Endothelium-Dependent Contractions in Hypertension

Abstract

Most isolated arteries respond to shear stress and several vasodilator substances, as demonstrated first for acetylcholine,1 by releasing endothelium-derived relaxing factor (or nitric oxide [NO]), and various endothelium-derived hyperpolarizing signals.2,–,5 However, in certain blood vessels, when exposed to stretch, agonists such as thrombin, acetylcholine, and adenosine nucleotides (adenosine diphosphate [ADP] and adenosine triphosphate [ATP]) or calcium ionophores, the endothelium produces diffusible cyclooxygenase (COX)-derived vasoconstrictor prostanoids (endothelium-derived contracting factors [EDCF])6,–,11 Endothelial cells also produce vasoconstrictor peptides, in particular, endothelin-1.12 The attribution of a role to endothelin-1 in instantaneous changes in vascular tone has been made difficult by the almost insurmountable nature of the vasoconstriction caused by the peptide that can only be tempered by NO or calcitonin gene-related peptide.13,14 Likewise, the evidence linking acute release of endothelin-1 to constriction of arteries is still limited.15 Therefore, the present article focuses on the mechanisms leading to the production of endothelial COX-derived vasoconstrictors, in particular, in the rat aorta, which has been the standard preparation used by the author and his collaborators for the study of EDCF-mediated responses However, the occurrence of such EDCF-mediated responses can vary widely, depending on the species and the blood vessel studied. For example, they are prominent in canine veins but not arteries.6 In the mouse, endothelium-dependent contractions are more pronounced in the carotid artery than in the aorta.16,17 Further, in any given blood vessel, the production of endothelium-derived vasoconstrictor prostanoids is exacerbated by aging and disease, in particular, hypertension.10,11,18,19 ### The Trigger: Calcium Acetylcholine (which activates endothelial M3-muscarinic receptors)20 and ADP and ATP (which activate endothelial purinoceptors)21,22 evoke endothelium-dependent contractions and release of calcium from the sarcoplasmic reticulum.23 Lowering the …