Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

Abstract

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 Ϫ6 to 10 Ϫ4 mol/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: Ϫ41.6%Ϯ10.7%, group 2: Ϫ4.7%Ϯ11.9%, group 3: 11.4%Ϯ7.4%). Conclusions-Chronic

The effect of DA-8159, a novel PDE5 inhibitor, on erectile function in the rat model of hypercholesterolemic erectile dysfunction

“…11 Furthermore, the plasma cholesterol, endothelin and ADMA concentrations were also increased. Similar results have been reported by Best et al 21 and Yu et al 22 In general, it is well known that hypercholesterolemic disease is commonly associated with structural and functional modifications that can take place at the level of the endothelium, the vascular smooth muscle and the extracellular matrix of the blood vessel and/or carvernosal tissue. Therefore, alterations in the endothelium-dependent relaxation might be implicated with ED due to hypercholesterolemia.…”

Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia

“…Female domestic pigs (23 to 35 kg) were fed for 12 weeks with either a normal (nϭ6) or atherogenic (nϭ6) diet of 2% cholesterol and 15% lard (TD-93296, Harlan Teklad). 2 Blood samples were collected after completion of the diet for measurement of plasma cholesterol levels, and the animals were then euthanized with intravenous pentobarbital (20 mL of Sleepaway [Fort Dodge Laboratories]).…”

“…HC is used in experimental animals as a surrogate for early coronary atherosclerosis 1 and is characterized by impaired endothelial function of the epicardial coronary arteries. 2 Even in the absence of overt atherosclerotic changes in the vascular wall, 3 these functional abnormalities are associated with subtle morphological alterations, such as an increase in the density of vasa vasorum in the coronary adventitia. 3 Like the epicardial arteries, the intramyocardial microvessels (diameter Ͻ500 m) may also manifest endothelial dysfunction 4 due to HC and may conceivably undergo alterations similar to those observed in the vasa vasorum microvessels.…”

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

“…79,80 Upregulation of the ET system is thought to have a role in the renal and cardiovascular complications of CKD. Systemic administration of the selective endothelin-type A (ET A ) receptor antagonist, BQ-123, to hypertensive patients with CKD produced a substantial reduction in BP (10 mm Hg) and increased renal blood flow, supporting an upregulation of the ET system in CKD-associated hypertension.…”