Introduction Introduction

background Arginine-vasopressin(avp) is a physiological co-activator of the hypothalamus-pituitary-adrenal-axis(hpa), together with corticotrophin-releasing hormone (crh). A synthetic analogue of avp, desmopressin(ddavp) is often used as pharmacological tool to assess co-activation in health and disease. The relation between ddavp’s neuroendocrine, cardiovascular, pro-coagulatory, antidiuretic and non-specific stress effects has not been studied. objectives A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers(6: 6). ddavp was administered intravenously as a 10μg bolus (over one minute) or a 30μg incremental infusion (over 60 minutes). Neuroendocrine, cardiovascular, pro-coagulatory, antidiuretic effects and adverse events (ae’s) were recorded, and autonomic nervous system (ans) activation evaluated. results The incremental infusion reached 1.8 fold higher ddavp concentrations than the bolus. Neuroendocrine effects were similar for the 10μg ddavp bolus and the 30μg incremental infusion, while cardiovascularand coagulatory effects were greater with the 30μg dose. Osmolality and ans activity remained uninfluenced. ae’s corresponded to ddavp’s side-effect profile. conclusions The neuroendocrine effects of a 10μg ddavp bolus administered over one minute are similar to those of a 30μg incremental infusion administered over one hour, despite higher ddavp concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10μg ddavp bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen. 37 chapter 2 • hpa axis modulation with ddavp 38 pharmacological aspects of corticotrophinergic and vasopressinergic function tests for hpa axis activation Introduction Arginine-vasopressin (avp) is the nonapeptide modulator of the human vasopressinergic system. It acts as neurotransmitter within the central nervous system (cns) and as neuroendocrine hormone in the peripheral circulation (Ring, 2005). avp produced by hypothalamic parvocellular neurones of the medial paraventricular nucleus (pvn) is not only released into the cns but also secreted into the pituitary portal circulation (Aguilera and Rabadan-Diehl, 2000; Scott and Dinan, 2002). Centrally acting avp is believed to play a role in the regulation of learning and memory, social behaviours, circadian rhythmicity and thermoregulation (Ring, 2005). Furthermore, following acute psychological and/or physical stress, it acts as co-activator of the hypothalamus-pituitary-adrenal (hpa) axis by inducing acth release via the vc receptor (vc or Vab) on the anterior pituitary (Dinan and Scott, 2005; Scott and Dinan, 1998). Co-activation is believed to occur in the presence of the main hpa axis activator corticotrophin-releasing hormone (crh) (Scott and Dinan, 2002). Subsequently, the stress hormone cortisol is released into the circulation from the adrenal cortices, causing various systemic and metabolic effects in peripheral tissues, and different behavioural and cognitive effects in the cns. In addition to these actions on the hpa-axis, avp originating from magnocellular neurons of the supraoptic nucleus and pvn of the hypothalamus is secreted peripherally via the posterior pituitary (Ring, 2005). Peripheral release is triggered by hypo-osmolality, hypovolemia, reduced blood pressure, hemorrhage, hypoglycemia, fever and pain. After release, it acts principally at Vaa receptors of the renal tubular cells restoring plasma volume and osmolality (Ring, 2005). Hyperactivity of the avp system of the anterior pituitary has been implicated in hpa axis dysregulation during chronic stressrelated psychopathology (Pariante and Lightman, 2008; Scott and Dinan, 2002). Preclinical data indicate that avp sustains hpa axis hyperactivity under conditions of chronic stress (Spiga et al., 2008). Humans with (subtypes of) depressive disorder display hypercortisolism, indicating chronic hpa axis hyperactivation. Also, these patients have an enhanced neuroendocrine response to the combined dexamethasone-corticotrophin release hormone (dex/ hcrh) function test, This potentiation of the response to hcrh is