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Endothelium
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
Apart from an influence on blood pressure, other roles of EDHF include:to help increase blood flow to exercising muscle, by dilating small feed arteries (ascending, conducted vasodilatation; see Section 13.7) and generally co-ordinate blood flow within the microcirculation;to contribute to the cholinergic vasodilatation of small resistance vessels in the small number of tissues with a cholinergic autonomic innervation (Sections 14.2 and 14.3);to contribute to the vasodilatation of inflammation.
Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
The impaired endothelial function and dysregulated coronary blood flow in CAD eventually contribute to the onset and progression of atherosclerosis and thrombosis (Kinlay et al., 2001). Substantial evidence has demonstrated that CYP-generated EETs serve as endothelial-derived hyperpolarizing factor (EDHF) in the coronary circulation (Campbell et al., 1996). EDHF activates the large-conductance calcium-activated potassium (BK) channels and the Na+-K+-ATPase, and therefore induces hyperpolarization of vascular smooth muscle cells. This results in smooth muscle relaxation, therefore reducing contractile force and oxygen utilization of the muscle, leading to vasodilation (Fleming, 2014; Schinzari et al., 2017). Plasma concentrations of EETs have been demonstrated to be elevated in patients with CAD compared to healthy controls (Theken et al., 2012). It has been suggested that EETs may become up-regulated to compensate for the overall endothelial dysfunction. The key role of CYPs and EDHF is further supported from their expression modulation by the dihydropyridine calcium channel blocker nifedipine. This drug was able to up-regulate expression of CYP2C, but not 2J or 2B, in coronary endothelium. Furthermore, it stimulated EET biosynthesis and potentiated hyperpolarization of coronary artery smooth muscle cells mediated through bradykinin and EDHF (Fisslthaler et al., 2000). The cardioprotective role of EETs has also been demonstrated in transgenic animal model. Transgenic mice with selective overexpression of CYP 2J2 in cardiomyocyte exhibited better post-ischemic recovery of left ventricular function after prolonged ischemia. This protective effect was however abolished in the presence of the CYP epoxygenase inhibitor N-methylsulfonyl-6-(2-proparglyloxphenyl) hexamide (Seubert et al., 2004). This was further supported by studies in both adult mongrel dogs and rats (Gross et al., 2011) using the same inhibitor. These findings are in agreement with the reduced formation of atherosclerotic injury in apoplipoprotein E knockout mice observed following sEH inhibition (Ulu et al., 2008). Some other studies demonstrated beneficial effects of EETs on long-term endpoints post-infarction. A study using male rats treated with an sHE inhibitor, GSK2188931B (N-(4-bromo-2-[(trifluoromethyl)oxy]phenyl)methyl)-1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-4 piperidine carboxamide) immediately following permanent ligation of the left anterior descending coronary artery exhibited anti-remodeling effects such as reduced hypertrophy, lower inflammation, decreased ventricular fibrosis and sustained systolic function 5 weeks post-infarction (Kompa et al., 2013). More recently, in vivo studies demonstrated that a selective sHE inhibitor, 4-[[trans-4 [[(tricyclo [3.3.1.13,7]dec-1-ylamino)carbonyl] amino] cyclohexyl]oxy]-benzoic acid (t-AUCB) conferred protection against ischemic injury by preserving cardiomyocyte function and maintaining mitochondrial efficiency (Akhnokh et al., 2016). In another study, improved coronary endothelial function and attenuated cardiac remodeling and diastolic dysfunction were observed in obese insulin-resistant mice following treatment with t-AUCB (Roche et al., 2015).
Hyperoside ameliorates cerebral ischaemic–reperfusion injury by opening the TRPV4 channel in vivo through the IP3-PKC signalling pathway
Published in Pharmaceutical Biology, 2023
Lei Shi, Chenchen Jiang, Hanghang Xu, Jiangping Wu, Jiajun Lu, Yuxiang He, Xiuyun Yin, Zhuo Chen, Di Cao, Xuebin Shen, Xuefeng Hou, Jun Han
Accumulating evidence has shown that TRPV4 activation influences vascular dilation by inducing the production of EDHF, NO or PGI2 (Liu et al. 2021). Similar to previous studies, we also found that Hyp-induced vasodilatation is dependent on EDHF production in an NO- and PGI2-independent manner in endothelial cells from the CBA of IR rats. To further investigate the mechanism by which Hyp affects TRPV4 expression, we focused on IP3 and PKC. IP3-associated and PKC-mediated signalling pathways play a critical role in inducing PGI2- and NO-independent vasodilation. IP3 is an important second messenger that binds to inositol triphosphate receptors on the sarcoplasmic reticulum to cause Ca2+ release and an increase in intracellular Ca2+ concentration (Ivanova et al. 2017). Studies have shown that IP3 activation promotes the opening of TRPV4 channels (Heathcote et al. 2019). PKC induces vasodilation through the EDHF mechanism by activating TRPV4, which plays an important role in regulating vasomotor function (Sonkusare et al. 2014). The results herein showed that the expression of IP3R and PKC was markedly increased by the Hyp treatment, and this effect was reduced by treatment with an IP3R inhibitor (2APB) or an inhibitor of PKC (BisI). Importantly, the effect of Hyp on TRPV4 expression was considerably suppressed by the 2APB and BisI treatment, suggesting that Hyp upregulates TRPV4 expression through the activation of the IP3 and PKC signalling pathways.
Effect of inflammation on cytochrome P450-mediated arachidonic acid metabolism and the consequences on cardiac hypertrophy
Published in Drug Metabolism Reviews, 2023
Mohammed A. W. ElKhatib, Fadumo Ahmed Isse, Ayman O. S. El-Kadi
Metabolites of AA possess a wide range of biological activities. For instance, 20-HETE is associated with myogenic tone modulation and vasoconstriction (Tsai et al. 2017). Conversely, EETs possess cardioprotective, vasodilatory, and anti-inflammatory properties and can influence migration of vascular smooth muscles, which is pivotal in atherosclerosis and vascular remodeling. It is highly likely that enantiomers of EETs and HETEs have different biological profiles (Kiss et al. 2008). The EETs intracellular levels are tightly controlled via sEH activity, which produces the corresponding DHETs. DHETs have demonstrated reduced activity compared to the EETs. Although EETs share similar biological functions, their actions differ to some extent. For instance, some EETs demonstrated better pro-angiogenic properties than others in vitro and in vivo (Wang Y et al. 2005; Zhang B et al. 2006). Strikingly, EETs are best known for their hyperpolarizing action in some organs such as the heart. They are identified as endothelium-derived hyperpolarizing factors (EDHF), due to their role in modulating vascular functions (Campbell et al. 1996). EETs are reported to exert their vasorelaxation through a G-protein coupled receptor or transient receptor potential (TRP) channel activation (Campbell and Fleming 2010). EETs possess cardioprotective properties against hypertension, chronic non-ischemic cardiomyopathy, and acute ischemia-reperfusion injury
Moringa oleifera leaf extract induces vasorelaxation via endothelium-dependent hyperpolarization and calcium channel blockade in mesenteric arterial beds isolated from L-NAME hypertensive rats
Published in Clinical and Experimental Hypertension, 2020
Direk Aekthammarat, Patchareewan Pannangpetch, Panot Tangsucharit
EDHF is a proposed substance or electrical signal that originates from the endothelium, which could subsequently produce the hyperpolarizing current in adjacent vascular smooth muscle and cause vasorelaxation. EDHF plays a major role in the endothelium-derived hyperpolarization and relaxation of small resistant arteries where NO is less crucial (21). In the present study, EDHF-mediated vasorelaxation in response to MOE was characterized by the non-NO and non-PGI2 component of endothelium-dependent vasorelaxation that was sensitive to high K+ medium. However, the definite identity of factors causing EDHF-mediated relaxation remains unclear. Traditional candidates for the role of EDHF include endothelium-derived K+ ions, hydrogen peroxide, epoxyeicosatrienoic acids, and hydrogen sulfide (19).