Nitric Oxide Inhibition of Endothelin-1 Release in the Vasculature

Abstract

A key function of endothelial derived nitric oxide (NO) is to limit the constrictor capacity of endothelin (ET)-1.1,2 Thus, an imbalance between NO and ET-1 can result in ET-1-dependent increased vascular tone.1 Indeed, the importance of sustained, NO inhibition of the ET-1 drive to increase tone is exemplified in vivo by the rapid, ET-1-mediated arterial pressure elevation after acute NO synthase (NOS) inhibition. Moreover, the ET-1 pressor effect after NOS inhibition is independent of other pressor systems and, thus, reflects the relative importance of NO suppression of this ET-1 drive.2 Two, nonmutually exclusive mechanisms thought to underlie the ET-1 dependency of the increased vascular tone responsible for the NOS inhibitor-induced pressure elevation are (1) NO inhibition of constriction to endogenously released ET-1.1,2 This mechanism is essentially supported by demonstrations that NOS inhibitor enhanced the constrictor effects of exogenous ET-1 in several in vivo and ex vivo preparations. 3-14Thus, an assumption underlying these observations is that the constrictor actions of exogenous and endogenous ET-1 are similarly affected by NO; (2) NO inhibition of ET-1 release. 1,2Although the detailed mechanism underlying the NO inhibition of acute ET-1 release has not been clearly established, possibilities include decreased conversion of the immediate precursor to ET-1, big ET-1, to ET-1 15 and inhibition of pathways involved in the exocytosis of Weibel-Palade bodies, 16 endothelial granules that store ET-1. 17 However, it should be noted that in vivo findings that actually demonstrate the fundamental phenomenon of NO inhibition of ET-1 release are generally lacking.2 Thus, studies purported to demonstrate NO inhibition of ET-1 release have relied largely on isolated vessels and cultured endothelium, as described herein.This review assessed these in vitro findings, with a specific focus toward elucidating the mechanism underlying the NO-mediated negative regulation of ET-1-dependent increased arterial pressure, as demonstrated after acute NOS inhibitor in vivo.2 Findings referred to are mainly those of ET-1 release rather than contractility (eg, those in which ET receptor antagonist prevented the NOS inhibitor-induced decreased flow/increased pressure/tension). 12,18-25 The rationale for this emphasis is that findings based on contractility could reflect NOS inhibitor enhancement of ET-1 constriction rather than increased ET-1 release. Furthermore, we also focus on whether laminar shear stress influences the manifestation of NO inhibition of ET-1 release. That is, the endothelium of arteries that are anatomically linear is subjected to high levels of shear stress while, for example, at bifurcated arterial locations is subjected to low levels of shear stress, regions associated with atherosclerosis. 26 Acute NOS Inhibition/No Donors and ET-1 Release ArteriesIn rat heart perfused at constant flow, increased amounts of ET-1 were detected in the coronary effluent of samples collected for the final 5 to 15 minutes ...

Endothelin

“…Endothelial nitric oxide synthase is constitutively active, generates NO in response to shear stress and other physiologic stimuli and can limit the constrictor action of ET-1. This has recently been reviewed ( Rapoport, 2014 ). A number of pathophysiological conditions are associated with endothelial cell dysfunction and loss of nitric oxide.…”

Hypotonic contrast media is more toxic than isotonic contrast media on endothelial cells in vivo and in vitro

“…Therefore, NO and ET are used as biomarkers to reflect the function of endothelial cells (22). In CIN models, the expression of ET is downregulated, leading to vasoconstriction (23). The results demonstrated that both iopamidol and iodixanol upregulate ET levels, indicating that the two CMs are able to induce injury in endothelial cells.…”

Bifurcation in Blood Oscillatory Rhythms for Patients with Ischemic Stroke: A Small Scale Clinical Trial using Laser Doppler Flowmetry and Computational Modeling of Vasomotion

“…In our model, myogenic oscillations were phenomenologically considered as forcing tension applied to the vessel wall from VSMs. The model phenomenologically takes into account the modulation of SMC activity by vascular endothelium signaling (Koenigsberger et al, 2005; Delgado et al, 2010; Rapoport, 2014). One of the molecular mechanisms of this modulation may be explained through the release of vasoactive substances such as e.g., nitric oxide and/or Endotheli-1 expression as a result of activation of mechanosensitive channels in response to the shear stress (Vallance and Hingorani, 1999).…”