Thromboxane‐prostanoid receptor activation blocks ATP‐sensitive potassium channels in rat aortas

Abstract

K+ channel activation is one of the major mechanisms involved in vasodilation. Vasoconstrictor agonists such as angiotensin II promote ATP‐dependent potassium channels (KATP) dysfunction. This study evaluates whether thromboxane‐prostanoid (TP receptor) activation by the agonist U46619 increases reactive oxygen species (ROS) production in rat aortas, which could contribute to KATP channel dysfunction and impaired NO‐dependent vasodilation. TP receptor activation with the selective agonist U46619 increased ROS in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), but the TP receptor antagonist SQ29548 abolished this effect. ECs and VSMCs incubation with ROS scavengers like Tiron or PEG‐Catalase impaired U46619‐induced ROS production. U46619 at the concentrations of 0.1 and 1 µmol/L induced contractions with similar amplitude. KATP channel activation with pinacidil‐induced relaxation was lower for the contractions induced with 0.1 or 1 µmol/L U46619 than with 10 nmol/L U46619. Acetylcholine‐induced relaxation provided similar results. In aortas pre‐contracted with 10 nmol/L U46619, neither Tiron (100 µmol/L) nor catalase (300 U/mL) affected pinacidil‐induced relaxation. However, in aortas pre‐contracted with 0.1 µmol/L U46619, catalase potentiated pinacidil‐induced relaxation. Pinacidil potentiated acetylcholine‐induced relaxation in aortas pre‐contracted with 0.1 and 1 µmol/L U46619. Incubation with 10 nmol/L U46619 increased NO concentration in ECs. Taken together, these results show that high concentrations of the TP receptor agonist U46619 impair KATP channels, which is probably due to ROS production. It is likely that hydrogen peroxide is the ROS.

An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging

“…These results agree, at least in part, with previous evidence showing that agmatine blocks L-type voltage-gated Ca 2+ channels and other types of voltage-gated Ca 2+ channels in cultured rat hippocampal neurons ( Weng et al, 2003 ; Zheng et al, 2004 ). However, other mechanisms such as increased reactive oxygen species production, K ATP channel dysfunction and impaired NO-dependent vasodilation contribute to the thromboxane A 2 analogue U46619 vascular smooth muscle contractions ( Santos et al, 2021 ). This evidence may explain slight differences found between the inhibitory effect of nifedipine and MCR5 on U46619 versus KCl concentration-response curves.…”

Chloroquine inhibits vasodilation induced by ATP-sensitive potassium channels in isolated rat aorta

“…The production of reactive oxygen species (ROS) including superoxide has been reported to inhibit vasodilation induced by K ATP channels (Kinoshita et al 2004(Kinoshita et al , 2006Haba et al 2009;Santos et al 2021). Chloroquine has been shown to induce ototoxicity and cardiotoxicity in a rat model of pressure overload hypertrophy through ROS production and consequent oxidative stress (Chaanine et al 2015;Oliveira et al 2019).…”

“…However, the effect of lipid emulsions on the chloroquine-mediated alteration of K ATP channel-induced vasodilation remains to be determined. On the basis of previous reports (Davis 1997;Kinoshita et al 2004Kinoshita et al , 2006Haba et al 2009;Chaanine et al 2015;Oliveira et al 2019;Santos et al 2021), this study tested the biological hypothesis that chloroquine inhibits K ATP channel-induced vasodilation via ROS production. Thus, the goals of this study were to examine the effects of chloroquine and a lipid emulsion, alone or in combination, on vasodilation induced by the K ATP channel agonist levcromakalim in isolated rat aortas and to clarify the underlying mechanism of these effects.…”