Endothelium-dependent vasoconstrictions in isolated vessel grafts: a novel mechanism of vasospasms? Running head: Endothelium-dependent vasoconstrictions

Background: YC-1 (3-(5'-hydroxymethyl-2'furyl)-1-benzyl-indazole) is an allosteric activator of soluble guanylyl cyclase (sGC) and a vasodilator. This study describes a paradox action of YC-1 in isolated vessels of coronary artery disease (CAD) patients which appears to trigger an endothelium-dependent vasoconstrictor pathway present in vessels with endothelial dysfunction. Methods: Effects of YC-1 on isolated vessel tensions were investigated in an organ bath. Vasoconstrictors released from vessels were quantified by ELISA. Results: YC-1 elicited long-lasting constrictions in saphenous veins and radial arteries from CAD patients, but not in human umbilical veins. Half-maximal effective dose was 1.0 μmol L. Constrictions were attenuated by nifedipine (L-type Ca channel blocker), bosentan (ETA/ETB inhibitor), BQ-788 (ETB inhibitor), and by denuding, but not by ODQ (sGC inhibitor), BQ-123 (ETA inhibitor), and phosphoramidon (endothelin converting enzyme inhibitor). Indometacin (cyclooxygenase-1/2 inhibitor) and SQ 29,548 (TP receptor antagonist) suppressed YC-1 induced constrictions, whereas 5,5-dimethyl-3-(3-fluorophenyl)-4-(4methylsulphonyl)phenyl-2(5H)-furanone (DFU, cyclooxygenase-2 inhibitor) had no effect. Saphenous vein rings released significantly more endothelin-1 in the presence of YC-1. Conclusions: YC-1 induced vasoconstrictions demonstrate the existence of an endothelium-dependent vasoconstrictor pathway in vessels of CAD patients which to date has only been described in animal models of hypertension. CAD patients with elevated endothelin-1 plasma levels are thus prone to endothelium-dependent vasoconstrictions which may also play a role in graft vasospasms.