Endothelium-Dependent Contractions in Hypertension

Abstract

M ost 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][3][4][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 (endotheliumderived 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 extracellular calcium concentration reduces endothelium-dependent contractions, 24 whereas calcium ionophores, in particular, A23187, evoke endotheliumdependent contractions. [25][26][27][28][29] During endothelium-dependent contractions induced by acetylcholine, the endothelial cytosolic calcim concentration increases 28,29 and this increment is larger in aortae of spontaneously hypertensive rats (SHR) than in those of normotensive Wistar-Kyoto rats, in line with the larger EDCF-mediated responses in the preparations of the hypertensive strain. 8,28,30 Taken in conjunction, those findings imply that an increase in endothelial cytosolic calcium concentration is the initiating event leading to the release of EDCF. In the case of acetylcholine, the muscarinic agonist binds to G-protein-coupled M 3 receptors on the endothelial cell membrane and activates phospholipase C, which produces inositol triphosphate, causing...

Acetylcholine produces contractions mediated by the cyclooxygenase pathway in arterial vessels in the Chilean frog (Calyptocephalella gayi)

“…In addition, our studies showed that ACh-mediated vasoconstriction was coupled to the ACh-COX contraction pathway previously described in fish Urriola-Urriola, 2014, 2015). This was similar to that reported in human and rat hypertension models (Vanhoutte et al, 2005;Shi et al, 2008) where there was an endothelium dysfunction because of a lower bioavailability of NO due to the increase in oxidative stress that stimulates COX and production of prostaglandin vasoconstrictors (Vanhoutte, 2011). Therefore, we propose that ectotherm animals such as amphibians could have a similar pattern of vascular response as that described in fish.…”

“…In mammals, on the other hand, ACh induces vascular smooth muscle relaxation by activation of muscarinic receptors expressed in endothelial cells (Furchgott and Zawadzki, 1980). However, ACh-mediated vasoconstriction suggests that a coupled ACh-COX contraction described in our study in fish is similar to that reported in human hypertension and hypertension rat models (Vanhoutte et al, 2005;Shi et al, 2008) where there was an endothelium dysfunction because of a lower bioavailability of NO due to the increase in oxidative stress that stimulates COX and production of prostaglandin vasoconstrictors (Vanhoutte, 2011).…”

One or Two, Does it Matter as Long as the Arterial Wall Is Coxygenated?

“…However, the latter agent interferes with several other flavoenzyme oxidoreductases, and the former is regarded (at least in Frankfurt) as a nonselective antioxidant that should yield effects comparable with those of ascorbic acid. Similarly, the lovers of the role of thromboxane-prostanoid (TP) receptor activation in COX-mediated endothelial dysfunction 4,5 could argue that it is swept under the carpet of the e-supplemental information with one concentration of a single TP antagonist, without providing data that in the studied preparations under the experimental conditions tested TP antagonism actually is achieved… It is not surprising that vascular COX produces free radicals during stimulation with acetylcholine. 6 Thus, when viewing the data presented by Virdis et al, 1 one can only bow to the logical conclusion reached that in the human arteries studied COX plays a major role in producing ROS, curtailing the relaxations to acetylcholine solely by reducing the bioavailability of endothelium-derived NO.…”

The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

“…Furthermore, none of the PRL concentrations modified the basal production of NO in either the presence or the absence of L-NAME (control), confirming that this metabolite does not mediate the vascular effects induced by PRL ( Figure 7C). We therefore hypothesized that PGs and other major vasodilatory agents [48] may mediate the dilatory effect of the hormone. The aortic rings were preincubated for 30 min with INDO prior to precontraction with Phe, followed by the administration of 0.01 nmol/L of PRL.…”