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NEUROSCIENCE |
1 Cardiology Research, Royal Perth Hospital Unit, School of Medicine and Pharmacology, The University of Western Australia, GPO Box X2213, Perth 6487 Australia
2 Division of Health Science, Murdoch University, Perth 6150 Australia
The intracellular second messenger, cyclic guanosine monophosphate (cGMP), a soluble guanylate cyclase (GC) product, is a primary mechanism for the transduction of a nitric oxide (NO)-initiated signal in the central nervous system. NO is produced from L-arginine by neuronal nitric oxide synthase (NOS), which is found in sympathetic preganglionic neurons of the intermediolateral cell column. This suggests the possibility that NO is a modulator of sympathetic nervous activity (SNA) through a cGMP-mediated mechanism. The aim of this study was to determine the effects of intrathecally injected membrane-permeant 8-bromo-cGMP and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of the soluble form of GC, on arterial pressure in urethane anaesthetized (1.4 g kg–1 I.P.) rats. The effects of intrathecal cGMP and ODQ on haemodynamic responses to haemorrhage were also investigated. Finally, L-arginine, the NO precursor, was also injected intrathecally, alone and in the presence of ODQ. Baseline mean arterial pressure (MAP) increased significantly after intrathecal 8-Br-cGMP injection (10 µl, 1, 3, 10, 30, 100 µM). A dose–effect relationship (1 µM to 100 µM) was also established (EC50 = 6.03 µM). During continuous haemorrhage, MAP was maintained in animals injected with 8-Br-cGMP, relative to the control group. Although no change in baseline MAP was observed as a result of intrathecal ODQ injection (10 µl, 100 mM), a greater rate of fall in MAP was observed during haemorrhage. Injecting L-arginine (10, 100, 1000 µM, 10 µl) showed a pressor effect that was consistent with the effect of the downstream messenger, cGMP. Furthermore, its pressor effect was blocked by ODQ pre-administration. The results indicate that cGMP increases blood pressure, and thus suggest that cGMP increases SNA. This supports the hypothesis that the sympathoexcitatory effects of spinal delivery of NO are mediated by a cGMP-dependent mechanism.
(Received 13 February 2006;
accepted after revision 1 March 2007;
first published online 8 March 2007)
Corresponding author D. J. McKitrick: Cardiology Research, Level 4, South Block, Royal Perth Hospital, Wellington Street, Perth 6000, Australia. Email: doug.mckitrick{at}uwa.edu.au
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