Abstract
This study examines the downstream NO release pathway and the contribution of different vasodilator mediators in the acetylcholine-induced response in rat aorta 5-months after the loss of ovarian function. Aortic segments from ovariectomized and control female Sprague-Dawley rats were used to measure: the levels of superoxide anion, the superoxide dismutases (SODs) activity, the cGMP formation, the cGMP-dependent protein kinase (PKG) activity and the involvement of NO, cGMP, hydrogen peroxide and hyperpolarizing mechanisms in the ACh-induced relaxation. The results showed that ovariectomy did not alter ACh-induced relaxation; incubation with L-NAME, a NO synthase inhibitor, decreased the ACh-induced response to a lesser extent in aorta from ovariectomized than from control rats, while ODQ, a guanylate cyclase inhibitor, decreased that response to a similar extent; the blockade of hyperpolarizing mechanisms, by precontracting arteries with KCl, decreased the ACh-induced response to a greater extent in aortas from ovariectomized than those from control rats; catalase, that decomposes hydrogen peroxide, decreased the ACh-induced response only in aorta from ovariectomized rats. In addition, ovariectomy increased superoxide anion levels and SODs activity, decreased cGMP formation and increased PKG activity. Despite the increased superoxide anion and decreased cGMP in aorta from ovariectomized rats, ACh-induced relaxation is maintained by the existence of hyperpolarizing mechanisms in which hydrogen peroxide participates. The greater contribution of hydrogen peroxide in ACh-induced relaxation is due to increased SOD activity, in an attempt to compensate for increased superoxide anion formation. Increased PKG activity could represent a redundant mechanism to ensure vasodilator function in the aorta of ovariectomized rats.
Highlights
Vascular endothelium plays a critical role regulating vascular tone by releasing relaxing and contracting factors [1]; among these factors, nitric oxide (NO) is of singular relevance [2]
Concerning NO, it is important to take into account that vascular functionality of endothelial NO depends on its bioavailability, which is determined by the rate of NO production and by the rate it is scavenged by superoxide anions
We have previously demonstrated that the loss of ovarian function increases the production of prostanoids derived from cyclooxygenase-2 (COX-2), while it does not modify the release of nitric oxide (NO) [19]
Summary
Vascular endothelium plays a critical role regulating vascular tone by releasing relaxing and contracting factors [1]; among these factors, nitric oxide (NO) is of singular relevance [2]. Concerning NO, it is important to take into account that vascular functionality of endothelial NO depends on its bioavailability, which is determined by the rate of NO production and by the rate it is scavenged by superoxide anions. It is well understood that alterations in any step of the NO pathway determines its effect on the vascular tone. In addition to the activation of the cGMP-PKG pathway, NO may stimulate vascular hyperpolarization [7]. Hyperpolarizing factors/mechanisms are important regulators of the membrane potential and of vessel tone [2]. Hyperpolarization induced by NO [7], cGMP [11], superoxide anion [12] and other reactive oxygen species [13] has been reported
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