Acid stress reduces the function of Na+-K+-ATPase in superior mesenteric artery of Capra hircus
Subash Chandra Parija, Ipsita Mohanty
Department of Pharmacology and Toxicology, Faculty of Veterinary Sciences, Orissa University of Agriculture and Technology, Bhubaneswar, Odisha, India
|Date of Submission||19-Dec-2017|
|Date of Decision||25-Jan-2018|
|Date of Web Publication||17-Jan-2019|
Subash Chandra Parija
Department of Pharmacology and Toxicology, Faculty of Veterinary Science and Animal Husbandry, Orissa University of Agriculture and Technology, Bhubaneswar - 751 003, Odisha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: Extracellular hydrogen ion concentration (pHo) is an important physiological regulator of vascular tone, maintained within 7.35–7.45 and any change in it leads to complex health problem including maintenance of normal blood pressure. Aims: This study aims to examine the altered function of Na+-K+ pump and inward rectifier potassium channels (Kir) channels in extracellular acidosis in goat superior mesenteric artery (GSMA). Subjects and Methods: Isolated GSMA rings were mounted in an automatic organ bath containing 20-ml modified Krebs–Henseleit solution at pH 7.4/6.8/6.0 and KCl-induced contraction was elicited either in the absence or presence of ouabain, barium (Ba2+), and combination of ouabain and Ba2+. Rings were dilated with potassium chloride either in the absence or presence of ouabain, Ba2+ and combination of ouabain and Ba2+ while maintaining at acidic pH. The responses were recorded isometrically by highly sensitive isometric force transducer connected to Powerlab and analyzed using LabChart 7.1.3 software. Statistical Analysis Used: Data were analyzed in GraphPad Prism 5 software. Results: K+ vasorelaxation response in K+-free solution precontracted rings the percent maximal response (93.57 ± 2.57%, 62.60 ± 3.56%, and 53.38 ± 5.41%) was decreased with decrease pHo (7.4, 6.8 and 6.0). Ouabain, Ba2+, and ouabain and Ba2+ inhibited the maximal vasorelaxation of potassium chloride (26.20 ± 3.48%, 17.39 ± 0.54%, 31.92 ± 1.10%) at pHo7.4, (42.74 ± 2.48%, 16.12 ± 3.49%, 22.32 ± 1.63%) at pHo6.8, and (53.87 ± 2.18%, 25.24 ± 2.90%, 39.71 ± 0.14%) at pHo6.0, respectively. Conclusions: Attenuated vasodilation in acidosis is due to reduced function or expression of ouabain-sensitive sodium–potassium ATPase (Na+-K+-ATPase) and Kir channels. In clinical acidosis, agents augmenting the activity of Na+-K+-ATPase and K+-Channel could improve hypertensive crisis.
Abbreviations used: Ba2+: Barium; Emax: Percent maximal response; EBmax: Percent maximal response in presence of antagonist; KATP: Adenosine triphosphate-sensitive potassium channel; Kir: Inward rectifier potassium channels; KCa: Calcium-activated potassium channels; Na+-K+-ATPase: Sodium–potassium ATPase; NO: Nitric oxide; pHi: Intracellular hydrogen ion concentration; pHo: Extracellular hydrogen ion concentration; VSMCs: Vascular smooth muscle cells.
Keywords: Acidosis, Capra hircus, hypotension, Kir channel, mesenteric artery, sodium pump
|How to cite this article:|
Parija SC, Mohanty I. Acid stress reduces the function of Na+-K+-ATPase in superior mesenteric artery of Capra hircus. Phcog Mag 2018;14:558-63
|How to cite this URL:|
Parija SC, Mohanty I. Acid stress reduces the function of Na+-K+-ATPase in superior mesenteric artery of Capra hircus. Phcog Mag [serial online] 2018 [cited 2021 Sep 17];14:558-63. Available from: http://www.phcog.com/text.asp?2018/14/59/558/250184
- Extravascular reduction of pHo from 7.4 to 6.0 induces cellular acidosis in GSMA model.
- Acidosis causes hypertention which may be due to significant attenuation vasodilatation response to KCl.
- The underlying mechanism of acidosis–induced hypertension is due to reduced function of sodium pump or Kir channels.
| Introduction|| |
Extracellular hydrogen ion concentration (pHo) is generally maintained within a narrow range of 7.35 and 7.45, but local or systemic acidifications may cause some pathological conditions such as ischemia, hypoxia, metabolic disorders, gastrointestinal disorders, and renal dysfunctions. Extracellular acidosis promotes vasodilation mediated by nitric oxide and/or K+ channels such as adenosine triphosphate-sensitive potassium channel (KATP) and calcium-activated potassium channels (KCa) in vascular bed., The vasodilatory effects of acidosis have been well described in animals both in vivo and in vitro., Acidosis-induced vasodilatory effect is influenced with respect to the agonist employed, species, genetic strain, vascular location and caliber,, and experimental model.,
Modulation of vascular contractility affecting the activities of ion channels and pumps in acidic pH has been reported in several vascular beds. In bovine pial and porcine coronary arteries, an increase in intracellular hydrogen ion concentration (pHi) potentiated the Ca2+ currents through L-type channels. In addition, acidosis influences Ca2+-activated K+ channels in the porcine coronary artery smooth muscle cells,, and ATP-sensitive K+ channels in rat thoracic aorta. Information vasorelaxation of the mesenteric artery under altered pHo is almost limited to rat. In rat mesenteric artery, K+-induced relaxation in SMCs is mediated by Kir2.1 channels and this channel expression increases as diameter decreases. An increase in pHo potentiates and a decrease in pHo inhibits inward rectifier potassium channels (Kir) currents and Na+-K+-ATPaseactivity. Na+-K+-ATPase plays an important role in generation and maintenance of electrochemical gradient by extrusion of three sodium ions and influx of two potassium ions across the cell membrane by utilizing the energy derived from ATP hydrolysis. Similarly, ouabain-sensitive α2 and α3 subunits isoforms of sodium–potassium ATPase (Na+-K+-ATPase) have been reported to contribute K+ vasorelaxation in rat mesenteric myocyte. The phenylephrine-induced elevation of intracellular Ca2+ stimulates K+ efflux, predominantly through BKCa that lead to an extracellular K+ “cloud,” and this prevents any further activation of ouabain-sensitive Na+-K+-ATPase in response to elevation of extracellular K+. Recent study from our laboratory indicates that adrenergic stimulated contractile response was decreased with increase in extracellular pHo and that is due to reduced function and expression of α1D-adrenoceptor in the superior mesenteric artery (SMA) of Capra hircus. Our previous study revealed that vasorelaxation of goat mesenteric artery is mediated by endothelial ouabain-sensitive Na+-K+-ATPase. Thus, we hypothesize that in goat mesenteric artery increase in extracellular pHo could reduce the function of ouabain-sensitive Na+-K+-ATPase. The present work examines how does mesenteric vascular bed responds to acidic pH (acidosis) and what is the relative contribution of Na+-K+ pump and Kir channels in acidosis-induced altered vasorelaxation in this vascular bed.
| Subjects and Methods|| |
Ouabain (Sigma (USA) and barium (Ba2+) chloride (Qualigens India) were employed for isometric contraction study. All the solutions were prepared in deionized distilled water. This work has been approved by the Institutional Animal Ethical Committee (Registration No: 433/CPCSEA/20/06/2001) vide ID. No. 130/CVS/dt. 31.03.2015 for conducting randomized animal tissue experiments.
Preparation of superior mesenteric artery and tension recording
After careful exposure of goat intestinal mesentery, a branch of SMA adjacent to the duodenum and jejunum just before its branching into inferior branch was dissected out and placed in cold aerated modified Krebs–Henseleit saline (MKHS) solution of the following composition: (mM): NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 1.2, NaHCO3 11.9, KH2 PO4 1.2, and dextrose 11.1 (pH 7.4). The solution was adjusted to either pHo7.4, 6.8, or 6.0 using 1 N HCl. Then, these arterial rings were cleared of fascia and subcutaneous fat, cut into 1.5–2 mm long circular rings and further employed for isometric contraction studies. Na+-K+-ATPase activity was studied by assessing K+-induced relaxation (1 μM–0.1 mM) on K+ free MKHS-induced contractile response in goat SMA (GSMA). KCl induced vasorelaxation in the absence or presence of ouabain (1 μM) or Ba2+ (30 μM) or ouabain (1 μM) and Ba2+ (30 μM) at different pHo. The change of isometric tension was measured by a highly sensitive isometric force transducer (Model: MLT0201, AD instrument, Australia) and analyzed using LabChart 7.1.3 software (ADInstruments Pty Ltd, New South Wales, Australia). Vasodilatation effects were expressed as the percentage of maximal response considering plateau tension induced by K+ free as 100%.
The concentration related contractile response curve was analyzed using GraphPad Prism5 and percent maximal response/Emax in the presence of antagonist (Emax/EBmax) (%), pD2 were compared using unpaired Students t-test using GraphPad Software Quick Calcs (San Diego, CA, U. S. A). P < 0.05 was considered statistically significant.
| Results|| |
GSMA rings exposed to K+-free MKHS maintained at different pHo (7.4, 6.8, and 6.0) induced a slow phasic contraction followed by sustained (plateau) contractile response. The mean peak and plateau tension at pHo7.4 (1.43 ± 0.27 g; 1.32 ± 0.25 g, n = 22) was reduced (0.99 ± 0.11 g; 0.97 ± 0.14 g, n = 16) at pHo6.8 and (0.64 ± 0.07 g; 0.63 ± 0.07 g, n = 10) at pHo6.0, respectively. The proportionality of mean peak tension (1: 0.71: 0.45) did not differ from the mean plateau tension (1: 0.72: 0.47) at different pHo (7.4, 6.8, 6.0).
KCl (1 mM) reduced the plateau contraction induced by K+-free MKHS by 83.58 ± 2.87% (pHo7.4), 57.19 ± 3.88% (pHo6.8), and 34.60 ± 4.41% (pHo6.0), respectively [Figure 1] and [Figure 2]. The concentration-related vasorelaxation response curve of KCl (1 μM–10 mM) at pHo7.4 (Emax93.57 ± 2.57%, pD2 3.82 ± 0.12) was shifted to the right with significant (P < 0.05) decrease in Emax and pD2 (62.60 ± 3.56%, 4.16 ± 0.12) at pHo6.8 and (53.38 ± 5.41%, 4.21 ± 0.14) at pHo6., respectively [Table 1] and [Figure 3]. The maximal relaxation responses to K+ were inhibited at acidic pH.
|Figure 1: KCl (1 mM)-induced concentratile response in goat superior mesenteric artery incubated with K+-free modified Krebs–Henseleit saline maintained at pH 7.4, 6.8, and 6.0|
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|Figure 2: Tracings indicating KCl (1 mM)-induced vasorelaxation in goat superior mesenteric artery incubated with K+-free modified Krebs–Henseleit saline maintained at pH 7.4, 6.8, and 6.0|
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|Table 1: Comparison of Emax/EBmax or pD2 of KCl (1μM to 10mM)-induced vasorelaxation at different pHo (7.4, 6.8 and 6.0) either in absence or presence of Ouabain (1μM), Barium (30μM), Ouabain (1μM) and Barium (30μM) in GSMA rings. All values are expressed as mean±SEM, n=8 (KCl and Ouab); n=4 (Ba and Ouab +Ba)|
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|Figure 3: KCl-induced concentration-related contractile response curve in goat superior mesenteric artery incubated with K+-free modified Krebs–Henseleit saline at extracellular hydrogen ion concentration 7.4, 6.8, and 6.0|
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Effect of pHo (7.4 or 6.8 or 6.0) on KCl-induced vasorelaxation in K+-free MKHS in the absence or presence of ouabain (1 μM) or Ba2+ (30 μM) or ouabain (1 μM) and Ba2+ (30 μM), [Table 1] represents the influence of pHo (7.4–6.0) on vasotonic effect of ouabain or Ba2+ or ouabain and Ba2+- on K+-induced vasorelaxation in GSMA rings. Ouabain (1 μM) caused rightward shift of KCl-induced concentration-related vasorelaxation curve with significant (P < 0.05) decrease in EBmax and pD2 at pHo7.4 (26.20 ± 3.48%, 4.30 ± 0.19), pHo6.8 (42.74 ± 2.48%, 5.07 ± 0.13), and pHo6.0 (53.87 ± 2.18%, 4.70 ± 0.11) [Figure 4]. In the presence of Ba2+ (30 μM), the K+-induced concentration-related vasorelaxation curve was shifted to right with a significant (P < 0.05) decrease in EBmax and pD2 (17.39 ± 0.54%, 4.59 ± 0.07) at pHo7.4, (16.12 ± 3.49%, 4.64 ± 0.08) at pHo6.8, and (25.24 ± 2.90, 1.95 ± 0.24) at pHo6.0 [Figure 5]. A combination of ouabain (1 μM) and Ba2+ (30 μM) caused rightward shift of KCl-induced concentration-related vasorelaxation curve with a significant (P < 0.05) decrease in EBmax (31.92 ± 1.10%) and decrease in pD2 (3.55 ± 0.12) at pHo7.4, increase in EBmax (22.32 ± 1.63%) and decrease in pD2 (2.88 ± 0.07) at pHo6.8, and increase in EBmax (39.71 ± 3.76%) and decrease in pD2 (3.34 ± 0.08) at pHo6.0 [Figure 6].
|Figure 4: Effect of extracellular hydrogen ion concentration (7.4 or 6.8 or 6.0) on KCl-induced vasorelaxation in K+-free modified Krebs–Henseleit saline in the presence of ouabain (1 μM)|
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|Figure 5: Effect of extracellular hydrogen ion concentration (7.4 or 6.8 or 6.0) on KCl-induced vasorelaxation in K+-free modified Krebs–Henseleit saline in the presence of barium (30 μM)|
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|Figure 6: Effect of extracellular hydrogen ion concentration (7.4 or 6.8 or 6.0) on KCl-induced vasorelaxation in K+-free modified Krebs–Henseleit saline in the presence of ouabain (1 μM) and barium (30 μM)|
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| Discussion|| |
This study provides evidence to indicate that the Na+-K+ pump and Kir channels participate in the pHo dependent control of vascular contractility and membrane Na+-K+-ATPase may have a secondary role in K-induced relaxation in the goat mesenteric artery. The major observations are as follows: A decrease in pHo (7.4–6.0), (1) decreased maximal vasotonic response to K+-free medium, (2) progressively attenuated vasorelaxation to KCl, (3) reduced ability of ouabain to inhibit K+-induced vasorelaxation that could be due to reduced activity or expression of ouabain-sensitive Na+-K+ pump, and (4) attenuated inhibitory effect of Ba2+ that could be due to reduced function or densities Kir channels.
There was proportionate decrease in both mean peak tension (1: 0.71: 0.45) and mean plateau tension (1: 0.72: 0.47) with reduction of pHo (7.4, 6.8, and 6.0) on incubation of GSMA rings in K+-free medium. The reduction of both peak and plateau tensions were in identical proportion. Vasocontractility arising from the removal of K+ extracellular medium is due to the basal influx of Ca2+., Hence, the progressive reduction of vasotonic response to K+-free medium in acidosis could be attributed in part to decrease in Ca2+ influx.
KCl-induced relaxation in vascular smooth muscles may involve several independent mechanisms, such as activation of sarcolemmal Na+-K+-ATPase and/or activation of inwardly rectifying K+-channels. K+-induced dilation of the small renal artery attributed to the activation of smooth muscle Na+-K+-ATPase with no role for Kir channel. Similarly, K+ vasorelaxation in goat ruminal artery is predominantly mediated by ouabain-sensitive Na+-K+-ATPase has been reported from our previous study. One of the distinguishing features of vascular relaxation by K+ involving Na+-K+-ATPase is that the extracellular concentration of K+ is <5 mM, whereas Kir-channels primarily mediate K+-induced relaxation above the physiological K+-concentration (>5 mM). In addition, (K+)o elevation increases Kir-channel conductance and activates Na+-K+ pump, thus hyperpolarize membrane potential. This hyperpolarization inhibits voltage-gated Ca2+ channels and relaxes the vascular smooth muscle. In contrast, vascular smooth muscle contracts in response to (K+)o elevation to <25 mM and 12 or 15 mM K+ may be enough to evoke K+-induced relaxation. Na+-K+ pump and Kir channels maybe the main contributor in K+-induced relaxation as Kir2.1 gene has been expressed in arterial smooth muscle. In SMA rings of Capra hircus, K+ (1 μM-10 mM)-induced vasorelaxation was increased dose dependently and attained Emax (>95%) at pHo7.4. This findings clearly demonstrate that Na+-K+ pump and Kir-channels are main contributors in K+-induced relaxation in SMA rings of Capra hircus as observed in rat mesenteric arterial rings. In contrast, with a decrease in pHo from 7.4–6.0, K+-induced maximal vasorelaxation was attenuated by about 31% and 40% at pHo6.8 and 6.0, respectively. The decrease in pHo in isolated rat SMA from 7.8–6.4 significantly reduced apparent affinity (pD2) to norepinephrine (NE) and maximal contraction by NE, which were more prominent in larger-diameter arteries and also reduced Ba2+-sensitive K+-induced relaxation in the first branch and inhibited Kir currents in cultured smooth muscle cells of SMA. In the present finding, we observed that K+ (1 μM)-induced vasorelaxation in GSMA was reduced with reduction of pHo from 7.4 to 6.0, with a clear-cut rightward shift of K+-induced concentration-related vasorelaxation curve. Concisely, at pHo6.8 and 6.0, K+-induced vasorelaxation was significantly attenuated with increased affinity and reduced efficacy as compared to pHo7.4 that is identical to the observation obtained in rat mesenteric artery.
Considering that the Na+-K+-ATPase activity is ouabain-sensitive in several vascular beds and ouabain-inhibited K+-induced vasorelaxation, we incubated the GMSA rings with ouabain before eliciting K+-induced vasorelaxation at different pH. Our present results showed that ouabain inhibited the KCl-induced vasorelaxation with a decrease in EBmax by about 66%, 19%, and 0% and in pD2 by about 0.5, 1.0, and 0.5 log units at pHo7.4, 6.8, and 6.0, respectively. Thus, attenuation of K+-induced vasorelaxation by ouabain is maximum at pHo 7.4 and minimum at pHo6.8 and almost abolished at pHo6.0. This could be due to a graded reduction of ouabain-sensitive Na+ efflux and K+ influx arising from reduced function or activity of Na+-K+-ATPase in the acidic pHo. This proportional inhibition of Na+-K+-ATPase by H+ ion accumulation during acidosis is not fully understood as such observed in mouse ventricular cells and rat SMA. Endogenous ouabain increases vasotonic response indirectly by increasing the intracellular calcium through depolarization and reducing intracellular calcium buffering mechanism during cellular acidosis. In squid giant axon, influence of pHo and pHi on sodium pump fluxes over the pH range of 6.0–8.6 revealed that changes of pHi (but not pHo) resulted in a graded inhibition of ouabain-sensitive Na+ efflux and K+ influx in both acidic or alkaline direction which was maximum at pHi of 7.2–7.4 and any variations away from this optimal pHi resulted in a graded inhibition of ouabain-sensitive Na+ efflux and K+ influx in either the acidic or alkaline direction. Basing on above functional evidence on ouabain-induced vasotonic response physiological and altered pHo (acidic/alkaline), the reduced sensitivity to ouabain due to acidosis in GSMA could be attributed to interference with the intracellular calcium buffering mechanism arising from reduced activity of Na+-K+-ATPase. It could be possible that the reduction in the binding ability of ouabain to active sites of Na+-K+-ATPase is interfered by acidic pH that results in nonreversal of K+ vasorelaxation in GSMA under acidosis. Na+-K+-ATPase exists in the plasma membrane as a heterodimer consisting of a catalytic α-subunit and a glycosylated β-subunit. In vascular smooth muscle, the occurrence of α1, α2, and α3 subunits has been reported in rat mesenteric artery, rat aorta myocytes, rat thoracic, superior mesenteric, and tail arteries. Consistent with the expression of the sodium pump isoforms in rodents, studies on gene-targeted mice emphasize a significant role of the α2 isoform in regulating contractility of blood vessels in vitro and regulation of blood pressure in vivo. The α1 isoform has been found to be having a “housekeeping role” in mouse aorta, and α2 isoform has been shown to possess a high affinity to low (submicromolar) concentrations of ouabain in the pulmonary vasculature. Thus far, there is no information on the physiological roles of α1 and α2 isoforms in goat mesenteric artery; the present functional study suggests that α2 isoform may have a major role in regulating contractility of this vasculature and acidosis could be substantially reducing its affinity to ouabain. Conversely, the shift of balance between vasotonic and vasorelaxation in reduced pHo may be due to decreased expression of α2 isoform of Na+-K+-ATPase in this vasculature.
K+-induced vasodilatation following stimulation of Na+-K+-ATPase is also mediated by Kir channels or Ba2+ sensitive and inwardly rectifying potassium channels mostly localized in the small artery and arterioles., BaCl2 has been reported to antagonize both KATP and Kir-channels at 30 mol/L in rat cerebral arterioles, and Kir channels at 50 mol/L in rat arterial SMCs. In the present study, Ba2+ (30 mM) was employed to assess the role of Kir-channels in K+ vasorelaxation as influenced by reduced pHo. Kir channels play an important role in acidosis-mediated vasodilatation in rat coronary and cerebral arteries, rat cerebral arterioles, and rat mesenteric artery. A decrease in pHo inhibits Kir currents., Kir2.3 current inhibition by extracellular acidification started at pH 7.0 and plateaued at pH 6.0 with a pK of 6.7. Similarly, Ba2+-sensitive Kir-induced relaxation was markedly reduced in rat mesenteric artery at pHo values of 6.9 and 6.4. Our present work revealed that in the presence of Ba2+ (30 μM), K+-induced vasorelaxation was attenuated with decrease in EBmax by about 76%, 46%, and 28% at pHo7.4, 6.8, and 6.0, respectively. In contrast, pD2 was increased by about 0.7, 0.5 log units at pHo7.4, 6.8 and decreased by 2.2 log units at pHo6.0. On comparison, Ba2+-sensitive Kir-channel activity did not alter by decreasing pHo7.4–6.8, but it was significantly reduced at pHo6.0. Further, we observed that ouabain significantly reduced inhibitory effect of Ba2+ by about 14% at pHo7.4, 6.0 and by about 6% at pHo6.8. Hence, it could be inferred that Ba2+-sensitive Kir-channel activity is markedly reduced at pHo6.0 but not at pHo6.8 when compared with that of pHo7.4 which in agreement with functional study obtained in rat coronary and cerebral arteries, rat cerebral arterioles, and rat mesenteric artery.
Based on the evidence gathered on reduced function and expression of Kir channels in other vascular bed including rat mesenteric bed our observation is well in agreement with the fact that in GSMA, decreased K+ vasorelaxation arising due to reduction of pHo is due to in part reduced function and expression of Kir-channels. Further, we observed that ouabain significantly reduced inhibitory effect of Ba2+ by about 14% at pHo7.4, 6.0 and by about 6% at pHo6.8. Such a reduction in the sensitivity to Ba2+ in the presence of ouabain could be attributed to net combined inhibitory effect on K+ vasorelaxation arising from shifting of membrane K+ efflux mechanism to possibly opening of BKca channels as reported in the rat mesenteric artery. Attenuation of vasorelaxation in GSMA in acidic stress is due to a reduction in function/expression of Na+-K+ pump and Kir channels. This reduced vasorelaxation is predominantly mediated by reduction in ouabain-sensitive Na+-K+-ATPase activity. In clinical acidosis, it is well predicted that a decreased vascular resistance may be arising from the inability of the vascular bed to dilate that could be due to reduced function of Na+- K+ pump in vascular smooth muscle cells.
Activation of ouabain-sensitive Na+-K+-ATPase and Kir channels contributes to the K+-induced vasorelaxation in goat mesenteric artery at normal pHo. The reduction in K+-induced vasorelaxation with decrease in pHo (acidosis) occurs due to the attenuation of function or sensitivity of Na+-K+-ATPase and Kir channels could be implicated to one of the possible mechanisms of hypertensive crisis in acidosis.
| Conclusions|| |
Attenuated vasodilation in acidosis is due to reduced function or expression of ouabain-sensitive Na+-K+-ATPase and Kir channels. In clinical acidosis, agents augmenting the activity of Na+-K+-ATPase and K+-channel could improve hypertensive crisis.
The authors are grateful to the Orissa University of Agriculture and Technology, Bhubaneswar, for providing necessary logistic support and student fellowship grant during the research work of Ipsita Mohanty (one of the authors).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]