Nitric oxide‐mediated modulation of the endothelin‐1 signalling pathway in the human cardiovascular system

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Abstract
We studied the ability of nitric oxide (NO) to physiologically antagonize endothelin‐1 (ET‐1) induced constrictions in human internal mammary artery (IMA). We also investigated the hypothesis that NO interacts directly with ET‐receptor binding in human heart and aorta. ET‐1 potently contracted IMA (EC50 6.86 nM, 95% CI: 3.5 – 13.4 nM; n=12). The constrictor response to 10 nM ET‐1 was fully reversed by the NO‐donor diethylamine NONOate (DEA/NO; EC50 2.0 μM, 95% CI: 0.8 – 4.8 μM; n=5). The guanylate cyclase inhibitor ODQ (100 μM) reduced the response to DEA/NO but did not abolish it (EMAX 50.9±8.5% in the presence of ODQ; 113.0±8.4%, control). The increase in cyclic GMP by 30 μM DEA/NO was abolished in the presence of 100 μM ODQ (n=6). In saturation binding experiments the NO‐donor Diethyltriamine NONOate (DETA/NO; 1 mM) caused a 90% reduction in maximum binding of [125I]‐ET‐1 in human heart, without affecting the affinity. This reduction in binding was abolished by haemoglobin. Pre‐incubating either the radiolabel or the tissue with NO‐donors did not reduce binding. A similar effect was observed in aortic smooth muscle. We have shown that DEA/NO is able to reverse ET‐1‐induced contractions in the human vasculature. The binding studies suggest a direct interaction between NO and the ET receptor or receptor‐ligand complex in human ventricular and aortic tissue. NO is released continuously in vivo, thus this apparent modification of ET‐receptor binding may provide an additional mechanism by which NO counter‐balances the effects of ET. British Journal of Pharmacology (2001) 132, 213–220; doi:10.1038/sj.bjp.0703834