Effects of Combined Oxytocin Receptor (OTR) with Vasopressin Receptor (V1aR or V1bR) Blockade within Paraventricular Nucleus (PVN) on Neurocardiovascular Responses

Abstract

Vasopressin (VP) released from dendrites of magnocellular neurons within PVN may influence systemic hemodynamics and sympathetic nerve activity. PVN neurons possess all three receptor subtypes: V1aR, V1bR and OTR. We have shown that inhibition of any one of these receptors alone dose dependently blocks the rise in MAP and reflex changes in heart rate (HR) and renal sympathetic nerve activity (RSNA) with injection of VP into PVN. Here we test the hypothesis that a subthreshold dose of OTR antagonist combined with either subthreshold V1aR or V1bR blockers within PVN will result in additive inhibition of hemodynamic and RSNA changes induced by 100 ng VP into PVN. Male Sprague Dawley rats were instrumented and studies performed in awake unrestrained rats 24 ‐ 48 hr after recovery from anesthesia. Baseline parameters did not differ. VP increased MAP by 18.2 ± 3.1 mmHg (P < 0.001) while HR and RSNA decreased 33 ± 14 bpm and 13.6 ±10.6 %baseline, respectively (P <0.05). The response to combined subthreshold inhibitory doses of (d(CH₂)₅¹,Tyr(Me)²,Arg⁸)‐Vasopressin (V1aR, 20 ng), nelivaptan (V1bR, 0.5 ng) and (d(CH₂)₅¹,Tyr(Me)²,Thr⁴,Orn⁸,des‐Gly‐NH₂⁹)‐Vasotocin (OTR, 1 ng) attenuated the rise in MAP by 43% as well as the reflex changes in HR and RSNA. Neither V1aR+OTR blockade nor V1bR+ OTR blockade resulted in greater blockade of the responses (45% and 49%, respectively. Vehicle did not block any responses. These findings suggest that V1aR, V1bR and OTR activated pathways share intracellular and/or neural pathways that regulate system hemodynamics and sympathoexcitatory responses to VP within the PVN.