Faculty Collaboration Database

Prolonged L-NAME exposure changes the vasodilator factor from NO to H₂O₂ in human arterioles in response to A23187. Vascul Pharmacol 2024 Dec;157:107440

Date

11/14/2024

Pubmed ID

39537001

Pubmed Central ID

PMC11624973

DOI

10.1016/j.vph.2024.107440

Scopus ID

2-s2.0-85208761085 (requires institutional sign-in at Scopus site)

Abstract

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.

Author List

Zinkevich NS, Drachuk K, Zhang DX

Authors

Kostiantyn Drachuk Postdoctoral Researcher 2 in the Medicine department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Arterioles
Calcimycin
Catalase
Coronary Artery Disease
Enzyme Inhibitors
Female
Humans
Hydrogen Peroxide
Male
Middle Aged
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Vasodilation
Vasodilator Agents