Relcovaptan

Hyponatremia is the most common electrolyte disturbance in hospitalized patients. Symptoms of hyponatremia include attention deficits and cognitive impairments. The cause of such abnormalities may be disturbances in the regulation of microcirculation. Previous studies have shown that increased vasopressin (AVP) concentration to 15 pg/ml in the presence of decreased Na+ concentration to 121 mM, which mimics AVP-associated hyponatremia in vivo leads to dysfunction, i.e., constriction and impaired endothelial regulation of small intracerebral blood vessels—parenchymal arterioles (PA). One of the possible causes of this dysfunction may be excessive production of superoxide anion (O2•−). The superoxide anion binds nitric oxide (NO) in a reaction that produces aggressive nitrogen-free radical, peroxynitrite (ONOO−), which simultaneously reduces the bioavailability of NO. The present studies were performed in the organ chamber on isolated, perfused, and pressurized rats’ PA in low sodium environment in the presence of AVP. These studies aimed to investigate the mechanism leading to PA dysfunction, i.e., constriction and disturbed endothelial regulation. L-NAME (N(ω)-nitro-L-arginine methyl ester) did not elicit constriction of PA, indicating reduced involvement of NO in maintaining basal tone of PA. Vasopressin V1a receptor antagonist (SR 49059), endothelin ETA/ETB receptors antagonist (PD 142,893), peroxynitrite decomposition catalyst (FeTMPyP) and ROS scavengers: superoxide dismutase (SOD) and catalase (CAT) improved studied responses. Dihydroethidium (DHE) staining confirmed the increased superoxide anion formation in low sodium environment in the presence of AVP. Thromboxane A2/prostaglandin H2 receptor blocker (SQ 29,548), an inhibitor of the production of 20-HETE (HET0016), and L-arginine, a precursor of NO, did not improve dysfunctions of PA. Thus, in studied conditions, endothelial dysfunction occurs due to oxidative/nitrosative stress. These findings provide novel insight into the detrimental effects of decreased Na+ concentration in the presence of increased AVP concentration that mimic hyponatremia, on the regulation of cerebral microcirculation.