McKenna, Charles J.

Background—Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.Methods and Results—Acetylcholine (10−6to 10−4mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: −41.6%±10.7%, group 2: −4.7%±11.9%, group 3: 11.4%±7.4%).Conclusions—Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.

Background —As endothelin binds to ET A receptors, it stimulates vascular smooth muscle cell proliferation and may thus be pivotally involved in the pathogenesis of restenosis. This study assessed the ability of a potent and selective ET A antagonist to reduce neointimal hyperplasia in a porcine coronary artery stented injury model. Methods and Results —Fifty-five pigs were randomized to receive placebo or the oral ET A -selective antagonist ABT147627 twice daily for 28 days in one of three doses: 0.75 mg/kg (low), 3.75 mg/kg (mid), and 10.0 mg/kg (high). Each underwent oversized stent deployment in two randomly assigned major epicardial coronary arteries. Three animals (5.5%) died as a consequence of stent thrombosis within 24 hours of the procedure. The remaining 52 animals (13 pigs per group) survived without complication until predetermined euthanasia at 28 days. In the placebo group, mean injury score was 1.73±0.80, with a mean neointimal response of 0.45±0.24 mm. By comparison, the low-dose group had a similar mean injury score of 1.79±0.75 with reduced neointimal response, 0.36±0.22 mm ( P <0.01). Mean injury score in the mid-dose animals was significantly greater than in the placebo group (1.94±0.92; P <0.05). The neointimal hyperplasia associated with this injury was less than with placebo, although the difference did not reach statistical significance (0.40±0.25 mm; P =0.05). In the high-dose pigs, mean injury score was also significantly greater than in the placebo arm (1.93±0.73; P <0.05). Despite this, neointimal response was also significantly less (0.37±0.37 mm; P <0.01). Conclusions —Oral, selective ET A receptor antagonism significantly reduced neointimal hyperplasia forming over porcine coronary stented injuries in the first 28 days. This strategy may have clinical potential for the limitation and treatment of coronary restenosis after percutaneous revascularization.