Effect of experimental hypoosmolar hyponatremia on the blood brain barrier and brain edema formation

Abstract

Abstract The most frequent cause of hyponatremia is water retention due to the increase in blood levels of antidiuretic hormone (vasopressin, AVP). Hyponatremia is associated with neurological deficits, which are mainly linked to brain edema. Although the cytotoxic mechanism of brain edema in hyponatremia is commonly known, the role of a vasogenic mechanism is ambiguous. The present studies aimed to evaluate the effect of both acute and chronic hyponatremia on brain edema, blood–brain barrier (BBB) permeability, and mRNA expression of the tight junctions. Acute hyponatremia was induced for 5 h by subcutaneous (s.c.) injection of vasopressin or a synthetic analog of vasopressin-desmopressin (dDAVP) with intraperitoneal (i.p.) water loading in the amount of 11% body weight. Chronic hyponatremia was induced for 4 days with the help of AVP or dDAVP released continuously from subcutaneously implanted ALZET mini-osmotic pumps and a liquid diet. Because of the vascular action of vasopressin, either vasopressin or desmopressin was used to induce hyponatremia to assess whether the observed changes were characteristic of AVP-associated hyponatremia or hyponatremia alone. Brain water content was determined using the wet-dry method. BBB permeability was studied using sodium fluorescein. Gene expression of claudin-5, occludin, and zonula occludens (ZO-1) was assessed by real-time PCR (RT-PCR). Osmolarity, Na+, and Cl− concentrations were analyzed using the electrolyte and blood gas analyzer. Hypoosmotic acute hyponatremia led to increased brain water content and downregulation of tight junction gene expression, although leakage of the BBB was not observed. These results, except for the gene expression of claudin-5, were comparable in both groups with acute hyponatremia, regardless of whether AVP or dDAVP induced it. In chronic hyponatremia, irrespective of the mode of induction, there were no changes in the studied parameters. These results demonstrate a new insight into the nature of edema in acute hypoosmotic hyponatremia due to signs of vasogenic edema.