Hydrogen peroxide activates store‐operated Ca²⁺ entry in coronary arteries

Background and Purpose

Abnormal Ca²⁺ metabolism has been involved in the pathogenesis of vascular dysfunction associated with oxidative stress. Here, we have investigated the actions of H₂O₂ on store‐operated Ca²⁺ (SOC) entry in coronary arteries and assessed whether it is impaired in arteries from a rat model of metabolic syndrome.

Experimental Approach

Simultaneous measurements of intracellular Ca²⁺ concentration and contractile responses were made in coronary arteries from Wistar and obese Zucker rats, mounted in microvascular myographs, and the effects of H₂O₂ were assessed.

Key Results

H₂O₂ raised intracellular Ca²⁺ concentrations, accompanied by simultaneous vasoconstriction that was markedly reduced in a Ca²⁺‐free medium. Upon Ca²⁺ re‐addition, a nifedipine‐resistant sustained Ca²⁺ entry, not coupled to contraction, was obtained in endothelium‐denuded coronary arteries. The effect of H₂O₂ on this voltage‐independent Ca²⁺ influx was concentration‐dependent, and high micromolar H₂O₂ concentrations were inhibitory and reduced SOC entry evoked by inhibition of the sarcoplasmic reticulum ATPase (SERCA). H₂O₂‐induced increases in Fura signals were mimicked by Ba²⁺ and reduced by heparin, Gd³⁺ ions and by Pyr6, a selective inhibitor of the Orai1‐mediated Ca²⁺ entry,. In coronary arteries from obese Zucker rats, intracellular Ca²⁺ mobilization and SOC entry activated by acute exposure to H₂O₂ were augmented and associated with local oxidative stress.

Conclusion and Implications

H₂O₂ exerted dual concentration‐dependent stimulatory/inhibitory effects on store‐operated, IP₃ receptor‐mediated and Orai1‐mediated Ca²⁺ entry, not coupled to vasoconstriction in coronary vascular smooth muscle. SOC entry activated by H₂O₂ was enhanced and associated with vascular oxidative stress in coronary arteries in metabolic syndrome.

DOI: 10.1111/bph.13322

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