Key result
Activation of SKCa channels with CyPPA enhanced l-arginine uptake and induced relaxations in porcine retinal arterioles, an effect potentiated by extracellular l-arginine.
Why the study?
To investigate whether extracellular l-arginine contributes to relaxations induced by activating small-conductance Ca2+-activated potassium channels.
Answers are grounded in this paper and cite their sources.
SKCa channel activity regulates l-arginine uptake through the y+ transporter system, enhancing vasodilation in porcine retinal arterioles.
We investigated whether the substrate for nitric oxide (NO) production, extracellular l-arginine, contributes to relaxations induced by activating small (SKCa) conductance Ca2+-activated potassium channels. In endothelial cells, acetylcholine increased 3H-l-arginine uptake, while blocking the SKCa and the intermediate (IKCa) conductance Ca2+-activated potassium channels reduced l-arginine uptake. A blocker of the y+ transporter system, l-lysine also blocked 3H-l-arginine uptake. Immunostaining showed co-localization of endothelial NO synthase (eNOS), SKCa3, and the cationic amino acid transporter (CAT-1) protein of the y+ transporter system in the endothelium. An opener of SKCa channels, cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) induced large currents in endothelial cells, and concentration-dependently relaxed porcine retinal arterioles. In the presence of l-arginine, concentration-response curves for CyPPA were leftward shifted, an effect unaltered in the presence of low sodium, but blocked by l-lysine in the retinal arterioles. Our findings suggest that SKCa channel activity regulates l-arginine uptake through the y+ transporter system, and we propose that in vasculature affected by endothelial dysfunction, l-arginine administration requires the targeting of additional mechanisms such as SKCa channels to restore endothelium-dependent vasodilatation.
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Simonsen et al. (2019) studied this question. Extracellular l-arginine and CyPPA was evaluated on Relaxation of porcine retinal arterioles and l-arginine uptake. Activation of SKCa channels with CyPPA enhanced l-arginine uptake and induced relaxations in porcine retinal arterioles, an effect potentiated by extracellular l-arginine.
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