Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats

Abstract

The paraventricular nucleus of the hypothalamus (PVN) plays a crucial role in cardiovascular and neuroendocrine regulation. Application of nitric oxide donors to the PVN stimulates GABAergic transmission, and may suppress sympathetic nerve activity (SNA) to lower arterial pressure. However, the role of endogenous nitric oxide within PVN in regulating renal SNA chronically remains to be established in conscious animals. To address this, we used our previously established lentiviral vectors to selectively knock down neuronal nitric oxide synthase (nNOS) in the PVN of conscious Wistar rats. Blood pressure (BP) and renal SNA were monitored simultaneously and continuously for 21 days (n = 14) using radio-telemetry. Renal SNA was normalised to maximal evoked discharge and expressed as a percent change from baseline. The PVN were microinjected bilaterally with a neurone-specific tetracycline-controllable lentiviral vector, expressing a short hairpin miRNA-30 (shRNA) interference system targeting nNOS (n = 7) or expressing a mis-sense as control (n = 7). Recordings continued for a further 18 days. The vectors also expressed GFP, and successful expression in the PVN, and nNOSknockdown, was confirmed histologically post-hoc. Knock-down of nNOS expression in the PVN resulted in a sustained increase in BP (95 ± 2 to 104 ± 3 mmHg, P < 0.05), with robust concurrent sustained activation of renal sympathetic nervous activity (>70%, P < 0.05). The study reveals a major role for nNOS-derived nitric oxide within the PVN in chronic set-set point regulation of cardiovascular autonomic activity in the conscious, normotensive rat.

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