Impaired Role of Epoxyeicosatrienoic Acids in the Regulation of Basal Conduit Artery Diameter During Essential Hypertension

Abstract

In young healthy subjects, epoxyeicosatrienoic acids synthesized by endothelial cytochrome P450 epoxygenases maintain basal conduit artery diameter during altered NO availability. Whether this compensatory mechanism is effective during essential hypertension is unknown. Radial artery diameter, blood flow, and mean wall shear stress were determined in 14 nontreated essential hypertensive patients and 14 normotensive control subjects during 8 minutes of brachial infusion for inhibitors of cytochrome P450 epoxygenases (fluconazole, 0.4 µmol/min) and NO synthase ( N G -monomethyl- l -arginine, 8 µmol/min) alone and in combination. In controls, the radial artery diameter was reduced by fluconazole (−0.034 ± 0.012 mm) and N G -monomethyl- l -arginine (−0.037 ± 0.010 mm) and to a larger extent by their combination (−0.137 ± 0.011 mm), demonstrating a synergic effect. In contrast, the radial diameter in hypertensive patients was not affected by fluconazole (0.010 ± 0.014 mm) but was reduced by N G -monomethyl- l -arginine (−0.091 ± 0.008 mm) to a larger extent than in controls. In parallel, N G -monomethyl- l -arginine decreased local plasma nitrite to a lesser extent in hypertensive patients (−14 ± 5 nmol/L) than in controls (−50 ± 10 nmol/L). Moreover, the addition of fluconazole to N G -monomethyl- l -arginine did not further decrease radial diameter in patients (−0.086 ± 0.011 mm). Accordingly, fluconazole significantly decreased local epoxyeicosatrienoic acid plasma level in controls (−2.0 ± 0.6 ng/mL) but not in patients (−0.9 ± 0.4 ng/mL). Inhibitors effects on blood flow and endothelium-independent dilatation to sodium nitroprusside were similar between groups. These results show that, in contrast to normotensive subjects, epoxyeicosatrienoic acids did not contribute to the regulation of basal conduit artery diameter and did not compensate for altered NO availability to maintain this diameter in essential hypertensive patients.

Schisandrin C targets Keap1 and attenuates oxidative stress by activating Nrf2 pathway in Ang II‐challenged vascular endothelium

“…Endothelial dysfunction plays a crucial role in the pathogenesis of various cardiovascular complications, including hypertension (Wallace et al, ) and atherosclerosis (Bellien, Remy‐Jouet, et al, ). Endothelial dysfunction manifests as damage to the vascular tone and homeostasis and is responsible for significant morbidity and mortality in patients of cardiovascular diseases (CVDs; Bellien, Iacob, et al, ; Modena, Bonetti, Coppi, Bursi, & Rossi, ).…”

Orally Active Epoxyeicosatrienoic Acid Analogs

“…In normal and hypertensive subjects treated with aspirin and N G -monomethyl-L-arginine to block vascular prostaglandin and nitric oxide synthesis, bradykinin increases forearm blood flow that is inhibited by the CYP inhibitor sulfaphenazole (45). Other studies document the dilator role of EETs in humans and human arteries (38, 43, 46). …”

The role of epoxyeicosatrienoic acids in the cardiovascular system

“…Another group reported no difference in basal plasma concentrations of EETs between healthy control subjects and hypertensive patients, but an impairment in induced EET release, in combination with NO and reactive oxygen species balance, and the endothelin-1 pathway contributed to endothelial dysfunction of conduit arteries (measured by flow mediated dilatation) in essential hypertensives [125]. The same group later demonstrated that inhibition of CYP450 reduced basal conduit arterial diameter only in healthy subjects, and not in essential hypertensives, but it did not change resistance arterial flow in both groups [55]. This is consistent with another study, which reported that a CYP450 inhibitor did not change basal flow within both normotensive and hypertensive patients, but conversely, it significantly blunted both acetylcholine and bradykinin induced flow only in hypertensives.…”

“…The physiological role of EETs in maintaining basal tone appears to be limited. Basal flow response was investigated in six human in vivo studies, and five reported no change in basal flow in healthy subjects , and one reported 13% and 17% reduction in response to fluconazole in 26 healthy subjects and seven patients with cardiovascular risk factors, respectively . Three of these in vivo studies assessed basal tone in fewer than 10 subjects , and thus were significantly underpowered.…”

“…The diagram shows that both EDHF and NO mediate smooth muscle relaxation by reducing smooth muscle cell intracellular calcium, whereas PGI 2 mediates relaxation via a calcium independent mechanism. EDHF, endothelium derived hyperpolarising factor; K + , potassium; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; PKG, cGMP-dependent protein kinase; PGI 2 , prostacyclin; cAMP, cyclic adenylate monophospate; PKA, cAMP-dependent protein kinase; Ca 2+ , calcium; MLCK, myosin light chain kinase; MLC, myosin light chain investigated in six human in vivo studies, and five reported no change in basal flow in healthy subjects [51][52][53][54][55], and one reported 13% and 17% reduction in response to fluconazole in 26 healthy subjects and seven patients with cardiovascular risk factors, respectively [56]. Three of these in vivo studies assessed basal tone in fewer than 10 subjects [51][52][53], and thus were significantly underpowered.…”