In vivo gene transfer demonstrates that reduced endothelial nitric oxide synthase activity in the NTS lowers arterial pressure in the spontaneously hypertensive rat

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University of Central Lancashire / University of Liverpool (2002) J Physiol 543P, S008

Communications: In vivo gene transfer demonstrates that reduced endothelial nitric oxide synthase activity in the NTS lowers arterial pressure in the spontaneously hypertensive rat

Hidefumi Waki*†, Ezihe Okwuadigbo*, David Murphy‡, Tsuyoshi Shimizu†, Sergey Kasparov* and Julian F.R. Paton*

*Department of Physiology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, †Department of Physiology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan and ‡University Research Centre for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK

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We demonstrated previously that endogenous endothelial nitric oxide synthase (eNOS) activity in the nucleus tractus solitarii (NTS) depresses baroreceptor reflex gain (BRG) in conscious normotensive rats (Waki et al. 2001). In this study, we investigated whether excessive eNOS activity in the NTS contributes chronically to the blunted baroreceptor reflex gain and sustained levels of arterial pressure found in the spontaneously hypertensive rat (SHR).

A recombinant adenoviral vector driving expression of a dominant negative mutant form of eNOS (so-called TeNOS; Lee et al. 1995) was microinjected bilaterally into the NTS (see Paton et al. 2001, for details) to disable endogenous eNOS activity in the SHR and their progenitor, aged-matched controls Ð Wistar-Kyoto rats (WKY; 10Ð11 weeks old). We used radio-telemetry to acquire arterial pressure data and from this determined the spontaneous baroreceptor reflex gain (BRG) using both spectral analysis and the time-series technique (see Oosting et al. 1997) before, and 1Ð2 weeks following, viral transfection. Both transmitter implantation and transfections were performed under anaesthesia using ketamine (60 mg kg-1) and medetomidine (250 mg kg-1) given I.M. and reversed with a subcutaneous injection of atipamezole (1 mg kg-1). Control rat groups consisted of NTS microinjection of an adenovirus that expressed enhanced green fluorescent protein (eGFP). Student’s paired t test was used for statistical analysis and results were expressed as means ± S.E.M.

After TeNOS transfection in the SHR, BRG measured by both spectral analysis and time-series techniques significantly increased (time-series technique: from 1.00 ± 0.12 to 1.58 ± 0.26 ms mmHg-1, n = 4, P < 0.05; spectral analysis: from 1.23 ± 0.18 to 3.03 ± 0.67 ms mmHg-1, n = 4, P < 0.05) while mean arterial pressure (MAP) and HR significantly decreased (MAP: from 118 ± 4 to 108 ± 4 mmHg, n = 4, P < 0.01; HR: from 310 ± 8 to 259 ± 19, n = 4, P < 0.05). There was no significant alteration in any of the cardiovascular variables measured in the eGFP-transfected SHR (n = 5) but in the TeNOS-transfected WKY (n = 5), BRG increased, HR decreased and there was no change in MAP.

Our results indicate that endogenous eNOS activity in the NTS plays a major role in determining levels of arterial pressure, HR and BRG in pathological hypertension. Further, they demonstrate that restoring transmission of the baroreceptor reflex at the level of the NTS may help to normalize blood pressure.

British Heart Foundation and Japan Space Forum funded this research.

All procedures accord with current UK legislation.

Where applicable, experiments conform with Society ethical requirements.

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