Participation of Prostacyclin in Endothelial Dysfunction Induced by Aldosterone in Normotensive and Hypertensive Rats

Blanco-Rivero, Javier; Cachofeiro, Victoria; Lahera, Vicente; Aras-López, Rosa; Márquez-Rodas, Iván; Salaíces, Mercedes; Xavier, Fabiano E.; Ferrer, Mercedes; Balfagón, Gloria

doi:10.1161/01.hyp.0000171479.36880.17

Cited by 115 publications

(102 citation statements)

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“…46,62 During endothelium-dependent contractions of the SHR aorta to acetylcholine, the production of PGI 2 is by far larger than that of other prostaglandins and reaches levels compatible with the activation of TP receptors of the vascular smooth muscle cells, making the prostanoid a major EDCF. 11,18,51,55 During endothelium-dependent increases in tension to ADP and A23187, the release of thromboxane A 2 is augmented as well, and those contractions, unlike the one in response to acetylcholine, are reduced partially by inhibitors of thromboxane A 2 synthase. 26,56,63 Thus, thromboxane A 2 contributes to EDCF-mediated responses elicited by these agonists.…”

Section: The Mediators: Prostanoidsmentioning

confidence: 99%

Endothelium-Dependent Contractions in Hypertension

2011

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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...

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Section: The Mediators: Prostanoidsmentioning

confidence: 99%

Endothelium-Dependent Contractions in Hypertension

2011

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“…Mineralocorticoid receptor blockade also improved endothelial function and reduced oxidative stress in Ang II-infused rats [68], suggesting that aldosterone induces actions usually attributed to direct effects of Ang II. Moreover, aldosterone may induce endothelial dysfunction and inflammation through activation of COX-2 (cyclo-oxygenase-2) in normotensive and hypertensive rats [69].…”

Section: Part II -Role Of the Renin-angiotensin-aldosterone System Onmentioning

confidence: 99%

Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation

Raimondo¹,

Tuttolomondo²,

Buttà³

et al. 2012

CPD

111

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Abstract:The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosteron system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Recpetor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflmmatory effect of drugs bocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors.

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“…These results may partially explain the beneficial effects of mineralocorticoid antagonism in chronic heart failure in the RALES study, as well as in the recent Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS) with the more selective MR blocker eplerenone in postmyocardial infarction subjects. 16 Chronic treatment with aldosterone resulted in impaired acetylcholine-induced relaxations of aorta in both WistarKyoto and spontaneously hypertensive rats (SHRs) 17 and increased aortic cyclooxygenase (COX)-2 protein expression associated with enhanced acetylcholine-induced aortic production of 13,14-dihydro-15-keto prostaglandin (PG)F 2␣ , PGE 2 , and 6-keto-PGF 1 ␣, whereas in SHRs, acetylcholine only stimulated generation of 6-keto-PGF 1 ␣. Aldosterone may, thus, produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive rats.…”

Section: Endotheliummentioning

confidence: 99%