Combined V1a and V1b Receptor Activation Within the Paraventricular Nucleus Contributes to Sympathoexcitation and Hypertension in Rats Exposed to Chronic Mild Unpredictable Stress

Abstract

The paraventricular nucleus (PVN) in the brain has been recognized as a major integrative center for neurohumoral regulation which receives a broad array of afferent inputs. As such, the function of the PVN becomes even more important in times of physical or physiological stress. Two distinct neuronal populations we are interested in include the magnocellular and parvocellular neurons. Specifically, we are interested in deciphering how intranuclearly released vasopressin (AVP) from the magnocellular neurons acts upon the parvocellular pre‐sympathetic neurons and glia that are richly endowed with V1a and V1b receptors in a rat model of depression. It has been demonstrated that V1a receptor activation depolarizes PVN pre‐sympathetic neurons and initiates an action potential, which puts forth a signaling cascade that increases sympathetic nerve activity, arterial pressure and heart rate. Additionally, we previously published that renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) responses to AVP microinjected in the PVN is significantly attenuated when the rats were pretreated with V1b receptor antagonist nelivaptan. In this study, we set out to identify differences in baseline RSNA, MAP and HR between rats exposed to the chronic mild unpredictable stress protocol (CMS) and their normal counterparts, as well as their responses to AVP microinjected into the PVN in the presence of the V1a receptor antagonist, Manning compound, and the V1b receptor inhibitor, nelivaptan. We observed that baseline MAP is higher in CMS rats (110 ± 2 mmHg vs. 115 ± 1 mmHg; P < 0.05). Furthermore, in control rats, combined inhibition of AVP with nelivaptan and Manning compound resulted in near complete abolition of the rise in MAP and baroreflex‐mediated decreases in HR and RSNA. CMS rats exhibited exaggerated baseline RSNA, 43.6 ± 9.97 μV.ms compared with control rats, 8.04 ± 3.24 μV.ms (P < 0.025). PVN AVP injection increased RSNA by 52.1 ± 3.3 %baseline in controls and was blocked by the dual blockade. RSNA did not increase significantly after PVN AVP in CMS rats and V1a receptor and V1b receptor blockade did not change this response. CMS rats displayed higher baseline RSNA 43.6 ± 9.9 μV.ms vs control rats 8.0 ± 3.9 μV.ms P < 0.025). Moreover, dual blockade significantly decreased RSNA from baseline values only in CMS rats: −12.6 ± 0.4 μV.ms compared with control rats −1.1 ± 0.6 μV.ms (P < 0.05). These findings are consistent with the concept that arterial pressure and RSNA are increased during chronic stress via dendritic release of AVP within the PVN thereby contributing to sympathoexcitation and hypertension.Support or Funding InformationDepartment of Veterans Affairs Merit Award to NFRThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.