A Novel Vasopressin Dual V1A/V2 Receptor Antagonist, Conivaptan Hydrochloride, Improves Hyponatremia in Rats with Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH)

We investigated the effects of intravenous administration of conivaptan hydrochloride, a dual vasopressin V1A and V2 receptor antagonist, on blood electrolytes and plasma osmolality in rats with an experimental syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The experimental SIADH rat model was developed by means of continuous administration of arginine vasopressin (AVP) via a subcutaneously implanted osmotic mini pump, and hyponatremia was induced by additional water loading. This model possesses similar characteristics to those observed in patients with SIADH, specifically decreases in blood sodium concentration and plasma osmolality. In this experimental model, intravenous administration of conivaptan (0.1, 1 mg/kg) significantly increased blood sodium concentration and plasma osmolality On the other hand, intravenous administration of furosemide (10 mg/kg) did not increase either blood sodium concentration or plasma osmolality in the SIADH rats. Moreover, furosemide significantly lowered blood potassium concentration. These results show that conivaptan improves hyponatremia in rats with SIADH, supporting the therapeutic potential of conivaptan in treatment of patients with hyponatremia associated with SIADH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a clinical state in which the secretion of antidiuretic hormone (ADH), also called arginine vasopressin (AVP), is not suppressed appropriately when plasma osmolality falls below the osmotic threshold and may lead to impaired renal water excretion, increased total body water, and hyponatremia. 1) SIADH is associated with a number of underlying clinical conditions, such as malignancy, lung disease, and central nervous system and hormonal disorders. 2) AVP is a peptide hormone that is released from the posterior pituitary gland in response to an increase in plasma osmolality and volume depletion. Three classes of specific receptor have been identified in the periphery. The vasopressin V1A receptor, which has been identified in vascular smooth muscle cells, hepatocytes and platelets, and the vasopressin V1B receptor, which is found predominantly in the anterior pituitary, are coupled to the phosphoinositide pathway and elevation of intracellular Ca2+. The vasopressin V2 receptor, which is located in the kidney and the vascular endothelium, is coupled to the adenylate cyclase pathway, causing an increase in c-AMP. 3) AVP elicits a potent water reabsorption ef