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Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
The role of 20-HETE and EETs in vascular and tubular abnormalities of renovascular disease (RVD) has been extensively investigated. As a form of secondary hypertension, RVD is one of the major causes of end-stage renal failure, and has been linked to increased cardiovascular mortality (Fatica et al., 2001; Johansson et al., 1999). 20-HETE is a potent vasoconstrictor and an inhibitor of sodium transport in the proximal tubule and thick ascending loop of Henle, whereas EETs induce dilatation of arterioles and inhibit sodium transportation in the proximal tubule and collecting duct, hence promote sodium excretion (Alonso-Galicia et al., 2002). 20-HETE acts by regulating MAPKs, protein kinase C (PKC), tyrosine kinase and Rho kinase pathways. These result in depolarization of vascular smooth muscle cells following blockade of BK channel (Fan et al., 2013), and through inhibition of calcium-sensitive potassium (KCa) channels (Obara et al., 2002) as well as increase in l-type calcium channel activity (Zeng et al., 2010). The increased 20-HETE level in the renal microcirculation will therefore enhance nephrovascular resistance, which in turn results in decrease in the glomerular filtration rate and capillary pressure. The pressure in the postglomerular circulation is lowered at the same time thus shifting the pressure natriuresis relationship to higher pressures (Williams et al., 2007), resulting in volume retention and hypertension. EETs have been demonstrated to increase the cAMP levels via binding to cell-surface receptors that activate the BK channel, leading to vasodilation. This is also partially due to the stimulation of protein phosphatase 2A and activation of the BK channel in preglomerular arterioles (Imig, 2013). EETs additionally activate small and intermediate calcium-activated potassium (KCa) channels in the endothelium which alter calcium entry, and possibly increase level and action of nitric oxide. Moreover, EETs enhance sensitivity of the vasodilator response of the renal arterioles to bradykinin, acetylcholine and adenosine (Imig, 2013). Besides changing the vascular tone, 20-HETE inhibits sodium-hydrogen exchanger 3 in the proximal tubule and sodium-potassium-chloride (NKCC2) transporter in the loop of Henle therefore altering sodium and water reabsorption (Alonso-Galicia et al., 2002). On the other hand, EETs’ action on tubular transport of sodium is mediated via regulation of ENaCs activity (Wang et al., 2014).
Cardiac contractility modulation for the treatment of moderate to severe HF
Published in Expert Review of Medical Devices, 2021
Force production in the cardiac myocyte depends largely on calcium concentration in the cytosol of the cell. The process of contraction begins when a triggering amount of calcium enters the cell via the L-type calcium channel and triggers the ryanodine receptor on the sarcoplasmic reticulum (SR) to release its calcium content to the cytosol. It is this calcium that is responsible for facilitating actin-myosin cross-bridging, which leads to filament sliding and force production. Calcium must be removed from the cytosol to allow filament dissociation. Reuptake of calcium into the SR is facilitated by the protein SERCA2a.