dinoprost and clazosentan

Nitric oxide (NO) may normally impair endothelin (ET) activity in epicardial coronary arteries. Lifting this inhibitory feedback could reveal ET-dependent effects involving ET(A)- and/or ET(B)-receptor activation. In conscious dogs, the blockade of ET(A) receptors (intracoronary Ro-61-1790) increased external 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 intracoronary N(omega)-nitro-L-arginine methyl ester (L-NAME). In contrast, ET(B)-receptor blockade (intracoronary Ro-46-8443) did not influence baseline CD with and without L-NAME. In vitro, increases in tension caused by N(omega)-nitro-L-arginine (L-NNA) or PGF(2alpha) in arterial rings were reduced by ET(A)- but not ET(B)-receptor blockade. ET(A)-receptor blockade also reduced the increase in tension caused by L-NNA in human coronary arterial rings. Thus ET(A) receptors, but not ET(B) receptors, account for ET-dependent constriction in canine epicardial coronary arteries in vivo. ET-dependent effects were independent of the level of NO formation in vitro and in vivo. In human epicardial coronary arterial rings, ET(A)-receptor blockade also caused significant relaxation.

Topics: Animals; Arteries; Coronary Vessels; Dinoprost; Dioxanes; Dogs; Endothelin Receptor Antagonists; Endothelins; Enzyme Inhibitors; Humans; In Vitro Techniques; NG-Nitroarginine Methyl Ester; Nitroarginine; Pericardium; Pyridines; Pyrimidines; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Tetrazoles; Vasoconstriction; Vasomotor System