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 paradoxical action of YC-1 in isolated vessels of patients with coronary artery disease (CAD) that appears to trigger an endothelium-dependent vasoconstrictor pathway present in vessels with endothelial dysfunction. METHODS: Effects of YC-1 on the tensions of isolated vessels were investigated in an organ bath. Vasoconstrictors released from the vessels were quantified through enzyme-linked immunosorbent assay. RESULTS: YC-1 elicited long-lasting constriction in saphenous veins and radial arteries from patients with CAD, but not in human umbilical veins. The half-maximal effective dose was 1.0 μmol/L. Constriction was attenuated by nifedipine (an L-type Ca(2+)-channel blocker), bosentan (an endothelin [ET](A)/ET(B) inhibitor), BQ-788 (N-[(cis-2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-D-norleucine; an ET(B) inhibitor), and by denuding, but not by ODQ (1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one; an inhibitor of sGC), BQ-123 (cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu); an ET(A) inhibitor), or phosphoramidon (an endothelin converting enzyme inhibitor). Indomethacin (an inhibitor of cyclooxygenase-1 and -2) and SQ29,548 ([1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; a thromboxane receptor antagonist) suppressed YC-1-induced constriction, whereas DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; a cyclooxygenase-2 inhibitor) had no effect. Rings of saphenous vein released significantly more endothelin-1 in the presence than in the absence of YC-1. CONCLUSIONS: YC-1-induced vasoconstriction demonstrates the existence of an endothelium-dependent vasoconstrictor pathway in the blood vessels of patients with CAD that to date has been described only in animal models of hypertension. Patients with CAD who have elevated plasma levels of endothelin-1 are thus prone to endothelium-dependent vasoconstriction, which may also play a role in vasospasm in vascular grafts.
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 paradoxical action of YC-1 in isolated vessels of patients with coronary artery disease (CAD) that appears to trigger an endothelium-dependent vasoconstrictor pathway present in vessels with endothelial dysfunction. METHODS: Effects of YC-1 on the tensions of isolated vessels were investigated in an organ bath. Vasoconstrictors released from the vessels were quantified through enzyme-linked immunosorbent assay. RESULTS:YC-1 elicited long-lasting constriction in saphenous veins and radial arteries from patients with CAD, but not in human umbilical veins. The half-maximal effective dose was 1.0 μmol/L. Constriction was attenuated by nifedipine (an L-type Ca(2+)-channel blocker), bosentan (an endothelin [ET](A)/ET(B) inhibitor), BQ-788 (N-[(cis-2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-D-norleucine; an ET(B) inhibitor), and by denuding, but not by ODQ (1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-one; an inhibitor of sGC), BQ-123 (cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu); an ET(A) inhibitor), or phosphoramidon (an endothelin converting enzyme inhibitor). Indomethacin (an inhibitor of cyclooxygenase-1 and -2) and SQ29,548 ([1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; a thromboxane receptor antagonist) suppressed YC-1-induced constriction, whereas DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; a cyclooxygenase-2 inhibitor) had no effect. Rings of saphenous vein released significantly more endothelin-1 in the presence than in the absence of YC-1. CONCLUSIONS:YC-1-induced vasoconstriction demonstrates the existence of an endothelium-dependent vasoconstrictor pathway in the blood vessels of patients with CAD that to date has been described only in animal models of hypertension. Patients with CAD who have elevated plasma levels of endothelin-1 are thus prone to endothelium-dependent vasoconstriction, which may also play a role in vasospasm in vascular grafts.