O’Brien F, Williams BM, Pratt HM, Barrett‐Jolley R. CVS role of TRPV: from single channels to HRV assessment with Artificial Intelligence. The FASEB Journal. 2018 Apr;32:732-6.
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.2018.32.1_supplement.732.6
Abstract
The paraventricular nucleus (PVN) of the hypothalamus is an important autonomic control centre in the brain with roles in stress, metabolism, cardiovascular function and homeostasis. Identified PVN neurones project directly to the spinal cord and can modulate cardiovascular function via sympathetic control, however, the underlying mechanisms are not fully understood. Work from our group has highlighted roles for TRPV4 in osmosensing and thermoregulation in the PVN. To investigate whether TRPV4 channels may play a role in modulating cardiovascular function, we have used a combination of in vivo, in vitro and in silico techniques.
Heart rate, blood pressure (BP) and tail blood volume were recorded from CD1 mice using noninvasive tail plethysmography at varying cage temperatures. To record cardiovascular parameters and internal body temperature in unrestrained animals, we employed radio-telemetry in Wistar rats. To analyse ECG signals, we began by comparing an artificially intelligent (AI) 1D Convolutional Neural Network beat detection model (in Python-Keras) with traditional peak detection methods. We used heart rate variability analyses (HRVA) to investigate autonomic nervous system influences with and without a TRPV4 agonist. To characterise TRPV4 channel gating, we used patch-clamp electrophysiology on PVN neurones from mouse hypothalamic brain slices. Results are given as mean ± SEM; significances were assessed by one-way ANOVA or Student’s t-tests where appropriate.
Intraperitoneal administration of the selective TRPV4 antagonist GSK 2193874 (300 μg/kg) resulted in an increased temperature evoked vasodilation, which was not observed in controls (n=3, 5 p<0.01). In radio telemetry experiments, the blind AI detected beat frequency significantly correlated (Rho 0.88, p<0.001, n=10) to the human supervised peak detection methods in the physiological range (<800bpm, >400bpm) and was therefore used for the remaining analysis. Intraperitoneal administration of the the TRPV4 agonist GSK 1016790A (50 μg/kg) caused no change in mean HR, but a significant increase in Low Frequency (LF) power, consistent with an effect on the autonomic system. In brain slice experiments on PVN neurones, ion channels that fit the TRPV4 ‘gating profile, for example the slope conductance (58±9 pS), reversal potential (-8±3 mV), sensitivity to 4αDD and gating kinetics were sensitive to temperature changes (n=4-6, p<0.05).
Our electrophysiology results illustrate that temperature changes lead to activation of TRPV4- like channels on PVN neurones. We show that inhibition of TRPV4 channels has profound effects on thermosensing responses such as vasodilation, further iimplicating its role in thermoregulation and modulation of autonomic outflow from the PVN.
