Mitochondrial monoamine oxidase A‐mediated hydrogen peroxide generation enhances 5‐hydroxytryptamine‐induced contraction of rat basilar artery

Background and purpose: We evaluated the role(s) of monoamine oxidase (MAO)‐mediated H₂O₂ generation on 5‐HT‐induced tension development of isolated basilar artery of spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats.

Experimental approach: Basilar artery (endothelium‐denuded) was isolated for tension measurement and Western blots. Enzymically dissociated single myocytes from basilar arteries were used for patch‐clamp electrophysiological and confocal microscopic studies.

Key results: Under resting tension, 5‐HT elicited a concentration‐dependent tension development with a greater sensitivity (with unchanged maximum tension development) in SHR compared to WKY (EC₅₀: 28.4 ± 4.1 nM versus 98.2 ± 9.4 nM). The exaggerated component of 5‐HT‐induced tension development in SHR was eradicated by PEG‐catalase, clorgyline and citalopram whereas exogenously applied H₂O₂ enhanced the 5‐HT‐elicited tension development in WKY. A greater protein expression of MAO‐A was detected in basilar arteries from SHR than in those from WKY. In single myocytes and the entire basilar artery, 5‐HT generated (clorgyline‐sensitive) a greater amount of H₂O₂ in SHR compared to WKY. Whole‐cell iberiotoxin‐sensitive Ca²⁺‐activated K⁺ (BK_Ca) amplitude measured in myocytes of SHR was ∼3‐fold greater than that in WKY (at +60 mV: 7.61 ± 0.89 pA/pF versus 2.61 ± 0.66 pA/pF). In WKY myocytes, 5‐HT caused a greater inhibition (clorgyline‐, PEG‐catalase‐ and GSH‐sensitive) of BK_Ca amplitude than in those from SHR.

Conclusions and implications: 5‐HT caused an increased generation of mitochondrial H₂O₂ via MAO‐A‐mediated 5‐HT metabolism, which caused a greater inhibition of BK_Ca gating in basilar artery myocytes, leading to exaggerated basilar artery tension development in SHR.