Nerve-induced release of nitric oxide in gastrointestinal and erectile tissue

Nitric oxide (NO) is an important messenger of the autonomic nervous system, innervating the gastrointestinal and urogenital tracts among many other tissues. The aim of the present thesis was to study the nitrergic neurotransmission in enteric and erectile tissue with special emphasis on modulation of nitrergic neurotransmission by the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)-pathway.

In organ bath experiments electrical stimulation of autonomic neurons in the guinea pig colon elicited relaxations. This inhibitory response was partly mediated via release of NO from nitrergic neurons. The nitrergic response was solely mediated by stimulation of the sGC/cGMPpathway and NO did not exert any cGMP-independent effects. Apart from NO, there is an additional inhibitory component activated by electrical field stimulation. This component is earlier in onset than NO and utilises a cGMP-independent pathway.

The nerve-induced release of NO from guinea pig colon was quantified. The release was modulated by cGMP mimicking or modulating compounds in a positive fashion. This suggests that the sGC/cGMP-pathway exerts an enhancing effect on the formation or release of No from autonomic neurons.

In addition, the release of NO from rabbit corpus cavernosum was quantified. In the erectile tissue the evoked NO release originated from the neurons and was enzymatically formed. Neither cholinergic nor adrenergic blockage altered the neuronal release of NO, indicating that cholinergic and adrenergic neurons do not influence the nitrergic neurotransmission in erectile tissue. As in the enteric tissue, cGMP mimicking or modulating substances influenced the evoked release of NO in a positive manner, indicating that the sGC/cGMP-pathway is altering the nerveinduced release of NO in the erectile tissue. Taken together with the results from guinea pig colon, this suggests that the proposed positive feedback by cGMP might be a general phenomenon.

Selective inhibitors of phosphodiesterase (PDE) 5 elevate cGMP in tissues and are widely used in treatment of male erectile dysfunction. Application of selective PDE 5 inhibitors to the rabbit corpus cavernosum diminished the evoked release of NO by all three PDE 5 inhibitors used, and is in contrast to the increased release of NO by exogenous cGMP. This suggests that selective PDE 5 inhibitors exhibit an effect different from one raising the overall tissue levels of cGMP and suggests that cGMP effects in the neurotransmission are multiple and compartmentalized.

In conclusion, the present studies provide evidence that the sGC/cGMP-pathway is altering the release of NO from autonomic neurons in gastrointestinal and erectile tissue.

List of scientific papers

I. Olgart C, Hallen K, Wiklund NP, Iversen HH, Gustafsson LE (1998). Blockade of nitrergic neuroeffector transmission in guinea-pig colon by a selective inhibitor of soluble guanylyl cyclase. Acta Physiol Scand. 162(1): 89-95.
https://pubmed.ncbi.nlm.nih.gov/9492906

II. Hallen K, Olgart C, Gustafsson LE, Wiklund NP (2001). Modulation of neuronal nitric oxide release by soluble guanylyl cyclase in guinea pig colon. Biochem Biophys Res Commun. 280(4): 1130-4.
https://pubmed.ncbi.nlm.nih.gov/11162644

III. Hallen K, Gustafsson LE, Wiklund NP (2004). Nerve-induced release of nitric oxide from the rabbit corpus cavernosum is modulated by cyclic GMP. [Submitted]

IV. Hallen K, Wiklund NP, Gustafsson LE (2004). PDE 5 inhibitors influence the nerve-induced release of nitric oxide from the rabbit corpus cavernosum. [Submitted]