Prolonged L-NAME exposure changes the vasodilator factor from NO to H2O2 in human arterioles in response to A23187

• Published in: Vascular pharmacology Vol. 157; p. 107440
• Main Authors: Zinkevich, Natalya S., Drachuk, Kostiantyn, Zhang, David X.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.12.2024
• Subjects: A23187; Endothelium-dependent vasodilation; Microcirculation; Nitric oxide; Reactive oxygen species; NO; Reactive oxygen species; L-NAME; eNOS; O2; PGI2; ACh; CAD; HAAs; H2O2; A23187; Microcirculation; ET-1; ETC; Nitric oxide; ROS; ONOO; Endothelium-dependent vasodilation; VSMC; EDHF
• ISSN: 1537-1891; 1879-3649; 1879-3649
• DOI: 10.1016/j.vph.2024.107440

The Ca2+ ionophore A23187 induces endothelium-dependent and non-receptor-mediated vasodilation in human adipose arterioles (HAAs). The purpose of this study was to determine the mechanism of A23187-induced dilation in HAAs from patients with and without coronary artery disease (CAD). HAAs were freshly isolated from adipose tissues obtained from non-CAD (n = 25) and CAD (n = 14) patients, and vascular reactivity was studied by videomicroscopy. No difference in baseline dose response to A23187 was observed between non-CAD and CAD subjects. However, acute (30 min) incubation with N(omega)-nitro-l-arginine methyl ester (L-NAME), NO synthase inhibitor strongly reduced A23187-induced dilation in non-CAD arterioles, while catalase, an H2O2 scavenger, largely abolished dilation in CAD. Surprising, prolonged (90 min) incubation with L-NAME restored A23187 response in non-CAD subjects, which was subsequently inhibited by catalase. The action of prolonged L-NAME exposure was not reversible after washing with Krebs while the effect of acute L-NAME exposure was largely reversible. To further determine the role of mitochondria-derived ROS in A23187-induced dilation, arterioles were treated with rotenone, an inhibitor of complex I of the electron transport chain. Rotenone abolished A23187 response in CAD patients and in non-CAD arterioles after prolonged L-NAME, but not in non-CAD controls. These data indicate that NO contributes to A23187-induced dilation in HAAs from non-CAD patients and H2O2 contributes to the dilation in CAD patients. Prolonged L-NAME exposure induces a NO-H2O2 switch in the mechanism of dilation in non-CAD subjects. Moreover, the effect of prolonged L-NAME exposure is not readily reversible, while the action of acute L-NAME exposure is reversible. [Display omitted] •A23187-induced dilation of human arterioles is similar in non-CAD and CAD patients.•NO mediates A23187 response in non-CAD, while H2O2 – in CAD.•Prolonged exposure (90 min incubation) of L-NAME induces NO-H2O2 switch in non-CAD.•The effect of prolonged L-NAME exposure is not reversible.•Mitochondria are likely involved in H2O2-mediated pathway of A23187-induced dilation.