Interactions Between Nitric Oxide and Other NANC Inhibitory Neurotransmitters in the Periphery: Clues from the Endothelium

Abstract

From the beginning of the story of endothelium-dependent vasodilatation, another equally intriguing search was in progress for the identity of an inhibitory neurotransmitter released from certain nonadrenergic, noncholinergic (NANC) nerves innervating smooth muscle in the lower regions of the gut. Thus, it was perhaps of no surprise that when the endothelium-derived relaxing factor (EDRF) was identified as nitric oxide (NO), the NANC inhibitory factor in the gut was also proposed to be NO. Also not surprising was the realization that not all non-prostanoid-mediated, endothelium-dependent dilatation in the vasculature was due to NO. Another mechanism was known to occur in response to many endothelium-dependent vasodilators, that being smooth muscle hyperpolarization, and it soon became apparent that this was due to the release of a factor called endothelium-derived hyperpolarizing factor (EDHF). Given the parallel histories of endothelial cells and NANC inhibitory nerves as to how they signal smooth muscle cells to relax, it was a logical step to determine whether a similar non-NO hyperpolarizing factor was released with NO from NANC nerves. Furthermore, if there was such a factor, clues as to the identity of both it and EDHF might arise from further comparison of these systems. Therefore, in this chapter we hope to provoke new thought and discussion related to mechanisms of NANC nerve-mediated relaxation of gut smooth muscle. The link with endothelial cells will remain a strong theme, given the evolving similarities between NANC neurotransmission and endothelial cell “endotransmission.”