Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Alpha-1 adrenoceptor and small calcium-activated potassium channel contribute to endothelial dysfunctions caused by catecholamine excess
Z. Yang1, Y. Li1, X. Fan1, Z. Meng1, L. Qiao1, M. Huang1, I. El-Battrawy1, X. Zhou1, I. Akin1
1I. Medizinische Klinik, Universitätsklinikum Mannheim, Mannheim;

Backgrounds: Catecholamine excess can cause endothelial dysfunctions, resulting in abnormal vascular tone. However, the mechanisms of catecholamine excess induced endothelial dysfunction are not clarified. The study was aimed to explore adrenoceptor signaling involved in catecholamine excess induced endothelial dysfunctions.

Methods: Human cardiac microvascular endothelial cells (HCMECs) were treated with 300 µM epinephrine to mimic catecholamine excess.  ELISA and patch clamp analyses were performed.

Results: In HCMECs, the small and intermediate conductance Ca2+-activated K+ channel current (ISK1-3 and ISK4), the ATP-sensitive K+ current (IKATP), and the inward rectifier K+ current (IK1), but not the big conductance Ca2+-activated K+ current and T-type Ca2+ channel current, were detected. ISK1-3, ISK4 and IKATP but not IK1 could be activated by high concentration of epinephrine (Epi). Epi suppressed NO production, although it failed influence ET-1 production. Strikingly, the channel blockers apamin (ISK1-3 blocker) and TRAM-34 (ISK4 blocker) but not glibenclamide (IKATP blocker) attenuated Epi induced reduction of NO production, indicating that ISK1-3 and ISK4 but IKATP contributed to NO-generation. Further studies revealed that both a1-recepotor signaling mediated the enhancement of ISK1-3 and ISK4. ROS (reactive oxygen species) signaling participated also in the activation of SK1-3 and SK4 channels because a ROS blocker (NAC) abolished and H2O2 mimicked the effect of a1-agonist on the currents. Application of a blocker and an activator of PKC demonstrated that PKC is involved in the activation of SK channels by a1-receptor signaling. In addition, it was figured out that PKC is a downstream factor of ROS since the PKC blocker prevented ROS effect on SK currents. Finally, activation of SK channels hyperpolarized membrane potential of HCMECs, but a depolarization induced by KCl failed to enhance, instead reduced NO production, which excluded the possibility that SK channel activation reduced NO production by hyperpolarizing cells.

Conclusion: High concentration of catecholamine can cause endothelial dysfunction via activating a1-receptor/ROS/PKC/SK signaling, causing an imbalance of ET-1/NO in endothelial cells.

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