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Original Articles: Adult Cardiac

Endothelium-Dependent Vasoconstriction in Isolated Vessel Grafts: A Novel Mechanism of Vasospasm?

Department of Cardiothoracic Surgery, University of Regensburg Medical Center, Regensburg, Germany

Accepted for publication May 31, 2011.

^_* Address correspondence to Dr Hoenicka, Department of Cardiothoracic Surgery, University of Regensburg Medical Center, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany (Email: markus.hoenicka{at}klinik.uni-regensburg.de).

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 Ca²⁺-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.

Related Article

Invited Commentary

Jun Feng
Ann. Thorac. Surg. 2011 92: 1307. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				M. Hoenicka and S. Hirt YC-1 Induced Constrictions: No Dependency on Other Vasoconstrictor Ann. Thorac. Surg., May 1, 2012; 93(5): 1762 - 1762. [Full Text] [PDF]

				J. Feng Reply. Ann. Thorac. Surg., May 1, 2012; 93(5): 1762 - 1762. [Full Text] [PDF]

				J. Feng Invited Commentary Ann. Thorac. Surg., October 1, 2011; 92(4): 1307 - 1307. [Full Text] [PDF]