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Intrathecal cGMP elicits pressor responses and maintains mean blood pressure during haemorrhage in anaesthetized rats

Journal Article


Abstract


  • 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 μ m 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.

Authors


  •   Malik, Varun (external author)
  •   Holobotovskyy, Vasyl (external author)
  •   Phillips, Jacqueline K. (external author)
  •   McKitrick, Douglas J. (external author)
  •   Arnolda, Leonard F.

Publication Date


  • 2007

Citation


  • Malik, V., Holobotovskyy, V. V., Phillips, J. K., McKitrick, D. J. & Arnolda, L. F. (2007). Intrathecal cGMP elicits pressor responses and maintains mean blood pressure during haemorrhage in anaesthetized rats. The Journal of Physiology, 581 (2), 543-552.

Scopus Eid


  • 2-s2.0-34249689995

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/808

Number Of Pages


  • 9

Start Page


  • 543

End Page


  • 552

Volume


  • 581

Issue


  • 2

Abstract


  • 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 μ m 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.

Authors


  •   Malik, Varun (external author)
  •   Holobotovskyy, Vasyl (external author)
  •   Phillips, Jacqueline K. (external author)
  •   McKitrick, Douglas J. (external author)
  •   Arnolda, Leonard F.

Publication Date


  • 2007

Citation


  • Malik, V., Holobotovskyy, V. V., Phillips, J. K., McKitrick, D. J. & Arnolda, L. F. (2007). Intrathecal cGMP elicits pressor responses and maintains mean blood pressure during haemorrhage in anaesthetized rats. The Journal of Physiology, 581 (2), 543-552.

Scopus Eid


  • 2-s2.0-34249689995

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/808

Number Of Pages


  • 9

Start Page


  • 543

End Page


  • 552

Volume


  • 581

Issue


  • 2