The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure ControlNovelty and Significance
ATP-sensitive potassium channels (KATP) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that KATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that KATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle KATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit. Using a combination of molecular, electrophysiological, in vitro, and in vivo techniques, we confirmed the absence of Kir6.1 and KATP currents and responses specifically in smooth muscle. Mice with conditional deletion of Kir6.1 showed no obvious arrhythmic phenotype even after provocation with ergonovine. However, these mice were hypertensive and vascular smooth muscle cells failed to respond to vasodilators in a normal fashion. Thus, Kir6.1 underlies the vascular smooth muscle KATP channel and has a key role in vascular reactivity and blood pressure control.
See Editorial Commentary, pp 457–458
ATP-sensitive potassium channels (KATP) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability.1
KATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM KATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM KATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators.4–7
The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2.8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of KATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the KATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of KATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that KATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM KATP channel contributes modestly to vascular control.10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the KATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).
Generation of the Kir6.1 Mouse Strains
The details are given in the online-only Data Supplement.
Whole-cell patch-clamp recordings were performed as previously described.12 The pipette solution contained (mmol/L): 107 KCl, 1.2 MgCl2, 1 CaCl2, 10 EGTA, and 5 HEPES with 0.1 MgATP and 1 NaADP, pH 7.2 using KOH. The bath solution contained (mmol/L): 110 NaCl, 5 KCl, 1.2 MgCl2, 1.8 CaCl2, 15 NaHCO3, 0.5 KH2PO4, 0.5 NaH2PO4, 10 Glucose, 10 HEPES (pH 7.2).
The implantation of the telemetry probes has been described previously and in the online-only Data Supplement.13
BP was measured directly using radio-telemetry. Anesthesia was induced with 5% isoflurane and maintained with 1% to 1.5% isoflurane. PAC-10 probes (Data Sciences International) were used. The left carotid artery was isolated, a small incision made, and the probe catheter inserted to a depth of ≈1 cm and secured with sutures. The implant body was placed subcutaneously on the left side of the abdomen. Recordings were commenced 2 weeks postsurgery, using the Acquisition module of the Dataquest software (Data Sciences International) at a sampling rate of 2 kHz for 24 to 48 hours and analyzed using Ponemah P3 plus analysis software (Data Sciences International).
See the online-only Data Supplement for details on genotyping, gene expression data using quantitative real-time PCR, in vitro experiments using organ bath and myograph, isolation of vascular SMCs, and statistical analysis. All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and with British Home Office regulations (PPL/6732 and PPL/7665).
Characterization of the SM-Specific Kir6.1 Knockout Mouse
We generated a mouse in which exon 2 of the Kcnj8 gene encoding Kir6.1 was flanked by loxP sites (Kir6.1(+/flx), see Methods section and Figure 1A) and mice with global genetic deletion of Kir6.1 [Kir6.1(+/−)]. Two SM-cre lines were used: one that expresses from the SM myosin heavy chain promoter (smαMHC-cre)14 and another from the SM 22 promoter (sm22α-cre).15 The resulting smMHCcre+ Kir6.1(+/flx) or sm22cre+ Kir6.1(+/flx) or both mice were crossed with Kir6.1(flx/flx) or Kir6.1(+/flx) mice to generate tissue-specific knockout of Kir6.1 in SM [smMHCcre+ Kir6.1(flx/flx) and sm22cre+ Kir6.1(flx/flx)] (Figure 1A) and the relevant littermate controls. For the SM conditional lines the wild-type (WT) genotypes (including cre+ +/+ and cre− flx/flx and +/flx mice) were analyzed. We saw no obvious differences in expression and functional phenotype (Figure S1 in the online-only Data Supplement) and thus, these mice were pooled for the control (WT) group. Kir6.1(+/−) mice were crossed to generate Kir6.1(−/−) and littermate controls. The genotypes were identified by polymerase chain reaction on genomic DNA from tail snips and aorta of smMHCcre+ Kir6.1(flx/flx), sm22cre+ Kir6.1(flx/flx), Kir6.1(−/−), and control animals (see the Methods section and Figure 1). We found that sm22cre+ Kir6.1(flx/flx) mice had a significant survival advantage over Kir6.1(−/−) mice (2.4% versus 65% mortality at 7 weeks).
Kir6.1 Expression Is Reduced in SM From Kir6.1 Knockout Mice
To confirm the reduced expression of Kir6.1 (Kcnj8 gene) in SM, quantitative real-time PCR was performed on RNA from the heart, aorta, and brain. Kir6.1 expression was substantially reduced in the aorta from smMHCcre+ Kir6.1(flx/flx) and sm22cre+ Kir6.1(flx/flx) mice compared with control animals (Figure 1E). Expression in the heart and brain was not significantly different from that in control tissues (P>0.1). Kir6.1 expression in the brain and heart of Kir6.1(−/−) mice was reduced to background levels compared with WT and the 2 SM-specific lines (P<0.01). In contrast, the expression of Kir6.2 (Kcnj11 gene) was not affected in any tissue from any of the mouse lines (Figure 1F). Interestingly, SUR2 expression was reduced by ≈60% in the thoracic aorta of each of the 3 strains of genetically modified mice but not in WT mice (Figure 1G). However, this was not a consistent feature through all tissues and regions of the aorta (see below).
KATP Current Is Absent in Aortic and Mesenteric SMCs and Pinacidil-Induced Relaxation of Aortic and Mesenteric Ring Preparations Is Attenuated in Kir6.1 Knockout Mice
Whole-cell patch-clamp recordings from acutely isolated WT aortic SMCs show a K+-selective current activated by pinacidil and inhibited by glibenclamide (Figure 2A–2C). In contrast, currents from sm22cre+ Kir6.1(flx/flx) SMCs do not respond to pinacidil or glibenclamide, suggesting that the KATP current is absent in these cells. There is also no response to the KATP channel opener and blocker in SMCs from Kir6.1(−/−) mice (Figure 2A–2C). As a further control, we measured KATP currents in ventricular cardiac myocytes and saw no changes in the sm22cre+ Kir6.1(flx/flx), Kir6.1(−/−), and littermate control mice (Figure S3). Because of the almost-identical reduction in expression of Kir6.1 in SM and absence of KATP current in aortic SMCs from smMHCcre+ Kir6.1(flx/flx) and sm22cre+ Kir6.1(flx/flx) mice (Figure S2), we decided to concentrate mainly on the sm22cre+ Kir6.1(flx/flx) mouse line. At tissue level, we measured relaxation of endothelium-denuded aortic rings isolated from different mouse lines with pinacidil (100 nmol/L to 10 μmol/L) after phenylephrine-induced contraction (Figure 2D–2F). WT aortic rings relaxed but in comparison, rings from both sm22cre+ Kir6.1(flx/flx) and Kir6.1(−/−) showed relatively little relaxation.
To show tissue-specific deletion of Kir6.1 in other vascular beds, we used quantitative real-time PCR to study expression in the coronary, mesenteric, renal, and femoral arteries of Kir6.1-deleted mice (Figure S4). Kir6.1 expression was significantly reduced in all vessels from Kir6.1-deleted mice compared with those from WT mice (Figure S4). The reduction of Kir6.1 expression in mesenteric artery SM is complemented by whole-cell patch-clamp recordings from acutely isolated mesenteric artery SMCs of sm22cre+ Kir6.1(flx/flx) and Kir6.1(−/−) mice where the glibenclamide-sensitive current was markedly less compared with SMCs from WT mice (Figure S3). Furthermore, relaxation of endothelium-denuded mesenteric arteries isolated from sm22cre+ Kir6.1(flx/flx) mice was attenuated after phenylephrine-induced contraction (Figure S4). It is also worth commenting that there was little difference in the variability of responses between WT and the various lines of mice in cell-to-cell responses (and in the aorta), suggesting relatively uniform deletion of Kir6.1 in vascular SMCs using this cre. We also compared the expression of Kir6.1 in different regions of the aorta in the different murine strains and the deletion of Kir6.1 was relatively uniform in sm22cre+ Kir6.1(flx/flx) mice (Figure S5). We attempted to confirm these findings, using protein biochemistry but the commercial antibodies were not sufficiently sensitive to detect the low level of endogenous channel expression in control animals.
Mice With Deletion of Kir6.1 in SM Do Not Suffer Sudden Cardiac Death
Kir6.1 and SUR2 global knockout mice are prone to early sudden death because of cardiac arrhythmias.8,9 Using continuous ECG telemetry recordings, we observed a phenotype in Kir6.1(−/−) mice consistent with these studies. In these mice (3/5 where the event was captured), sudden death was preceded by ST elevation, bradycardia, and prolonged atrioventricular heart block (Figure 3A). Death typically occurs over ≈7 to 8 hours, ST elevation is followed by first-, second-, and third-degree atriovetricular block and severe bradycardia. Kir6.1(−/−) mice that survived during recording were bradycardic with longer RR and PR intervals and significant ST elevation compared with WT mice (Figure 3B–3F). The diurnal variation in the heart rate (HR) of these mice was also lost. Unlike Kir6.1(−/−) mice, sm22cre+ Kir6.1(flx/flx) mice did not present with an obvious ECG phenotype, although HR was slower, but not significantly so, compared with littermate controls. These mice showed normal diurnal variation in HR with only a slight increase in PR and RR intervals and no significant ST elevation (Figure 3). Neither the littermate controls nor SM-specific knockout mice died during ECG monitoring. Because sm22cre+ Kir6.1(flx/flx) mice do not exhibit sudden cardiac death because of possible vasospasm as observed in the Kir6.1(−/−) mice, we used ergonovine, an ergot alkaloid, to try to directly induce vasospasm by triggering vasoconstriction of vascular SM.16 Intravenous injection of ergonovine in anesthetized Kir6.1(−/−) mice prompted an obvious change in ECG complex morphology (Figure 3G). A broader QRS and T wave complex was observed with ST-depression in addition to pronounced bradycardia reflected in significant lengthening of RR intervals. Bradycardia was followed by heart block and subsequent death (in 4 of 5 mice). In sm22cre+ Kir6.1(flx/flx) mice, ergonovine also slowed HR and increased the RR interval though this was much less pronounced than in Kir6.1(−/−) mice (Figure 3G and 3H). Control mice did not exhibit significant changes in ECG parameters. Neither control nor sm22cre+ Kir6.1(flx/flx) mice developed heart block or died after injection of ergonovine. We observed similar results in the smMHCcre+ Kir6.1(flx/flx) mice (Figure S6).
BP Is Elevated in sm22cre+ Kir6.1(flx/flx) Mice and the Effect of the Vasodilator Calcitonin Gene-Related Peptide Abolished
To examine the possible changes in BP attributable to the absence of Kir6.1 in SM, we used continuous BP telemetry monitoring in conscious 8- to 12-week-old littermate controls, sm22cre+ Kir6.1(flx/flx), and Kir6.1(−/−) mice (Figure 4A and 4B). Kir6.1(−/−) mice were studied before developing bradycardia and heart block. Initially, BP was monitored in both male and female mice to observe potential sex differences in the Kir6.1(−/−) and sm22cre+ Kir6.1(flx/flx) mice. However, we did not see an obvious difference in phenotype, and therefore, all data were pooled (Figure S7). Littermate control mice showed typical circadian variation in systolic and diastolic BP with higher BP at night than during the day. Kir6.1(−/−) mice exhibited significantly elevated BP compared with littermate control mice and also lost diurnal variation in systolic BP. BP was also elevated in sm22cre+ Kir6.1(flx/flx) mice but this was not as pronounced as in Kir6.1(−/−) mice of a similar age. Both systolic and diastolic BP was elevated by ≈10 mm Hg and there was no substantial difference in day/night elevation. Furthermore, the hypotensive effect of pinacidil was substantially abrogated (Figure S8).
It has been suggested that vasodilators act through KATP channels to regulate vascular tone.1,5 Given that Kir6.1(−/−) and sm22cre+ Kir6.1(flx/flx) mice have significantly elevated BP, we investigated the actions of the vasodilating agent calcitonin gene-related peptide (CGRP) on the K+ currents and membrane potential of SMCs acutely isolated from the aorta of littermate control, Kir6.1(−/−), and sm22cre+ Kir6.1(flx/flx) mice (Figure 4C–4F). CGRP (50 nmol/L) increased WT SMC current but had no effect on Kir6.1(−/−) or sm22cre+ Kir6.1(flx/flx) currents, suggesting that CGRP acts via Kir6.1-containing KATP channels in SMCs (Figure 4C and 4D). To determine whether Kir6.1-containing KATP channels are involved in vasodilator-mediated regulation of vascular SMC membrane potential, we used current-clamp to measure changes in membrane potential on application of 50 nmol/L CGRP to aortic SMCs isolated from WT, Kir6.1(−/−), and sm22cre+ Kir6.1(flx/flx) mice. CGRP hyperpolarized the membrane potential of WT SMCs by ≈8 mV. Pinacidil further hyperpolarized the membrane potential by 7 to 8 mV (P<0.01 compared with CGRP) which was reversed to basal levels by glibenclamide (P>0.05 compared with basal; Figure 4E and 4F). The membrane potential of Kir6.1(−/−) and sm22cre+ Kir6.1(flx/flx) SMCs was not affected by CGRP, pinacidil, or glibenclamide. The hyperpolarizing effect of another vasodilator, adenosine (1 μmol/L), was also attenuated in SMCs from SM-specific knockout mice (Figure S9). The resting membrane potential of SMCs isolated from the Kir6.1(−/−) or sm22cre+ Kir6.1(flx/flx) lines was consistently found to be more depolarized than WT SMCs. This could be attributable to Kir6.1 contributing to the resting membrane potential or a potential change in expression of other ion channels in SM as a result of Kir6.1 deletion. Real-time qRT-PCR data show no significant change in a variety of ion channels in both the global and tissue-specific knockout mouse lines (Figure S10); Furthermore, there was no change in the tetraethylammonium-sensitive current in either knockout mouse line (Figure S10). Thus, it is likely that Kir6.1 contributes to the resting membrane potential of SMCs with the intracellular pipette solution that is used in this study. Taken together, these data suggest that the lack of an effect on KATP channels from vasodilating agents may contribute to the hypertensive phenotype seen in Kir6.1 knockout mice.
To address the tissue-specific role of Kir6.1-containing KATP channels in vascular SM, we generated a novel mouse model with conditional deletion of Kir6.1 in vascular SM, using the cre/loxP recombination system and compared this with a mouse with global genetic deletion of Kir6.1. The major novel findings in this study are that the vascular KATP channel, specifically the Kir6.1 subunit, has a role in BP control but is not solely responsible for the sudden death and atrioventricular block seen in Kir6.1(−/−) mice.
In a concerted effort to elucidate the physiological roles of KATP channels, genetically modified mouse models have been increasingly used. For example, global genetic deletion of Kir6.1 or SUR2 results in a high rate of sudden death attributed to coronary artery vasospasm, prolonged atrioventricular block, and hypertension.8,9 This phenotype was originally credited to the absence of Kir6.1 or SUR2 in vascular SM. However, these modified mice carried deletions of these genes affecting all tissues; hence the role of Kir6.1/SUR2 in other locations in the regulation of vasomotor tone could not be definitively ruled out. The 2 knockout lines do not seem equivalent in that the SUR2 global knockout mice seem to survive and live past 10 weeks, whereas as we and others have observed, only a few Kir6.1(−/−) do so.8 Another approach is to use a variety of transgenic strategies to overexpress constitutively active mutants, WT subunits, or dominant negative constructs behind tissue-specific promoters or transcriptional stop cassettes.17,18 The results from these approaches are intriguing but expression from the endogenous allele remains intact, expression varies widely depending on the site(s) of genetic integration and can leak, and critically Kir6.1 and Kir6.2 readily coassemble with each other and different SURs.19 A further development is to combine global knockout mice with tissue-specific transgenic expression of WT subunits. Indeed, when SUR2B is transgenically overexpressed specifically in SM in the SUR2 global knockout mouse, the sudden death phenotype in particular remained, suggesting that KATP channels in other locations may play a prominent physiological role in the control of vascular tone.10 In a similar vein, transgenic overexpression of SUR2A in cardiac myocytes in the SUR2 knockout mouse significantly attenuated episodes of apparent coronary vasospasm. A further complication for the interpretation of these studies is that there is evidence that a truncated SUR2 isoform may be expressed and functional from the targeted allele.20 Our studies substantially clarify these issues showing that Kir6.1-containing KATP channels have a role in BP control and electrophysiological responses to vasodilators but do not account alone for the sudden death phenotype.
Patch-clamp experiments in this study clearly show that Kir6.1 is the molecular pore-forming counterpart of the vascular KATP channel while also indirectly ruling out a significant component generated by Kir6.2. It is still possible that Kir6.2 might contribute to KATP currents in some vascular beds and the microcirculation but the Kir6.1 knockout mice are hypertensive, suggesting a role in the resistance vasculature which is predominantly responsible for BP control. Our gene expression data from several vascular beds, myography, and electrophysiological studies from the mesenteric circulation support this.
Early studies clearly identified a prominent KATP current in vascular and nonvascular SM. Furthermore, this current was prominently modulated by neurohumoral signaling pathways. Vasodilators such as CGRP activated the current and vasoconstrictors, including angiotensin II, neuropeptide Y, phenylephrine, histamine, and serotonin, inhibited it.4,7,21–23 The idea, backed up by ex vivo studies of vascular preparations using the organ bath or myography, was that vascular KATP channels were involved in vascular reactivity. Equivalent regulation by both vasodilators and vasoconstrictors might be expected to have a neutral effect on BP. However, our in vivo work shows that deletion of the vascular SM KATP channel leads to systolic and diastolic hypertension throughout the day in both sexes of mice, suggesting that KATP currents are responsible predominantly for some vasorelaxant tone under physiological conditions. The hypertension is an ≈10 mm Hg increase in sm22cre+ Kir6.1(flx/flx) mice, but it should be borne in mind that these mice are studied at a relatively young age (≈2 months) and have not been aged to see whether hypertension worsens and whether they develop end organ damage. The strategy was to enable an age-matched comparison between the Kir6.1(−/−) and sm22cre+ Kir6.1(flx/flx) mice. The magnitude of change in BP is similar to that seen in Kir6.1 loss of function (hypertension) and gain of function (hypotension) transgenic mice.18 The hypertensive effect may seem relatively modest; however, to put this in context, an increase in BP by as little as 2 mm Hg may increase the risk of stroke in man by 15%.16 Perhaps more revealing is that mice with the SM conditional deletion were less hypertensive compared with those with the global deletion of Kir6.1. Interestingly, both Kir6.1 (present study) and SUR29 knockout mice had BP elevated by ≈20 mm Hg compared with littermate controls, roughly 2-fold more than in conditional knockout mice, correlating well with the 2-fold greater pinacidil-induced decrease in mean arterial pressure measured in Kir6.1(−/−) mice compared with conditional knockout mice. Mice are nocturnal creatures and therefore are more active at night. This is reflected in a diurnal variation in BP (and HR) with animals being relatively hypertensive (and tachycardic) nocturnally. Interestingly, in our Kir6.1(−/−) mice, diurnal variation is lost but preserved in the mice with conditional deletion in vascular SM. Collectively, these data support the possibility that KATP channels in other cellular locations, such as endothelium, peripheral nerve endings, and central nervous system, might have additional physiological roles in the regulation of vascular tone and reactivity. For example, selective expression of a dominant-negative Kir6.1 KATP channel construct in endothelial cells leads to increased endothelin-1 release and a significant increase in coronary perfusion pressure.17 Regulating endothelin and NO release may be the underlying mechanism by which endothelial KATP channels promote vasodilation.24 It will therefore be interesting to study mice in subsequent work with conditional deletion of Kir6.1 in endothelial cells.
A prominent difference between Kir6.1(−/−) and sm22cre+ Kir6.1(flx/flx) mice was the decline in the incidence of sudden death in the mice with conditional deletion. Moreover, intravenous administration of ergonovine failed to induce significant changes in ECG complex morphology or result in death in sm22cre+ Kir6.1(flx/flx) mice. Thus, deletion of Kir6.1 in vascular SMCs alone is not sufficient to reproduce this phenotype. However, it is interesting to note that there was a statistically significant but less prominent sinus bradycardia induced in the sm22cre+ Kir6.1(flx/flx) mice by ergonovine, suggesting a partial contribution to the phenotype.
We have shown that the SM KATP channels composed of Kir6.1 are important in vascular reactivity and BP control. However, mice with global genetic deletion of Kir6.1 have other phenotypes, including sudden death, and suggest that the channel subunit may have important roles outside SM. In the future, the development of new strains of mice with tissue specific deletion should help to explore these questions further.
We are grateful for the technical assistance of Tapsi Khambra and to Professor Michael Kotlikoff for kindly providing the smMHCcre+ mouse.
Sources of Funding
This research was supported by the British Heart Foundation (RG/10/10/28447 and FS/07/031) and facilitated by The National Institute for Health Research Barts Cardiovascular Biomedical Research Unit.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.114.03116/-/DC1.
- Received January 3, 2014.
- Revision received January 27, 2014.
- Accepted April 23, 2014.
- © 2014 American Heart Association, Inc.
- Quayle JM,
- Nelson MT,
- Standen NB
- Quinn KV,
- Giblin JP,
- Tinker A
- Kakkar R,
- Ye B,
- Stoller DA,
- Smelley M,
- Shi NQ,
- Galles K,
- Hadhazy M,
- Makielski JC,
- McNally EM
- Stoller DA,
- Fahrenbach JP,
- Chalupsky K,
- Tan BH,
- Aggarwal N,
- Metcalfe J,
- Hadhazy M,
- Shi NQ,
- Makielski JC,
- McNally EM
- Zuberi Z,
- Birnbaumer L,
- Tinker A
- Xin HB,
- Deng KY,
- Rishniw M,
- Ji G,
- Kotlikoff MI
- Malester B,
- Tong X,
- Ghiu I,
- Kontogeorgis A,
- Gutstein DE,
- Xu J,
- Hendricks-Munoz KD,
- Coetzee WA
- Li A,
- Knutsen RH,
- Zhang H,
- Osei-Owusu P,
- Moreno-Dominguez A,
- Harter TM,
- Uchida K,
- Remedi MS,
- Dietrich HH,
- Bernal-Mizrachi C,
- Blumer KJ,
- Mecham RP,
- Koster JC,
- Nichols CG
- Cui Y,
- Giblin JP,
- Clapp LH,
- Tinker A
- Bonev AD,
- Nelson MT
- Cole WC,
- Malcolm T,
- Walsh MP,
- Light PE
- Nilius B,
- Droogmans G
Novelty and Significance
What Is New?
KATP channels are membrane proteins that have been shown to be involved in modulating the tone of blood vessels. In this study we develop a novel mouse model where we can conditionally delete a subunit of the channel (Kir6.1).
What Is Relevant?
We show that the Kir6.1 subunit in vascular smooth muscle has a major role in blood pressure control through controlling the excitability of vascular smooth muscle cells to vasodilators. However, its absence specifically from smooth muscle is not responsible for the bradycardia and sudden death associated with global genetic deletion of this channel.
The tissue-specific ablation of the Kir6.1 subunit in smooth muscle gives a pathophysiological insight into its function in the intact organism in blood pressure control.