Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Abstract

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

Impaired Acetylcholine-Induced Endothelium-Dependent Aortic Relaxation by Caveolin-1 in Angiotensin II-Infused Apolipoprotein-E (ApoE−/−) Knockout Mice

“…In agreement with this hypothesis, we noticed a significant reduction in plasma nitrite and nitrate levels in AngII-infused mice. A reduced phenylephrine-induced aortic contraction was reported in hypercholesteremic rabbits in association with an alteration of the cyclooxygenase (COX) signalling pathway [26]. In this study, plasma cholesterol level was not different between the AngII- and vehicle- infused mice, minimizing the possibility that the observed responses were mediated by hypercholesteremia-altered COX signalling.…”

Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation

“…In addition, the release of endogenous TXA 2 acting on TP receptors altered the vasoconstriction induced by other mediators , suggesting a role of local TXA 2 release in the modulation of vascular tone. Although TXA 2 is not the major prostanoid released from experimentally injured abdominal aortas from cholesterol‐fed rabbits, norepinephrine caused decreased responses in these vessels, which were reversed with COX inhibitors . Although this study did not specifically address the role of TP receptor, a previous study showed that rabbits lacking TP receptor exhibited decreased phenylephrine‐induced vasoconstriction compared with wild‐type rabbits, only when fed a high cholesterol diet .…”

Selective and non-selective non-steroidal anti-inflammatory drugs differentially regulate pulmonary vein and atrial arrhythmogenesis

“…International Journal of Cardiology 184 (2015) [559][560][561][562][563][564][565][566][567] In addition, selective deletion of COX-2 in mice was reported to induce interstitial and perivascular fibrosis with an enhanced susceptibility to induced arrhythmias [16]. On the other hand, celecoxib has several ionic channel effects and interferes with the cardiovascular electrophysiology [12,17].…”