Oxytocin and Vasopressin Cross Talk Within the Brain Increases Blood Pressure

The paraventricular nucleus of the hypothalamus (PVN) orchestrates neuroendocrine and autonomic output to maintain systolic blood pressure (SBP). Emerging evidence suggests that the PVN utilizes paracrine signals to modulate neighboring neurons. Here, we test the hypothesis that OXT (oxytocin)-synthesizing neurons of the PVN (PVN^OXT) release paracrine signals that regulate SBP via modulation of AVP (arginine vasopressin)-synthesizing neurons of the PVN.

To test the hypothesis, experiments were conducted ex vivo and in vivo in mice with the expression of ChR2 (channelrhodopsin-2) and EYFP (enhanced yellow fluorescent protein) directed to cells synthesizing OXT.

We found >90% of EYFP-neurons were immunolabeled for OXT, and blue light elicited action potentials in these neurons. This confirmed directed/functional expression of ChR2-EYFP within PVN^OXT. In vivo optogenetic excitation of PVN^OXT increased SBP and elicited bradycardia in OXT-ChR2 (mice expressing EYFP-ChR2 in OXT-containing cells) compared with control OXT-Cre (mice expressing Cre-recombinase directed to the OXT gene) without ChR2. Ganglionic blockade had no effect on the increased SBP, but it abolished the bradycardia. These results suggest that exciting PVN^OXT likely recruits a neuroendocrine signal to promote vasoconstriction, thus eliciting the baroreflex to induce bradycardia. Consistent with this interpretation, optogenetic excitation of PVN^OXT increased circulating OXT; however, the elevated SBP persisted after administration of the OXT receptor antagonist. Intriguingly, in vitro optogenetic excitation of PVN^OXT evoked Ca²⁺ flux in Chinese hamster ovary cells expressing OXT receptors or vasopressin receptors (V1aR [vasopressin receptor 1a]), suggesting that firing of PVN^OXT promotes local release of OXT. Optogenetic excitation of PVN^OXT augmented firing of vasopressin-synthesizing neurons of the paraventricular nucleus and tended to increase circulating AVP. Remarkably, systemic or central administration of a V1aR antagonist abolished the increased SBP and bradycardia after excitation of PVN^OXT.

Collectively, our results reveal that firing of PVN^OXT promotes paracrine release of OXT, which via activation of V1aR(s) expressed on vasopressin-synthesizing neurons of the paraventricular nucleus, drives vasopressin secretion that elevates SBP.