Calcium handling coupled to the endothelin ET < sub > A < /sub > and ET < sub > B < /sub > receptor-mediated vasoconstriction in resistance arteries: Differential regulation by PI3K, PKC and RhoK

Eur J Pharmacol. 2023 Aug 2:175948. doi: 10.1016/j.ejphar.2023.175948. Online ahead of print.ABSTRACTAbnormal endothelin-1 (ET-1) activity is involved in the pathogenesis of vascular diseases such as essential and pulmonary arterial hypertension, coronary artery disease, and cerebrovascular disease, blockade of ET receptors having shown efficacy in clinical assays and experimental models of hypertension. Augmented Ca2+ influx and changes in Ca2+ sensitization associated with arterial vasoconstriction underlie increased systemic vascular resistance in hypertension. Since peripheral resistance arteries play a key role in blood pressure regulation, we aimed to determine here the specific Ca2+ signaling mechanisms linked to the ET receptor-mediated vasoconstriction in resistance arteries and their selective regulation by protein kinase C (PKC), Rho kinase (RhoK), the phosphatidylinositol 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK). ET-1-induced contraction was mediated by the endothelin ETA receptor with a minor contribution of vascular smooth muscle (VSM) endothelin ETB receptors. ET receptor activation elicited Ca2+ mobilization from intracellular stores, extracellular Ca2+ influx and Ca2+ sensitization associated with contraction in resistance arteries. Vasoconstriction induced by ET-1 was largely dependent on activation of canonical transient receptor potential channel 3 (TRPC3) and extracellular Ca2+ influx through nifedipine-sensitive voltage-dependent C...
Source: European Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research