A key role for Na+/K+-ATPase in the endothelium-dependent oscillatory activity of mouse small mesenteric arteries

Giachini, Fernanda R.; Carneiro, Fernando S.; Lima, Victor Vitorino; Carneiro, Zidonia N.; Brands, Micahel; Webb, R. Clinton; Tostes, Rita C.

doi:10.1590/s0100-879x2009005000033

Cited by 5 publications

(5 citation statements)

References 35 publications

(44 reference statements)

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“…Many cell types have in addition an ouabain-sensitive isoform (either ␣ 2 or ␣ 3 ), which accomplishes more specific regulatory functions. We (30,31) as well as others (13,15,41,47) have previously identified the expression of ␣ 1 and ␣ 2 isoforms (␣ 2 ) of the Na,K-pump in mesenteric small arteries. It has been documented that inhibition of the ouabain-sensitive Na,K-pump has significant effects on vascular function without changing smooth muscle cell (SMC) Na ϩ concentration (2,4,31).…”

Section: Namentioning

confidence: 93%

“…Previous studies strongly suggested the importance of a ouabain-sensitive Na,K-pump in endothelium-dependent relaxation (EDR) (12,14,15). Submicromolar and micromolar ouabain was shown to significantly attenuate the EDR when NO-and prostacyclin-dependent pathways were inhibited, suggesting an important role of a ouabain-sensitive Na,K-pump in the EDHF response (10).…”

Section: Downregulation Of ␣ 2 Isoform Inhibits Intercellular Communimentioning

confidence: 99%

“…Submicromolar and micromolar ouabain was shown to significantly attenuate the EDR when NO-and prostacyclin-dependent pathways were inhibited, suggesting an important role of a ouabain-sensitive Na,K-pump in the EDHF response (10). Although the specific isoforms involved in this ouabain-sensitive Na,K-pump are not clear due to similar pharmacological properties of the different isoforms, several expression studies have indicated the importance of the ␣ 2 for EDHF (12,15,47,52). Expression of ␣ 2 protein in SMCs and endothelial cells is controversial, but a recent study indicated localization of this isoform to myoendothelial contacts in the vascular wall (12).…”

Section: Downregulation Of ␣ 2 Isoform Inhibits Intercellular Communimentioning

confidence: 99%

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The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Matchkov

Moeller-Nielsen

Dam

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Matchkov VV, Moeller-Nielsen N, Dam VS, Nourian Z, Boedtkjer DM, Aalkjaer C. The ␣2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries. Am J Physiol Heart Circ Physiol 303: H36 -H46, 2012. First published May 4, 2012 doi:10.1152/ajpheart.00673.2011The specific role of different isoforms of the Na,K-pump in the vascular wall is still under debate. We have previously suggested that the ␣2 isoform of the Na,K-pump (␣2), Na ϩ , Ca 2ϩ -exchange (NCX), and connexin43 form a regulatory microdomain in smooth muscle cells (SMCs), which controls intercellular communication and contractile properties of the vascular wall. We have tested this hypothesis by downregulating ␣2 in cultured SMCs and in small arteries with siRNA in vivo. Intercellular communication was assessed by using membrane capacitance measurements. Arteries transfected in vivo were tested for isometric and isobaric force development in vitro; [Ca 2ϩ ]i was measured simultaneously. Cultured rat SMCs were well-coupled electrically, but 10 M ouabain uncoupled them. Downregulation of ␣ 2 reduced electrical coupling between SMCs and made them insensitive to ouabain. Downregulation of ␣2 in small arteries was accompanied with significant reduction in NCX expression. Acetylcholine-induced relaxation was not different between the groups, but the endotheliumdependent hyperpolarizing factor-like component of the response was significantly diminished in ␣2-downregulated arteries. Micromolar ouabain reduced in a concentration-dependent manner the amplitude of norepinephrine (NE)-induced vasomotion. Sixty percent of the ␣ 2-downregulated arteries did not have vasomotion, and vasomotion in the remaining 40% was ouabain insensitive. Although ouabain increased the sensitivity to NE in the control arteries, it had no effect on ␣ 2-downregulated arteries. In the presence of a low NE concentration the ␣ 2-downregulated arteries had higher [Ca 2ϩ ]i and tone. However, the NE EC50 was reduced under isometric conditions, and maximal contraction was reduced under isometric and isobaric conditions. The latter was caused by a reduced Ca 2ϩ -sensitivity. The ␣2-downregulated arteries also had reduced contraction to vasopressin, whereas the contractile response to high K ϩ was not affected. Our results demonstrate the importance of ␣ 2 for intercellular coupling in the vascular wall and its involvement in the regulation of vascular tone. Na ϩ , Ca 2ϩ exchanger; smooth muscle cell synchronization; short interfering RNA; norepinephrine contractility; endothelium-dependent hyperpolarizing factor THE ELECTROGENIC NA,K-PUMP modifies numerous cellular pathways by modulating Na ϩ -coupled transport. The functional significance of the Na,K-pump is dependent upon the isoform. The catalytic ␣-subunit exists in three isoforms (5). These isoforms have different affinities for cardiac glycosides, kinetics, and regulation but show high structural homology and are difficult to distinguish at a fu...

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Section: Namentioning

confidence: 93%

Section: Downregulation Of ␣ 2 Isoform Inhibits Intercellular Communimentioning

confidence: 99%

Section: Downregulation Of ␣ 2 Isoform Inhibits Intercellular Communimentioning

confidence: 99%

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The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

Matchkov

Moeller-Nielsen

Dam

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…This study did not identify any significant changes in the expression of Na,K-ATPase proteins in mesenteric small arteries from hypertensive rats in comparison with normotensive controls [ 238 ]. The α 1 and α 2 isoforms of the Na,K-ATPase are expressed in the arterial wall [ 40 , 235 , 239–242 ]. However, low plasma concentrations of ouabain are enough to induce hypertension in rodents [ 216 , 217 ], suggesting a primary role of the vascular α 2 isoform.…”

Section: The Role Of the Nak-atpase In Hypertensionmentioning

confidence: 99%

The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension

Staehr,

Aalkjaer,

Matchkov

2023

Clinical Science

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In the vascular wall, the Na,K-ATPase plays an important role in the control of arterial tone. Through cSrc signaling, it contributes to the modulation of Ca2+ sensitivity in vascular smooth muscle cells. This review focuses on the potential implication of Na,K-ATPase-dependent intracellular signaling pathways in severe vascular disorders; ischemic stroke, familial migraine, and arterial hypertension. We propose similarity in the detrimental Na,K-ATPase-dependent signaling seen in these pathological conditions. The review includes a retrospective proteomics analysis investigating temporal changes after ischemic stroke. The analysis revealed that the expression of Na,K-ATPase α isoforms is down-regulated in the days and weeks following reperfusion, while downstream Na,K-ATPase-dependent cSrc kinase is up-regulated. These results are important since previous studies have linked the Na,K-ATPase-dependent cSrc signaling to futile recanalization and vasospasm after stroke. The review also explores a link between the Na,K-ATPase and migraine with aura, as reduced expression or pharmacological inhibition of the Na,K-ATPase leads to cSrc kinase signaling up-regulation and cerebral hypoperfusion. The review discusses the role of an endogenous cardiotonic steroid-like compound, ouabain, which binds to the Na,K-ATPase and initiates the intracellular cSrc signaling, in the pathophysiology of arterial hypertension. Currently, our understanding of the precise control mechanisms governing the Na,K-ATPase/cSrc kinase regulation in the vascular wall is limited. Understanding the role of vascular Na,K-ATPase signaling is essential for developing targeted treatments for cerebrovascular disorders and hypertension, as the Na,K-ATPase is implicated in the pathogenesis of these conditions and may contribute to their comorbidity.

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“…Na + -K + -ATPase is an integral membrane enzyme, ubiquitously distributed in the plasma membrane of all eukaryotic cells. [ 1 ] It 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. [ 2 ] Endothelium has also been shown to regulate the Na + -K + -ATPase activity either by release of nitric oxide (NO) or endothelial diffusible factors like leukotrienes and prostaglandins.…”

Section: Introductionmentioning

confidence: 99%

Vasorelaxation of goat mesenteric artery is mediated by endothelial Na+-K+-ATPase

Sathiskumar¹,

Mohanty²,

Parija

2015

Journal of Pharmacology and Pharmacotherapeutics

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Objective:To examine the role of Na+-K+-ATPase and K+ channels in mediating vasorelaxation in the superior mesenteric artery of Capra hircus.Materials and Methods:Goat superior mesenteric artery (GSMA) was cut into 1.5–2 mm circular rings and mounted in a thermostatically controlled (37°C ± 0.5°C) organ bath containing 20 ml of modified Krebs-Henseleit saline (MKHS) (pH 7.4), with continuous aeration under 1.5 g tension for 90 min. Endothelium-intact (ED+) or endothelium-denuded (ED−) GSMA ring was contracted with phenylephrine (PE) or 5-hydroxytryptamine (5-HT) (1 μM–0.1 mM) in the absence or presence of ouabain (0.1 μM). KCl (1 μM–10 mM) was added cumulatively to K+-free MKHS-pre-contracted (ED+/−) rings in the absence or presence of ouabain (0.1 μM) or barium (1 μM) or 4-aminopyridine (1 μM).Results:Ouabain did not alter the basal tone of the arterial ring. The contractile response induced by PE (Emax: 50.46 ± 2.68, pD2: 5.53 ± 0.04) and 5-HT (Emax: 30.86 ± 1.33, pD2: 6.17 ± 0.03) in ED+ ring was significantly (P < 0.001) augmented in ED− rings (PE: Emax: 93.30 ± 2.11, pD2: 6.41 ± 0.04; 5-HT: Emax: 95.07 ± 0.99, pD2: 6.27 ± 0.03). The contractile response induced by PE and 5-HT in ED+ or ED− rings in the presence of ouabain was almost identical with that of ED− rings. Vasorelaxation of KCl (Emax: 2.90 ± 1.14, pD2: 3.9 ± 0.03) was significantly attenuated in the presence of ouabain (Emax: 73.8 ± 5.16, pD2: 4.3 ± 0.04), Ba2+ (Emax: 16.34 ± 4.7, pD2: 3.22 ± 0.02), 4-AP (Emax: 18.16 ± 2.4, pD2: 3.68 ± 0.03), ouabain and Ba2+ (Emax: 70.09 ± 3.66, pD2: 4.41 ± 0.04), and ouabain and 4-AP (Emax: 66.98 ± 4.61, pD2: 4.13 ± 0.06).Conclusion:The vasorelaxation in GSMA is mediated by the endothelium-derived hyperpolarizing factor (EDHFs) such as ouabain-sensitive Na+-K+-ATPase, KIR and Kv channels.

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A key role for Na+/K+-ATPase in the endothelium-dependent oscillatory activity of mouse small mesenteric arteries

Cited by 5 publications

References 35 publications

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension

Vasorelaxation of goat mesenteric artery is mediated by endothelial Na+-K+-ATPase

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A key role for Na+/K+-ATPase in the endothelium-dependent oscillatory activity of mouse small mesenteric arteries

Cited by 5 publications

References 35 publications

The α2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The α2 isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension

Vasorelaxation of goat mesenteric artery is mediated by endothelial Na+-K+-ATPase

Contact Info

Product

Resources

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The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries

The α₂ isoform of the Na,K-pump is important for intercellular communication, agonist-induced contraction, and EDHF-like response in rat mesenteric arteries