Proceedings of The Physiological Society

University of York (2002) J Physiol 539P, S005


Selective neuronal nitric oxide synthase inhibition reduces renal sympathetic nerve activity and heart rate in conscious rats

Donogh F. McKeogh and Virginia L. Brooks

Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, Oregon 97201, USA

Numerous lines of evidence support the theory that nitric oxide (NO) is a non-conventional neurotransmitter involved in the central regulation of the autonomic nervous system (Krukoff, 1999). NO can be produced within central autonomic ganglia both by neuronal and endothelial isoforms of nitric oxide synthase (NOS; Paton et al. 2001); however, whether NO from either of these sources is involved in the generation of basal sympathetic tone in conscious, intact animals is uncertain. In the present study we tested the hypothesis that NO produced by neuronal NOS contributes to the generation of basal sympathetic tone in conscious animals by determining the effect of selective neuronal NOS inhibition on renal sympathetic nerve activity (RSNA) in conscious, unrestrained rats.

Experiments were performed in accordance with the Guidelines of the National Institutes of Health, after local ethics committee approval. Sprague-Dawley rats (Rattus norvegicus) were anaesthetized with sodium pentobarbitone (60 mg kg-1 I.P.) and underwent surgery to place an intraperitoneal catheter, a renal nerve electrode, and femoral arterial and venous lines. After recovery overnight, the selective neuronal NOS inhibitor 7-nitroindazole (7-NI), 50 mg kg-1 (10 mg ml-1 in arachis oil), or vehicle, was administered I.P., and heart rate (HR), blood pressure (BP), and RSNA were monitored continuously for 90 min. Animals were killed at the end of the experiment with an overdose of barbiturate. Group mean (± S.E.M.) values were determined at 15 min intervals, and two-way ANOVA, with Tukey-Kramer post-hoc analysis, was used to examine for differences between the effects of 7-NI and vehicle alone over time.

A statistically significant fall in RSNA occurred within 15 min following administration of 7-NI, and by 90 min RSNA had fallen to 36 ± 5 % of the baseline level (n = 5; P < 0.01). A profound bradycardia also occurred, from 445 ± 27 beats min-1 at baseline to 281 ± 14 beats min-1 at 90 min (n = 6; P < 0.01); the fall in heart rate achieved statistical significance 30 min following 7-NI administration. A transient rise in BP, from 108 ± 2 mmHg at baseline to 122 ± 3 mmHg, occurred 15 min following 7-NI (n = 6; P < 0.01), but BP returned to baseline by 30 min post-drug administration, and remained at that level thereafter. In contrast to these changes seen in the intervention group, no significant change in RSNA, HR or BP occurred in the vehicle-treated group (n = 5).

These findings support the hypothesis that NO derived from neuronal NOS contributes to the generation of basal renal sympathetic tone in conscious, unrestrained rats.

This study was supported by the American Heart Association.

Where applicable, experiments conform with Society ethical requirements