Endothelin-1 is a key mediator of coronary vasoconstriction in patients with transplant coronary arteriosclerosis.
BACKGROUND
Transplant coronary arteriosclerosis (TCA) is the principal long-term complication in cardiac transplant recipients. The mediators responsible for vascular proliferation and vasoconstriction typical of TCA remain largely unknown. We tested whether endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, contributes to the pathogenesis and manifestations of TCA.


RESULTS
BQ-123, an ET-1 receptor-A antagonist, was infused into a coronary artery (40 nmol/min for 60 minutes) of 18 subjects, 6 + or - 4 years after transplantation. Vasomotor responses were measured in the infused artery and in a noninfused control artery in patients with (n=10) and without (n=8) advanced TCA (108 total coronary segments). Changes in diameters were compared at 15-minute intervals up to 60 minutes. Contribution of ET-1 to coronary constrictor tone was assessed by comparing vasodilation from BQ-123 with that of the maximal vasodilator nitroglycerin (200-microg intracoronary bolus). BQ-123 dilated coronary arteries of transplanted patients (8.4% at 60 minutes versus -0.4% in noninfused arteries, P<0.001). Dilation was greater for arteries with advanced TCA defined as diameter stenosis > or = 15% (dilation 15.2% with versus 0.6% without advanced TCA, P=0.004). Judged against the response to nitroglycerin, ET-1 accounted for 53.2% of coronary tone in advanced TCA but only 12.9% without advanced TCA.


CONCLUSIONS
This study shows for the first time in humans that ET-1 is an important mediator of coronary vasoconstriction in TCA and accounts for >50% of the increased vasomotor tone. Therapeutic targeting of ET-1 may retard the development of TCA.
Larose
Eric
E
Multidisciplinary Department of Cardiology, Quebec Heart and Lung Institute at Laval Hospital and Laval University, Quebec, Canada.
Behrendt
Dominik
D
Kinlay
Scott
S
Selwyn
Andrew P
AP
Ganz
Peter
P
Fang
James C
JC
D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003326:Coronary Circulation; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; C072247:cyclo(Trp-Asp-Pro-Val-Leu)