Over-expression of V1A receptors in PVN modulates autonomic cardiovascular control

Abstract

The hypothalamic paraventricular nucleus (PVN) is a key integrative site for the neuroendocrine control of the circulation and of the stress response. It is also a major source of the neuropeptide hormone vasopressin (VP), and co-expresses V1a receptors (V1aR). We thus sought to investigate the role of V1aR in PVN in cardiovascular control in response to stress.Experiments were performed in male Wistar rats equipped with radiotelemetric device. The right PVN was transfected with adenoviral vectors (Ads) engineered to over-express V1aR along with an enhanced green fluorescent protein (eGFP) tag. Control groups were PVN transfected with Ads expressing eGFP alone, or wild-type rats (Wt). Rats were recorded with and without selective blockade of V1aR (V1aRX) in PVN under both baseline and stressed conditions. Blood pressure (BP), heart rate (HR), their short-term variabilities, and baroreflex sensitivity (BRS) were evaluated using spectral analysis and the sequence method, respectively. Under baseline physiological conditions,V1aR rats exhibited reduced BRS and a marked increase of BP and HR variability during exposure to stress. These effects were all prevented by V1aRX pretreatment. In Wt rats, V1aRX did not modify cardiovascular parameters under baseline conditions, and prevented BP variability increase by stress.However, V1aRX pretreatment did not modify baroreflex desensitization by stress in either rat strain. It follows that increased expression of V1aR in PVN influences autonomic cardiovascular regulation and demarcates vulnerability to stress. We thus suggest a possible role of hypothalamic V1aR in cardiovascular pathology. KeywordsVasopressin, V1a receptor, paraventricular nucleus, adenoviral vector, baroreflex, blood pressure variability, heart rate variability Abbreviations BRS, baroreflex sensitivity; VLF, very low frequency short-term variability; LF, low frequency short-term variability; HF, high frequency short-term variability; VP, vasopressin;OT, oxytocin; OTR, oxytocin receptor; V1aR, vasopressin V1a receptor; V1bR, vasopressin V1b receptor; V2R, vasopressin V2 receptor; V1aRX, vasopressin V1a receptor antagonist, PVN, paraventricular nucleus; NTS, nucleus of the solitary tract; RVLM; rostroventrolateral medulla; IML, intermediolateral column of the spinal cord.

Electrophysiological Effects of Ghrelin in the Hypothalamic Paraventricular Nucleus Neurons

“…AVP integrates neurosecretory and pre-autonomic populations of PVN neurons, through a mechanism deemed “volume transmission,” in which the release of a neuromodulator by dendrites into the extracellular medium influences the activity of juxtaposed neurons that are not anatomically connected by axon-dendrite synapses (Stern, 2015). The dendro-dendritic AVP release by the PVN has been shown to be important for autonomic control (Lozić et al, 2016) and neurosecretory and pre-autonomic PVN neurons have been shown to interact in this manner (Son et al, 2013). Ghrelin influences adiposity and energy utilization (Theander-Carrillo et al, 2006), volume transmission could potentially mediate these effects, since they depend on long-term alteration in neurotransmission/neuromodulation.…”

Sudden death: Neurogenic causes, prediction and prevention

“… 58 Their role is to prime magnocellular neurons and also to integrate the activity of neurons located in the magnocellular and the parvocellular parts of the PVN, 59 involved respectively in humoral and autonomic neural control of the circulation. 60 Lozić and colleagues 61 , 62 have demonstrated that upregulation of vasopressin V 1A and OT receptors in PVN modulates autonomic control of the cardiovascular system and changes the vulnerability of the rat phenotype to stress, thus pointing to possible targets for new drug development in cardioprotection from neurocardiogenic injuries.…”

Vasopressin & Oxytocin in Control of the Cardiovascular System: An Updated Review

“…Stress normally reduces BRS to permit concomitant BP and HR increase, preparing the animal for escape [185]. By transgenic generation of distinct rat phenotypes [186,187], those over-expressing OTR or V1aR in the PVN and by microinjecting selective blockers into the PVN, we found that the OTR rat phenotype has a blunted neurocardiogenic response to air-jet stress. OTR rats showed no baro-receptor desensitization and the increase of sympathetically-mediated BP variability was buffered compared to wild type controls.…”

“…In OTR rats the HR variability profile uncovered concomitant sympathetic (harmful) and vagal (protective) activation, while wild type rats exhibited solely sympathetic cardiac activation [188]. In rats over-expressing V1aR [186,187] in the PVN air-jet stress produced even greater baro-reflex desensitization than in wild type controls. In V1aR rats, the increase of sympathetically mediated BP variability and HR variability was greater than in wild type controls.…”