Contribution of endogenous endothelin to large epicardial coronary artery tone in dogs and humans

Nitric oxide (NO) may normally impair endothelin (ET) activity in epicardia l coronary arteries. Lifting this inhibitory feedback could reveal ET-depen dent effects involving ETA- and/or ETB-receptor activation. In conscious do gs, the blockade of ETA receptors (intracoronary Ro-61-1790) increased exte rnal circumflex coronary artery diameter (CD) (sonomicrometry) by 0.10 +/- 0.01 from 3.04 +/- 0.12 mm (P < 0.01) without; altering coronary blood flow (Doppler). Similarly, CD increased (0.09 +/- 0.01 from 2.91 +/- 0.14 mm; P < 0.01) when Ro-61-1790 was given after blockade of NO formation with intr acoronary N-omega-aitro-L-arginine methyl eater (LNAME). In contrast, ETB-r eceptor blockade (intracoronary Ro-46-8443) did not influence baseline CD w ith and without L-NAME. In vitro, increases in tension caused by N-omega-ni tro-L-arginine (L-NNA) or PGF(2 alpha) in arterial rings were reduced by ET A- but not ETB-receptor blockade. ETA-receptor blockade also reduced the! i ncrease in tension caused by L-NNA in human coronary arterial rings. Thus E TA receptors, but not ETB receptors, account for ET-dependent constriction in canine epicardial coronary arteries in vivo. ET-dependent effects were i ndependent of the level of NO formation in vitro and in vivo. In human epic ardial coronary arterial ring, ETA-receptor blockade also caused significan t relaxation.