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Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats
Author(s) -
McBryde F. D.,
Liu B. H.,
Roloff E. V.,
Kasparov S.,
Paton J. F. R.
Publication year - 2018
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/ep086744
Subject(s) - nitric oxide , nitric oxide synthase , medicine , endocrinology , hypothalamus , chemistry , diencephalon , nucleus , sympathetic nervous system , blood pressure , neuroscience , biology
New FindingsWhat is the central question of this study? Does chronic reduction of neuronally generated nitric oxide in the hypothalamic paraventricular nucleus affect the set‐point regulation of blood pressure and sympathetic activity destined to the kidneys?What is the main finding and its importance? Within the hypothalamic paraventricular nucleus, nitric oxide generated by neuronal nitric oxide synthase plays a major constitutive role in suppressing long term the levels of both ongoing renal sympathetic activity and arterial pressure in conscious Wistar rats. This finding unequivocally demonstrates a mechanism by which the diencephalon exerts a tonic influence on sympathetic discharge to the kidney and may provide the basis for both blood volume and osmolality homeostasis.Abstract The paraventricular nucleus (PVN) of the hypothalamus 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 the PVN in regulating renal SNA chronically remains to be established in conscious animals. To address this, we used our previously established lentiviral vectors to knock down neuronal nitric oxide synthase (nNOS) selectively in the PVN of conscious Wistar rats. Blood pressure and renal SNA were monitored simultaneously and continuously for 21 days ( n = 14) using radio‐telemetry. Renal SNA was normalized to maximal evoked discharge and expressed as a percentage change from baseline. The PVN was microinjected bilaterally with a neurone‐specific tetracycline‐controllable lentiviral vector, expressing a short hairpin miRNA30 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 green fluorescent protein, and successful expression in the PVN and nNOS knockdown were confirmed histologically post hoc . Knockdown of nNOS expression in the PVN resulted in a sustained increase in blood pressure (from 95 ± 2 to 104 ± 3 mmHg, P < 0.05), with robust concurrent sustained activation of renal SNA (>70%, P < 0.05). The study reveals a major role for nNOS‐derived nitric oxide within the PVN in chronic set‐point regulation of cardiovascular autonomic activity in the conscious, normotensive rat.