Binding of the Non-Peptide Vasopressin V_1a Receptor Antagonist SR-49059 in the Rat Brain: An in vitro and in vivo Autoradiographic Study

Abstract

A potent non-peptide vasopressin (AVP) antagonist, SR-49059, displaying high stability and selective affinity for the V_1a AVP receptor subtype, has recently been described. The objective of this study was to assess the binding properties and the penetrability of this compound in the rat brain. Both in vitro and in vivo binding autoradiography experiments were performed. In all studies, the liver was used as a reference V_1a tissue. In vitro labelling of rat brain sections with [³H]SR-49059 was similar to that previously detected with [³H]AVP, which confirms that the majority of central AVP binding sites are V_1a sites similar to peripheral V_1a receptors. As expected, intense specific labelling occurred mainly in the lateral septum, the fundus striatum, the hypothalamic stigmoid nucleus and the area postrema-nucleus of the solitary tract complex. In vivo binding autoradiography showed that [³H]SR-49059 injected intravenously did not enter the brain parenchyma. Specific labelling was however clearly detectable in brain regions with permeable hematoencephalic barrier, the choroid plexus and other circumventricular organs expressing V_1a receptors, namely the subfornical organ, the pineal gland and the area postrema. The specificity of [³H]SR-49059 binding in the latter structures was confirmed by the fact that labelling was prevented by pretreatment of animals with high doses of nonradioactive SR-49059. In conclusion, our study shows that [³H]SR-49059 is a suitable probe to investigate V_1a receptors in the rat brain. We also demonstrate that although this compound is not able to enter the brain tissue from the peripheral circulation, it does bind specifically to regions devoid of blood-brain barrier and known to be involved in autonomic regulations.

Role of vasopressin V1Areceptor in the urethral closure reflex in rats

“…In this study, we indicated that V 1A R mRNA in the spinal L6 is specifically distributed in the lamina IX, which contains Onuf's nucleus in rats. Our findings are consistent with previous studies that used autoradiographic V 1A R antagonists and indicated the localization of V 1A R in Onuf's nucleus in adult rats (24,25). Therefore, it is likely that V 1A R plays an important role in the regulation of the urethral closure response.…”

“…The vasopressin receptor family consists of four subtypes, vasopressin V 1A , V 2 , V 1B , and the oxytocin receptor (V 1A R, V 2 R, V 1B R, and oxytocinR, respectively). V 1A R is identified in rat Onuf's nucleus by autoradiographic binding analysis (24,25). Additionally, AVP potentiates the neuronal activity of cultured motor neurons from Onuf's nucleus in neonatal rat via V 1A R, but not via the other vasopressin receptors, based on the findings of an electrophysiological study (16,20).…”

Effects of the Nonpeptide V 1 Vasopressin Receptor Antagonist SR49059 in Hypertensive Patients

“…This suggests that the V 1 R antagonist may alter AVP release either (1) directly or (2) via its vasodilation effect potentiating AVP osmotic release, but SR49059 does not cross the blood-brain barrier 32 ; the more probable mechanism is (3) via antagonism at the AVP receptor level.…”

Role of Arginine Vasopressin V1 and V2 Receptors for Brain Damage After Transient Focal Cerebral Ischemia

“…This effect, if present, seems to be restricted to penumbral tissue, because inhibition of AVP V 1 receptors does not affect CBF in the infarct core (Figure 1). Another explanation for AVP V 1 receptor-mediated neuroprotection might be that AVP V 1 receptors are widely expressed in the brain parenchyma (Brinton et al, 1984;Pearlmutter et al, 1988;Phillips et al, 1988;Young et al, 1999;Tribollet et al, 1999;Fernandez et al, 2001) where they have been implicated in intracellular calcium mobilization, activation of NMDA receptors, and superoxide anion generation (Urban and Killian, 1990;Hess et al, 1991;Gouzenes et al, 1999;Armstead, 2001), all conditions well known to be associated with neuronal cell death after cerebral ischemia (Lo et al, 2003). Accordingly, the positive effect AVP V 1 receptor inhibition on cell death might also be explained by a reduction of glutamate-and superoxide anion-mediated toxicity, as also discussed previously (Tanaka et al, 1994).…”