HYPERTONIC SODIUM CHLORIDE SENSING BY THE ORGANUM VASCULOSUM OF THE LAMINA TERMINALIS
Open Access
- Author:
- Kinsman, Brian J
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 08, 2018
- Committee Members:
- Kirsteen Nairn Browning, Dissertation Advisor/Co-Advisor
Kirsteen Nairn Browning, Committee Chair/Co-Chair
Charles H Lang, Committee Member
Urs Leuenberger, Committee Member
Leslie Joan Parent, Outside Member
Sean D. Stocker, Committee Chair/Co-Chair
Sean D. Stocker, Dissertation Advisor/Co-Advisor - Keywords:
- blood pressure
salt
NaCl
NaCl-sensing
osmoreceptor
sympathetic
hypothalamus
hypertension
salt-sensitive
sodium
ENaC
epithelial sodium channel
benzamil
OVLT - Abstract:
- High dietary NaCl intake is a significant risk factor for the development of hypertension. Time controlled studies in humans and rodents suggests that high salt intake elevates plasma and cerebrospinal fluid (CSF) NaCl concentrations and subsequently raises sympathetic nerve activity (SNA) and arterial blood pressure (ABP), potentially via osmosensitive neurons located in the organum vasculosum of the lamina terminalis (OVLT). However, the mechanism by which elevated extracellular [NaCl] acts in the brain to regulate SNA and ABP is poorly understood. Intriguingly, central infusion of benzamil, an amiloride analogue, attenuates the development of salt-sensitive hypertension models. This dissertation evaluated (i) the contribution of hypertonic NaCl-sensing by OVLT neurons to subsequent regulation of SNA and ABP, (ii) whether NaCl and osmolarity similarly affect these functions, and (iii) the role of benzamil-sensitive channels, namely epithelial sodium channels (ENaC), in OVLT neuron NaCl-sensing. These multifaceted studies in adult male Sprague Dawley rats utilized whole cell patch clamp recordings from OVLT neurons in hypothalamic slices and in vivo recordings of OVLT single-unit activity, end-organ SNA, and ABP in response to acutely administered hypertonic solutions. Initial investigations demonstrated that 2-5% elevations in extracellular [NaCl] intrinsically excite most OVLT neurons in vitro and in vivo. Hypertonic NaCl administered intracerebroventricularly (ICV) or intra-OVLT significantly increases lumbar and adrenal SNA and raises ABP. These responses are attenuated by inhibiting OVLT neurons with muscimol. Notably, ICV infusion or OVLT injection with equi-osmotic sorbitol did not alter SNA and ABP. Furthermore, most OVLT neurons in vitro and in vivo demonstrated greater increases in discharge frequency in response to hypertonic NaCl than equi-osmotic mannitol or sorbitol. Interestingly, hypertonic NaCl-sensing by OVLT neurons was attenuated by either 0.5µM benzamil or 10µM amiloride, yet 10µM amiloride did not affect excitation of OVLT neurons by mannitol. Finally, intra-OVLT benzamil injection reduced central NaCl-evoked sympathoexcitation. Collectively, these results indicate that OVLT neuron hypertonic NaCl-sensing, but not osmosensing, regulates SNA and ABP, and ENaC contributes to these NaCl-sensing functions in OVLT. Future investigations into the mechanisms of OVLT NaCl-sensing in salt-sensitive hypertension may facilitate development of targeted therapies that reduce NaCl-sensitive elevations in SNA and ABP.