Recent advances and future directions in preclinical research of arginine-vasopressin (AVP) receptor blocker conivaptan in the context of stroke.

Stroke is a major cause of mortality and permanent disability. The onset of stroke is followed by life-threatening pathophysiological responses including brain edema, elevation of intracranial pressure, disruption of blood-brain barrier (BBB), brain infarct and permanent tissue damage. Brain edema develops due to accumulation of water in intracellular and extracellular compartments of the brain, which causes an increase in brain volume and elevation of intracranial pressure, (Figure 1A). Compression of the brain tissue has an impact on cerebral blood flow which results in secondary brain injury. Often, clinical presentation of stroke is accompanied by hyponatremia caused either by the syndrome of inappropriate release of antidiuretic hormone (SIADH) or cerebral salt wasting (CSW) (Saleem et al., 2014). SIADH is the result of uncontrolled secretion of antidiuretic hormone (ADH) also called arginine-vasopressin (AVP). AVP acts on V1a and V2 receptors triggering vasoconstriction, platelet aggregation, and water retention followed by hypervolemic or normovolemic hyponatremia and low plasma osmolality (Saleem et al., 2014) (Figure 1A). CSW is manifested by a dramatic loss of sodium through the kidneys resulting in hypovolemic hyponatremia (Saleem et al., 2014). Both SIADH and CSW can quickly exacerbate post-ischemic brain edema if plasma sodium levels and osmolality are not properly managed and corrected in a patient. Because SIADH can often be confused with CSW the treatments have to be strategized carefully. Although pathophysiological mechanisms of SIADH-caused hyponatremia are identified, mechanisms of CSW-induced hyponatremia are unknown. Current therapeutic applications against brain edema (such as decompression craniotomy or hypertonic saline) do not fully address the complications caused by SIADH or CSW. Therefore, new research approaches are required to identify and target precise causes of stroke-induced brain edema.