Effects of exogenous ouabain on endothelium‐dependent vascular function

Endogenous ouabain is an inhibitor of sodium‐potassium adenosine triphosphatase (Na+/K+‐ATPase, also known as sodium‐pump). It is released by high sodium chloride concentrations from the hypothalamus and the adrenal cortex. Upon its release in the circulation, endogenous ouabain increases arterial constriction and peripheral resistance hence arterial blood pressure. In the clinical setting, digoxin, targeting the sodium pump as well, is an orally active agent exerting inotropic effects to treat heart failure or atrial arrhythmias. But toxicity often occurs due to overdose. The present study aimed to investigate the local effects when the sodium pump is inhibited by exogenous ouabain in acute settings. Aortae isolated from male Sprague Dawley rats (12 weeks old) were cut into rings and incubated in the organ chambers with Krebs‐Ringer solution for isometric tension recording, in the absence or presence of ouabain. They were contracted with phenylephrine and relaxed with increasing concentrations of endothelium‐dependent and ‐independent vasodilators, acetylcholine (ACh) and DETA NONOate, or exogenous arachidonic acid (AA). Ouabain inhibited endothelium‐dependent relaxations to ACh and AA in a concentration‐dependent manner. It reduced the maximal relaxation to ACh in aortae with endothelium where the nitric oxide signaling pathway plays a dominant role in vasodilatation, and increased the half maximal effective concentration (EC50) of DETA NONOate. The inhibitory effect of ouabain on AA‐induced relaxations was not observed in the presence of indomethacin (cyclooxygenase inhibitor). Ouabain potentiated the relaxations to AA when endothelial potassium channels involved in endothelium‐dependent hyperpolarization (EDH) signalings [namely intermediate‐ and small‐conductance calcium‐activated potassium channels (IKCa and SKCa, respectively)] were blocked by TRAM‐34 and UCL1684, respectively; the relaxation was not affected by the inhibition, with barium, of inwardly‐rectifying potassium channels (KIR, which also play a role in EDH pathway). Taken in conjunction, ouabain likely impairs the nitric oxide and/or cyclooxygenase pathways to reduce endothelium‐dependent relaxations. When the major mechanisms for the generation of endothelium‐derived relaxing signals (namely, nitric oxide, prostanoids and EDH) are inhibited, ouabain unmasks the relaxation to AA that is independent of KIR activation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.