Dataset Information

The Unexpected Role of Calcium-Activated Potassium Channels: Limitation of NO-Induced Arterial Relaxation.

ABSTRACT:

Background

Multiple studies have shown that an NO-induced activation of vascular smooth muscle BK channels contributes to the NO-evoked dilation in many blood vessels. In vivo, NO is released continuously. NO attenuates vessel constrictions and, therefore, exerts an anticontractile effect. It is unknown whether the anticontractile effect of continuously present NO is mediated by BK channels.

Methods and results

This study tested the hypothesis that BK channels mediate the vasodilatory effect of continuously present NO. Experiments were performed on rat and mouse tail and rat saphenous arteries using isometric myography and FURA-2 fluorimetry. Continuously present NO donors, as well as endogenous NO, attenuated methoxamine-induced vasoconstrictions. This effect was augmented in the presence of the BK channel blocker iberiotoxin. Moreover, the contractile effect of iberiotoxin was reduced in the presence of NO donors. The effect of the NO donor sodium nitroprusside was abolished by an NO scavenger and by a guanylyl cyclase inhibitor. In addition, the effect of sodium nitroprusside was reduced considerably by a protein kinase G inhibitor, but was not altered by inhibition of H₂S generation. Sodium nitroprusside attenuated the intracellular calcium concentration response to methoxamine. Furthermore, sodium nitroprusside strongly reduced methoxamine-induced calcium influx, which depends entirely on L-type calcium channels. It did not affect methoxamine-induced calcium release.

Conclusions

In summary, this study demonstrates the following: (1) continuously present NO evokes a strong anticontractile effect on rat and mouse arteries; (2) the iberiotoxin-induced augmentation of the effect of NO is associated with an NO-induced reduction of the effect of iberiotoxin; and (3) NO evoked a reduction of calcium influx via L-type calcium channels.

SUBMITTER: Schmid J

PROVIDER: S-EPMC5907584 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

The Unexpected Role of Calcium-Activated Potassium Channels: Limitation of NO-Induced Arterial Relaxation.

Schmid Johannes J Müller Bettina B Heppeler David D Gaynullina Dina D Kassmann Mario M Gagov Hristo H Mladenov Mitko M Gollasch Maik M Schubert Rudolf R

Journal of the American Heart Association 20180324 7

<h4>Background</h4>Multiple studies have shown that an NO-induced activation of vascular smooth muscle BK channels contributes to the NO-evoked dilation in many blood vessels. In vivo, NO is released continuously. NO attenuates vessel constrictions and, therefore, exerts an anticontractile effect. It is unknown whether the anticontractile effect of continuously present NO is mediated by BK channels.<h4>Methods and results</h4>This study tested the hypothesis that BK channels mediate the vasodila ...[more]

PMID: 29574460

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Project description:Background and purposeControlling vascular tone involves K(+) efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (K(Ca)2.3 and K(Ca)3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to neurovascular coupling.Experimental approachTransgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess K(Ca)2.3 and K(Ca)3.1 expression by immunohistochemistry and RT-PCR. K(Ca) currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of K(Ca)3.1 to neurovascular coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry.Key resultsK(Ca)3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic K(Ca)2.3 and K(Ca)3.1 mRNA expression. With 200 nM [Ca(2+)](i) , the K(Ca)2.1-2.3/K(Ca)3.1 opener NS309 increased whole-cell currents. CyPPA, a K(Ca)2.2/K(Ca)2.3 opener, was without effect. With 1 µM [Ca(2+)](i) , the K(Ca)3.1 inhibitor TRAM-34 reduced currents whereas apamin (K(Ca)2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing K(Ca)3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into neurovascular coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of K(Ca)3.1 and the large-conductance K(Ca) channel, K(Ca)1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%.Conclusion and implicationsAstrocytes express functional K(Ca)3.1 channels, and these contribute to neurovascular coupling.

Dataset Information

The Unexpected Role of Calcium-Activated Potassium Channels: Limitation of NO-Induced Arterial Relaxation.

Background

Methods and results

Conclusions

Publications

The Unexpected Role of Calcium-Activated Potassium Channels: Limitation of NO-Induced Arterial Relaxation.

Similar Datasets

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