Endothelin-1 Regulation of Exercise-Induced Changes in Flow: Dynamic Regulation of Vascular Tone.

Robert M Rapoport,Daphne Merkus

doi:10.3389/fphar.2017.00517

Abstract

Although endothelin (ET)-1 is a highly potent vasoconstrictor with considerable efficacy in numerous vascular beds, the role of endogenous ET-1 in the regulation of vascular tone remains unclear. The perspective that ET-1 plays little role in the on-going regulation of vascular tone at least under physiologic conditions is supported by findings that potential ET-1 constriction is minimized by the release of the vasodilator and ET-1 synthesis inhibitor, nitric oxide (NO). Indeed, ET-1 release and constriction is self-limited by ET-1-induced, endothelial ETB receptor-mediated release of NO. Moreover, even if the balance between ET-1 and NO were reversed as the result of lowered NO activity, as occurs in a number of pathophysiologies associated with endothelial dysfunction, the well-known resistance of ET-1 constriction to reversal (as determined with exogenous ET-1) precludes ET-1 in the dynamic, i.e., moment-to-moment, regulation of vascular tone. On the other hand, and as presently reviewed, findings of ET-1-dependent modulation of organ blood flow with exercise under physiologic conditions demonstrate the dynamic regulation of vascular tone by ET-1. We speculate that this regulation is mediated at least in part through changes in ET-1 synthesis/release caused by pulsatile flow-induced shear stress and NO.

Highlights

There is substantial evidence that increased release of the potent vasoconstrictor, endothelin (ET)1, underlies the sustained elevated vascular tone in numerous pathophysiologies associated with endothelial dysfunction (Félétou and Vanhoutte, 2000; De Mey and Vanhoutte, 2014)
The coronary endothelium has a greater capacity to release ET-1 with increased exercise intensity, an effect that is limited by nitric oxide (NO) inhibition of ET-1 synthesis
The dynamic regulation of flow by ET-1 is modulated by a dynamic balance between increased ET-1 synthesis and subsequent ET-1 release, and increased inhibition of ET-1 synthesis by enhanced NO

Summary

INTRODUCTION

There is substantial evidence that increased release of the potent vasoconstrictor, endothelin (ET), underlies the sustained elevated vascular tone in numerous pathophysiologies associated with endothelial dysfunction (Félétou and Vanhoutte, 2000; De Mey and Vanhoutte, 2014). Intrapulmonary artery infused ETA and ETA/B receptor antagonist increased flow/dilated the coronary vascular bed (Merkus et al, 2002, 2003, 2005, 2006; de Beer et al, 2011b; Zhou et al, 2014a; Table 1). Intrapulmonary artery infused ETA and ETA/B receptor antagonist increased coronary dilation, with the magnitude of increase slightly but significantly greater with ETA receptor antagonist at all levels of exercise intensity (Merkus et al, 2002, 2003, 2005, 2006; de Beer et al, 2011b; Zhou et al, 2014a; Table 1). These findings are consistent with NO synthase inhibitor-increased big ET-1, but not ET-1, constriction of isolated rat mesenteric artery (Bourque et al, 2012)

Conclusion and Speculation

OVERALL CONCLUSION AND SPECULATION