Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium‐derived hyperpolarization‐type dilations in thromboxane/prostaglandin receptor‐stimulated rat cerebral arteries

Abstract

Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SK input to EDH. These results reveal a novel mechanism whereby peroxynitrite could promote post-ischaemic brain injury.

Endothelium-Dependent Hyperpolarization (EDH) in Diabetes: Mechanistic Insights and Therapeutic Implications

“…The reason for the above-described contradictory results is not known but might be related to the differences in the agonist used, the vascular bed studied, the nature of ROS generated, or the amount and duration of ROS exposure among the studies. In fact, the effects of ROS on EDH were inconsistent and complex: Decreased [134], unaltered [135,136], and increased [137,138] EDH-mediated responses mediated by ROS have been reported in blood vessels from rats and mice. Although poorly understood, ROS, in particular H 2 O 2 , might augment EDH-mediated responses by potentiating intracellular endothelial Ca 2+ mobilization [138,139] or by exerting excitatory influences on K Ca channels [140] in some vascular beds in diabetes.…”

Uric acid therapy for vasculoprotection in acute ischemic stroke

“…Brain I/R impairs both basal and receptor-mediated endothelium-dependent vasodilation of large arteries, and parenchymal arterioles alike, despite it results in an increase in both endothelial nitric oxide (NO) synthase expression and endothelium-derived hyperpolarization-type dilations. [2526] I/R also result in loss of proportional and spatially controlled changes in CBF elicited by neural activity (neurovascular coupling), and a loss of myogenic tone and autoregulation, making the CBF to follow passively the changes in arterial pressure. [27] ROS and RNS as well as vasoactive factors such as NO, endothelin-1, vascular endothelial growth factor (VEGF), and angiopoietin I, play important roles in regulation of vascular tone and structure in the acute phase of the brain ischemia.…”

“…[43] Recent evidence suggests that ONOO – formed during I/R can disrupt endothelial filamentous-actin augmenting endothelium-derived hyperpolarization-type dilations of cerebral arteries, a mechanism whereby ONOO – could contribute to promote postischemic brain injury. [26] Ischemia also induces sustained contraction of pericytes on microvessels despite successful recanalization in mice, and suppression of ONOO – relieves pericyte contraction, reduces erythrocyte entrapment, restores microvascular patency, and improves the tissue survival. [44] Interestingly, by comparing the ROS-suppressing effect of N-tert-butyl-α-phenylnitrone (PBN) with its BBB impermeable analog 2-sulfophenyl- N-tert-butylnitrone (S-PBN) in mice, Taskiran-Sag et al .…”

Oxygen—to little, too much or just right

“…For hypoxia‐mediated angiogenesis, Helfinger et al describe a role of the NADPH oxidase Nox 4 in tumour angiogenesis, while Vanhoutte et al review the state of the art in endothelial dysfunction, with immediate clinical implications. Other authors have looked into hypoxia effects in distinct vascular beds of specific characteristics, such as cutaneous and cerebral perfusion. In the heart, Netzer et al had a look at right ventricular dimensions in response to normobaric hypoxia, describing a significant linear increase in all RV dimensions, with concomitant increases in right ventricular systolic pressure.…”