Physiological antagonism of endothelin‐1 in human conductance and resistance coronary artery

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 – 30 μ M ), atrial (ANP), brain (BNP) and C‐type (CNP) natriuretic peptide (0.1 – 300 n M ), to reverse endothelin‐1 (ET‐1; 10 n M ) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET‐1 (0.1 – 300 n M ) constricted resistance CA more potently than conductance CA ( P <0.05; EC 50 values 2.98 n M (95% CI: 1.49 – 5.95 n M and 8.58 (4.72 – 15.6 n M ) respectively)). The NO‐donor diethylamine NONOate fully reversed the ET‐1 constriction in conductance CA (E MAX 127±9.16%), however only partial reversal was observed in resistance CA (E MAX 78.8±8.13; P <0.05). The soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (100 μ M ) reduced the maximum response to diethylamine NONOate to 76.9±14.4% in conductance CA ( P <0.05), but had no effect on resistance CA (E MAX 77.2±18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC 50 values 4.25 n M (0.84 – 21.4 n M ) and 18.4 n M (2.92 – 116 n M ), E MAX 53.1±14.7% and 48.6±11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC 50 value was 2.4 n M (0.74 – 7.75 n M ), E MAX 54.5±14.9%. Concentration‐response curves to BNP were incomplete in resistance CA. Concentration‐response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET‐1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET‐1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.British Journal of Pharmacology (2001) 133 , 568–574; doi: 10.1038/sj.bjp.0704119