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Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats.
Exp Physiol. 2018 03 01; 103(3):419-428.EP

Abstract

NEW FINDINGS

What 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.

Authors+Show Affiliations

School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK. Cardiovascular Autonomic Research Cluster, Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK. Cardiovascular Autonomic Research Cluster, Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29215757

Citation

McBryde, F D., et al. "Hypothalamic Paraventricular Nucleus Neuronal Nitric Oxide Synthase Activity Is a Major Determinant of Renal Sympathetic Discharge in Conscious Wistar Rats." Experimental Physiology, vol. 103, no. 3, 2018, pp. 419-428.
McBryde FD, Liu BH, Roloff EV, et al. Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats. Exp Physiol. 2018;103(3):419-428.
McBryde, F. D., Liu, B. H., Roloff, E. V., Kasparov, S., & Paton, J. F. R. (2018). Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats. Experimental Physiology, 103(3), 419-428. https://doi.org/10.1113/EP086744
McBryde FD, et al. Hypothalamic Paraventricular Nucleus Neuronal Nitric Oxide Synthase Activity Is a Major Determinant of Renal Sympathetic Discharge in Conscious Wistar Rats. Exp Physiol. 2018 03 1;103(3):419-428. PubMed PMID: 29215757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypothalamic paraventricular nucleus neuronal nitric oxide synthase activity is a major determinant of renal sympathetic discharge in conscious Wistar rats. AU - McBryde,F D, AU - Liu,B H, AU - Roloff,E V, AU - Kasparov,S, AU - Paton,J F R, Y1 - 2018/01/19/ PY - 2017/10/17/received PY - 2017/11/30/accepted PY - 2017/12/8/pubmed PY - 2019/1/24/medline PY - 2017/12/8/entrez KW - arterial blood pressure KW - neuronal nitric oxide synthase microRNA KW - paraventricular nucleus KW - renal nerve KW - sympathetic nervous system SP - 419 EP - 428 JF - Experimental physiology JO - Exp Physiol VL - 103 IS - 3 N2 - NEW FINDINGS: What 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. SN - 1469-445X UR - https://www.unboundmedicine.com/medline/citation/29215757/Hypothalamic_paraventricular_nucleus_neuronal_nitric_oxide_synthase_activity_is_a_major_determinant_of_renal_sympathetic_discharge_in_conscious_Wistar_rats_ L2 - https://doi.org/10.1113/EP086744 DB - PRIME DP - Unbound Medicine ER -