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The use of exogenous nitric oxide (NO) has been shown to alter the regulation of other endothelially- derived mediators of vascular tone, such as endothelin-1 (ET-1). However, the interaction between NO and ET-1 appears to be complex and remains incompletely understood. One of the major actions of NO is the activation of soluble guanylate cyclase (sGC) with the subsequent generation of cyclic GMP (cGMP). Therefore, we undertook this study to test the hypothesis that NO regulates ET-1 production via the activation of the sGC/cGMP pathway. The results obtained indicated that the exposure of primary cultures of four-week-old ovine pulmonary arterial endothelial cells (4wkPAECs) to the long acting nitric oxide donor DETA NONOate induced both a dose- and time-dependent decrease in secreted ET-1. This decrease in ET-1 secretion occurred in the absence of changes in endothelin converting enzyme-1 or sGC expression but in conjunction with a decrease in preproendothelin-1 mRNA. The changes in ET-1 release were inversely proportional to the cellular cGMP content. Further, the NO-independent activator of sGC, YC-1, or treatment with a cGMP analogue, also produced significant decreases in ET-1 secretion. Conversely, pretreatment with the sGC inhibitor, ODQ blocked the NO induced decrease in ET-1. Therefore, we conclude that exposure of 4wkPAECs to exogenous NO decreases secreted endothelin-1 due to the activation of soluble guanylate cyclase and increased cGMP generation.
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