The Role of Arginine-Vasopressin in Stroke and the Potential Use of Arginine-Vasopressin Type 1 Receptor Antagonists in Stroke Therapy: A Narrative Review

Abstract

Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences.

Keywords: acute stress response; arginine-vasopressin; blood-brain barrier; cerebral edema; copeptin; ischemic stroke; neuroendocrine dysfunction; neuroinflammation; stroke pathophysiology; vasopressin receptors.

Figure 1

Main mechanisms causing arginine-vasopressin (AVP) release during stroke (A) and main local deteriorating effects caused by excessive AVP release (B). AVP neurons receive dense afferent input from baroreceptors, osmoreceptors, adrenergic, and glutaminergic neurons. Stroke induces the dysregulation of baroreceptors and the renin-angiotensin-aldosterone system, and increases the sympathetic stimulation of the paraventricular nucleus of hypothalamus (PVN) neurons (A). After the stroke, the initial disruption of the blood-brain barrier causes local hyperosmotic environment formation and stimulation of osmoreceptors (A). The release of AVP is also regulated by the interaction of astrocytes with AVP-containing neurons. During a stroke, the regulatory volume decrease of astrocytes occurs, followed by the downregulation of GFAP and AQP4 (A). Additionally, stroke causes the release of glutamate and pro-inflammatory cytokines, which stimulate AVP release (A). After the release, AVP activates the V1aR and V1b(V3)R located in the brain, brain vasculature, and pituitary, respectively (B). Upon release, AVP exacerbates brain edema formation (1). Consequently, the expanding brain edema can increase the intracranial pressure and exert direct pressure on adenohypophysis, further increasing the AVP release (1). Vasopressin causes time-dependent arteries and arterioles vasoconstriction and increases cerebral perfusion pressure (CPP) but not cerebral blood flow (CBF) (2). Vasopressin also acts synergistically with corticotropin (CRH), causing excessive cortisol release (3). Abbreviations: ACTH, adrenocorticotropic hormone; AQP4, aquaporin-4; AVP, arginine vasopressin; BBB, blood-brain barrier; CBF, cerebral blood flow; CPP, cerebral perfusion pressure; CRH, corticotropin-releasing hormone; GFAP, glial fibrillary acidic protein; IL-1, interleukin 1; IL -6, interleukin 6; PVN, paraventricular nucleus; RAAS, renin–angiotensin–aldosterone system; and RVD, regulatory volume decrease.