame-grabber board, and diameter reactions were analyzed online. The vessel was pressurized to 80 mm Hg under nonflow conditions allowing the development of a spontaneous myogenic tone. In some experiments, the endothelium was removed by passing air through the lumen of the vessel.21

For cell isolation, a piece of artery was placed into a microtube containing an enzyme solution consisting of 1.5 mg/mL papain, 1.6 mg/mL albumin, and 0.4 mg/mL DL-dithiothreitol and stored there overnight at 4°C. On the next day, the vessel was incubated for 5 to 10 minutes at 37°C and single cells were released by trituration with a polyethylene pipette. Patch-clamp recordings were made with an Axopatch 200 amplifier and the software package ISO2. To reduce the contribution of other potassium currents, 10-6 mol/L glibenclamide, 10-7 mol/L iberiotoxin, and 5x10-3 mol/L 4-aminopyridine were added to the bath solution. Ba2+ is a concentration-selective inhibitor of KIR channels, ie, at low concentrations it is selectively blocking KIR channels, whereas at higher concentrations it also inhibits other potassium channels. Thus, for the different experimental conditions used in the present study, various Ba2+ concentrations were chosen to ensure a selective action.

For reverse-transcription polymerase chain reaction, RNAs were extracted from freshly dissected tail small arteries using RNAzol B (16; AGS; Heidelberg, Germany) following the procedures described previously.22 For specific details and the oligonucleotide primers used, see the online supplement.

For immunocytochemistry, small pieces of the rat tail were fixed, cryoprotected, cut at a thickness of 30 µm, and mounted on gelatin-coated slides. Then, sections were incubated in the primary antibody, diluted 1:500 (KIR 2.1) or 1:200 (KIR 2.2), respectively. Thereafter, sections were transferred to the secondary antibody: a biotinylated anti-mouse IgG diluted 1:200. Afterward, the avidin-biotin-peroxidase complex was allowed to react. The immunoreactivity was visualized with the aid of 0.07% diaminobenzidine and 0.003% hydrogen peroxide. The antibodies were specific for their corresponding primary sequences.23 Negative controls were performed for all antibodies tested using an adsorbing antigen.


*    Results
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 up arrowIntroduction
 up arrowMethods
 *Results
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Effect of SNP on Diameter of Rat Tail Small Arteries
Application of SNP increased vessel diameter resulting in a concentration-dependent reversible dilation (Figure 1A). Half-maximal dilation occurred at an EC50 of 2.6x10-8 mol/L SNP. The concentration–response curve had a slope factor of n=0.78 and a maximum reaching 77% of the fully relaxed state (Figure 1B), whereas the latter was determined in Ca2+-free solution. Reversibility was obtained within 8 to 10 minutes (data not shown). Removal of the endothelium did not attenuate the SNP effect; the SNP concentration–response relationship was shifted to the left in endothelium-denuded vessels (n=6) compared with endothelium-intact vessels (n=8) (P<0.05) (Figure 1C).



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  		Figure 1. Effect of sodium nitroprusside (SNP) on diameter of rat tail small arteries. A, Example of the vasodilating effect of SNP; application of SNP indicated by diamonds. B, SNP concentration–response curve fitted with the equation y=ymaxx[cn/(cn+EC50n)]. C, SNP concentration–response curve in the presence (+E) and absence (-E) of the endothelium (n=8 and 6, respectively; P<0.05).

Inhibition of SNP-Induced Dilation by Ba2+
Pretreatment of vessels with 10-5 mol/L Ba2+, a blocker of KIR channels at micromolar concentrations,6,8,24 changed the SNP concentration–response curve (P<0.05); the maximal dilation was attenuated from 76.5%±4.0% to 53.1%±6.3% (n=6, P<0.05) (Figure 2A). The addition of Ba2+ at 10-5 mol/L slightly constricted the vessels by 4.0%±2.1% (n=6). However, Ba2+ pretreatment did not alter the dilation induced by cromakalim, an opener of ATP-sensitive potassium channels (n=6, P=0.26) (Figure 2B). Further, no difference between the first and a subsequent SNP concentration–response curve was observed (n=5, P=0.11) (Figure 2C).



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  		Figure 2. Effect of Ba2+ on the SNP-induced dilation. A, SNP concentration–response curve in the absence and presence of 10-5 mol/L Ba2+ (n=6, P<0.05). B, Cromakalim concentration–response curve in the absence and presence of 10-5 mol/L Ba2+ (n=6, P=0.26). C, SNP concentration–response curve for first (SNP 1st) and second (SNP 2nd) application of SNP (n=5, P=0.11). Time between SNP 1st and SNP 2nd was the same as between SNP in the absence and in the presence of Ba2+. D, SNP concentration–response curve in the absence and presence of 10-3 mol/L hydroxocobalamin, a NO scavenger (n=5, P=0.74).

Inhibition of SNP-Induced Dilation by a Nitric Oxide Scavenger
Pretreatment of vessels with 10-3 mol/L hydroxocobalamin, a nitric oxide (NO) scavenger,25 abolished the SNP-induced dilation (n=5, P<0.01) (Figure 2D). Hydroxocobalamin did not affect vessel diameter. However, pretreatment of vessels with 10-5 mol/L Ba2+ did not alter the dilation induced by DEA-NO, a direct NO-donor (n=5, P=0.17) (online Figure Ia, http://www.hypertensionaha.org). Pretreatment of vessels with 30 U/L rhodanese and 1.25x10-4 mol/L sodium thiosulfate, inactivators of cyanide that may also be released from SNP,26 did not alter the dilation induced by SNP (n=7, P=0.13) (online Figure Ib). Rhodanese and sodium thiosulfate did not affect vessel diameter. In addition, cyanide did not dilate the vessel (n=5) (online Figure Ic). Pretreatment of vessels with 10-5 mol/L Ba2+ in the presence of rhodanese and sodium thiosulfate still changed the SNP concentration–response curve (n=7, P<0.05) (online Figure Id).

Characterization of KIR Currents in Rat-Tail Small Artery Smooth Muscle Cells
Application of low concentrations of K+ produced a concentration-dependent reversible dilation. Pretreatment of vessels with 3x10-5 mol/L Ba2+ inhibited the KCl-induced dilation (n=5, P<0.05) (online Figure IIa, http://www.hypertensionaha.org). This inhibition provided functional evidence for the existence of KIR channels.

Indeed, in whole-cell experiments the application of voltage ramps from -150 mV to +50 mV from a holding potential of -40 mV to single freshly isolated smooth muscle cells resulted in current–voltage relationships showing inward rectification, ie, an inward current at potentials negative to the potassium equilibrium potential (EK), which was much larger than the outward current at potentials positive to EK (online Figure IIb). The inward, but not the outward, current was reduced considerably by 5x10-4 mol/L Ba2+ (online Figure IIb). A similar reduction of the inward current was observed with 10-5 mol/L Ba2+ at all potentials negative to EK, eg, at -70 mV 10-5 mol/L Ba2+ inhibited the current by 92.7%±1.5% (n=4). An increase in [K]o augmented the slope conductance, which was determined in the linear part of the current–voltage relationship at potentials more negative than the reversal potential (online Figure IIc). Slope conductances were 5.6±1.1 pS/pF (n=3), 14.5±3.2 pS/pF (n=6), and 31.0±3.3 pS/pF (n=4) in 6, 36, and 130 mmol/L [K]o, respectively, and were proportional to [K]o0.58. Further, an increase in [K]o shifted inward rectification and the reversal potential (Erev) of the barium-sensitive current, ie, the difference in current before and after application of 5x10-4 mol/L Ba2+, by 54.4 mV for a 10-fold change in [K]o to more positive potentials. Erev was close to the EK, being -77.0±1.0 mV (n=3) (EK -78.7 mV), -37.6±1.3 mV (n=6) (EK -34.0 mV), and -4.0±2.3 mV (n=4) (EK -1.9 mV) in 6, 36, and 130 mmol/L [K]o, respectively.

Molecular and Immunocytochemical Characterization of KIR Channels in Rat Tail Small Arteries
In tissue obtained from freshly dissected vessels, transcripts for KIR 2.1 and 2.2 were found, whereas KIR 2.3 and 2.4 were not detected (Figure 3). In addition, transcripts for the von Willebrand factor, a marker specific for endothelial cells, were found. The reverse-transcription polymerase chain reactions were repeated 3 or 4 times. In each reaction, the amplification of both the transcripts for KIR 2.1 and KIR 2.2 were found.



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  		Figure 3. Molecular characterization of KIR channels in rat-tail small arteries; 10% of the polymerase chain reaction product was separated on a 1.5% agarose gel. Lane 1, negative controls (H2O instead of cDNA template); lane 2, positive controls (cDNA templates obtained from muscle (KIR 2.1), or brain (KIR 2.2, 2.3 and 2.4); lane 3, artery. The molecular size of the polymerase chain reaction amplification products are indicated on the right side.

Sections of the small rat tail artery immunostained with the antibody against KIR 2.1 revealed a clear labeling of the tunica media (Figure 4). At high magnification, KIR 2.1 immunoreactivity is restricted to the circular layer of myocytes (Figure 4, labeled M). In contrast, KIR 2.1 immunopreparations in the presence of antigen and KIR 2.2 immunopreparations were devoid of immunoreactive structures in the tunica media (Figure 4). These experiments were repeated 4 or 5 times; in each case, the positive staining could be reproduced.



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  		Figure 4. Immunocytochemical visualization of KIR channels in rat-tail small arteries. KIR 2.1 immunoreactivity is evident in the tunica media (M) (upper panel) and is absent after preincubation block with its cognate antigen (middle panel). No immunostaining is detected after reaction with anti-KIR 2.2 antibodies (lower panel). Calibration bar: 10 µm.

Effect of SNP on the KIR Current in Rat-Tail Small Artery Smooth Muscle Cells
Application of SNP increased the inward rectifying, barium-sensitive, ie, KIR, current (see example in Figure 5A). At 10-4 mol/L, SNP increased the KIR current at -100 mV on average 1.79±0.23-fold (n=8), which is different from the 1.02±0.04-fold (n=6) change during time-control measurements (P<0.05) and different from the 0.94±0.07-fold (n=6) change during SNP application in the presence of 10-5 mol/L Ba2+ (P<0.05) (Figure 5B). The SNP-induced increase of the KIR current was observed at potentials between -140 and -50 mV; the current voltage relationships before and after addition of SNP were different (n=5, P<0.05) (Figure 5C). In addition, in current-clamp experiments 10-4 mol/L SNP hyperpolarized the membrane potential by 8.6±0.5 mV (n=9), which is different from the 0.5±1.6 mV (n=6) hyperpolarization during SNP application in the presence of 10-5 mol/L Ba2+ (P<0.001) (Figure 5D). However, application of 10-6 mol/L DEA-NO, a direct NO donor, did not alter the KIR current; at -100 mV, the KIR current changed 0.97±0.07-fold (n=6), which is not different from the 1.02±0.04-fold (n=6) change during time-control measurements (P=0.63).



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  		Figure 5. Effect of SNP on the KIR current of rat tail small artery smooth muscle cells. A, Example of the current (I)–voltage (MP) relationship of the KIR current before (ctrl) and after addition of 10-4 mol/L SNP [K]o=36 mmol/L; Vh=-40 mV. B, Summarized data of the effect of 10-4 mol/L SNP on the KIR current at a membrane potential (MP) of -100 mV (n=8, P<0.05 for comparison with time control as well as with SNP application in the presence of Ba2+). C, Summarized data of the current–voltage relationship of the KIR current before (ctrl) and after the addition of 10-4 mol/L SNP (n=5, P<0.05); current normalized to the current at -100 mV measured {approx}30 seconds before the recording of the control current. D, Summarized data of the effect of 10-4 mol/L SNP on the membrane potential in the absence and presence of 10-5 mol/L Ba2+ (n=9, P<0.001).


*    Discussion
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 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present experiments show that a KIR current exists in rat-tail small artery smooth muscle cells and are consistent with the hypothesis that this current is mediated by KIR 2.1 channels. It is also shown that the KIR current is involved in vessel dilations induced by SNP.

Evidence for the Existence of a KIR Current in Rat-Tail Small Artery Smooth Muscle Cells
The results clearly demonstrate the presence of a KIR current exhibiting characteristic properties.6,8,13 The KIR current could be inhibited with micromolar concentrations of Ba2+. Similarly, 10-5 mol/L Ba2+ inhibited the KIR current in rat cerebral and coronary artery smooth muscle cells by {approx}90% at -80 mV.6,8 The amplitude of the barium-sensitive inward current was greater than the outward current (inward rectification). The inward rectifying K current shifts along the voltage axis by changing [K]o and inward conductance increases with increasing [K]o similar to other KIR currents, whereas the conductance was proportional to [K]o0.5 in pig coronary artery9 and to [K]o0.45 in rat coronary artery8 smooth muscle cells.

A characteristic reaction of small arteries indicative of a functional role of KIR channels is a barium-sensitive dilation in response to low concentrations of extracellular potassium ([K]o). Thus, Ba2+ in the range of 3 to 5x10-5 mol/L inhibited, partly and sometimes completely, the [K]o-induced dilation and hyperpolarization in rat cerebral and coronary small arteries15,16 and rat hepatic arteries.12 Ba2+ in the same concentration range reduced the [K]o-induced dilation also in the present study. Thus, this finding provides additional functional evidence for the existence of KIR channels in rat-tail small arteries.

Molecular Identification of the K Channel Mediating the KIR Current
The molecular and immunocytochemical characterization of the KIR channel mediating the KIR current was performed on intact vessels. The detection of von Willebrand factor transcripts, a specific marker of endothelial cells, indicates that cDNA from the endothelium was present, ie, the KIR 2.1 and 2.2 found in the present study could be expressed in smooth muscle and/or in endothelial cells. However, a KIR 2.1 but not KIR 2.2 antibody stained the tunica media of the vessel, indicating that in smooth muscle cells only KIR 2.1 is expressed. This finding is supported by other reports showing that in the rat, KIR 2.1 but not KIR 2.2 and 2.3 channels are present in isolated smooth muscle cells from coronary, cerebral, and mesenteric small arteries13,14 and are required for potassium-induced vessel dilations.14 Thus, the data presented here are consistent with the idea that KIR 2.1 channels are present in smooth muscle cells from rat tail artery.

SNP Increases the Amplitude of the KIR Current
In the present study, application of SNP increased the amplitude of the KIR current considerably compared with the control current before SNP application as well as compared with a time-matched control current. In addition, SNP hyperpolarized the membrane potential of these cells. Both effects were almost abolished in the presence of 10-5 mol/L Ba2+. The effect of SNP was observed at a SNP concentration of 10-4 mol/L, which is 1 order of magnitude higher than the SNP concentration required to induce maximum dilation of the vessel. Such a dissociation between the SNP concentration required to produce dilation of the intact tissue and the one necessary to evoke effects on the cellular and subcellular level has already been reported before.27 In this regard, it should be taken into account that the release of NO from SNP is coupled to a process of bioactivation in the vascular tissue.28 Our measurements with an NO electrode placed in a solution containing no tissue showed that DEA-NO, which releases NO spontaneously, at 10-6 mol/L produced 0.60±0.05x10-6 mol/L (n=3) NO. SNP used at a 100-times higher concentration of 10-4 mol/L and measured under the same conditions produced only 0.02±0.01x10-6 mol/L NO (n=3), ie, {approx}30-times less.29 In contrast, measurements of vessel contractile reactions, ie, in the presence of tissue, showed that the vasodilator potency of DEA-NO was similar to the vasodilator potency of SNP (see Results). Thus, the requirement for higher SNP concentrations in the patch-clamp experiments compared with the myograph experiments is the consequence of the fact that the former had been conducted on an enzymatically isolated, single smooth muscle cell, ie, on a small piece of tissue altered to some extent by the enzymatic isolation procedure. The patch-clamp data presented here are supported by previous reports on expressed KIR channels with similar characteristics like the vascular smooth muscle KIR current showing their regulation by hormones or transmitters, for example by histamine,30 serotonin,31 carbachol,32 and growth factors.33 Thus, the data of the present study show for the first time to our knowledge that vascular smooth muscle cell KIR currents are regulated by NO donor; in this study, by SNP.

KIR Current Is Involved in Vessel Dilations Induced by SNP
The results show that 10-5 mol/L Ba2+ reduced the SNP-induced vasodilation considerably. At concentrations smaller than 5x10-5 mol/L, Ba2+ is well known as a selective inhibitor of vascular smooth muscle cell KIR channels;2 the half block constants were in the range of 2 to 8x10-6 mol/L at membrane potentials between -60 and -40 mV.6,8 KIR channels with a similar barium sensitivity also exist in endothelial cells.34 However, if endothelial KIR channels were involved in the effect of SNP, endothelium removal should result in an attenuation of the SNP effect. Because such attenuation was not observed in the present study, the participation of endothelial KIR channels in the SNP response is unlikely. Further, Ba2+ is known to be a charge carrier for Ca2+ channels. However, the maximum Ba2+ concentration used in the functional experiments was considerably smaller than required for a significant participation in the current through Ca2+ channels35,36 and therefore insufficient to produce a vasoconstriction, which could functionally antagonise vasodilations. Indeed, this argument is supported by data of the present study showing that Ba2+ did not affect the dilation induced by cromakalim, a well known opener of ATP-sensitive potassium channels. Furthermore, preliminary experiments had shown that 10-7 mol/L iberiotoxin, the selective inhibitor of the BKCa channel, a well known NO target, did not affect the SNP-induced vasodilation in this vessel. Taken together, it can be concluded that the effect of Ba2+ on the SNP-induced dilation is caused by a specific action of Ba2+ on KIR channels.

The complete inhibition of the effect of SNP by hydroxocobalamin, a NO scavenger,25 suggests that the effect of SNP is mediated by NO. In addition, the inability of cyanide, which may also be released from SNP, to produce vasodilation together with the unchanged effect of SNP in the presence of rhodanese and sodium thiosulfate, cyanide inactivators,26 and the preserved inhibition of the effect of SNP by Ba2+ in the presence of the cyanide inactivators suggest that cyanide ions do not mediate the effect of SNP, either alone or in cooperation with NO. However, the inability of the direct, noncyanide-containing NO donor DEA-NO to affect KIR currents and the absence of an effect of Ba2+ on the DEA-NO–induced vasodilation indicates that NO donors differ in their capability to use the signaling pathway involving KIR currents. Differences in the mechanism of action of NO donors on vascular tissue are well known and have been suggested to depend on the properties of the NO release like the particular NO species released, additional factors coreleased with NO and/or special features of the NO release process37.38 Taken together, these data suggest that the effect of SNP on the KIR current involves NO. Of note, recently it has been shown that the classical nitrovasodilator SNP, in contrast to a direct NO donor, closely resembles the effect of endothelium-derived NO on vascular tissue,39 emphasizing the physiological importance of the effect of the NO donor SNP described in the present study.

A complete inhibition of KIR currents at membrane potentials as observed in pressurised small arteries has been reported for Ba2+ concentrations in the range from 1x10-4 to 5x10-4 mol/L.6,8,11,13 However, in the present experiments, the requirement for selectivity allowed only Ba2+ concentrations of 1x10-5 mol/L to be used. Therefore, the degree of participation of KIR channels in the SNP-induced dilation ({approx}30%; Figure 2A) is underestimated. Nevertheless, the activation of KIR channels by SNP probably does not completely explain the SNP-induced vasodilation. Most likely, mechanisms affecting the calcium sensitivity of the contractile proteins are also involved.40 However, a role for KIR channels in the SNP-induced vasodilation is supported by previous reports suggesting an involvement of these channels in vessel dilations induced by bradykinin19 or dendraspis natriuretic peptide.41

In conclusion, the data of the present study are consistent with the hypothesis that KIR 2.1 channels exist in rat tail small artery smooth muscle cells. The novel observation of this study is that SNP increases the KIR current in these cells and that this effect is suggested to participate in the SNP-induced vasodilation.


*    Acknowledgments
 
This work was supported by Deutsche Forschungsgemeinschaft grants SCHU 805/5-2 and 5-3, 436 BUL 113/94, and Ve 187/1-2.

Received November 10, 2003; first decision December 1, 2003; accepted February 3, 2004.


*    References
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 *References
 

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