TY - JOUR
T1 - Endothelin type A receptor antagonism restores myocardial perfusion response to adenosine in experimental hypercholesterolemia
AU - Bonetti, Piero O.
AU - Best, Patricia J.M.
AU - Rodriguez-Porcel, Martin
AU - Holmes, David R.
AU - Lerman, Lilach O.
AU - Lerman, Amir
N1 - Funding Information:
This work was supported by the Northland Affiliate of the American Heart Association (grant 9960336Z), National Institute of Health grants HL-63282 and HL-63911, Miami Heart Research Institute, Margarete und Walther Lichtenstein Stiftung Basel, Switzerland, Freiwillige Akademische Gesellschaft Basel, Switzerland, and the Mayo Foundation. Additionally, we would like to thank Abbott Laboratories for providing ABT-627.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - Experimental hypercholesterolemia is characterized by increased endothelin-1 (ET-1) activity and is associated with an attenuated myocardial perfusion response and an inappropriate increase in coronary microvascular permeability during episodes of increased myocardial demand. This study was designed to determine the effect of chronic selective ET type A (ETA) receptor antagonism on coronary vascular response to simulated cardiac stress in experimental hypercholesterolemia. Twenty-one pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC), and HC diet plus ABT-627, a selective ETA receptor antagonist, (HC+ABT-627). After 12 weeks, cardiac electron beam computed tomography (EBCT) was performed before and during intravenous infusion of adenosine, and myocardial perfusion (ml/min per g) and coronary microvascular permeability index (arbitrary units) were calculated. Basal myocardial perfusion was similar in all groups (N: 0.91±0.10; HC: 0.95±0.08; HC+ABT-627: 1.03±0.09; P=0.64). Adenosine infusion led to a significant increase in myocardial perfusion in the N (1.32±0.15; P<0.001) but not in the HC (0.95±0.07) group. However, in the HC+ABT-627 group, adenosine also significantly increased myocardial perfusion (1.33±0.12; P=0.001). Basal permeability index did not differ between the groups (N: 1.56±0.13; HC: 1.34±0.19; HC+ABT-627: 1.62±0.10; P=0.38). Adenosine infusion significantly increased permeability index in HC pigs (2.29±0.22; P<0.001) but not in N (1.71±0.21) and HC+ABT-627 (1.82±0.08) pigs. We conclude that chronic selective ETA receptor antagonism preserves myocardial perfusion response and coronary microvascular integrity during episodes of increased myocardial demand in experimental hypercholesterolemia, indicating an important role for the endogenous endothelin system in this disorder.
AB - Experimental hypercholesterolemia is characterized by increased endothelin-1 (ET-1) activity and is associated with an attenuated myocardial perfusion response and an inappropriate increase in coronary microvascular permeability during episodes of increased myocardial demand. This study was designed to determine the effect of chronic selective ET type A (ETA) receptor antagonism on coronary vascular response to simulated cardiac stress in experimental hypercholesterolemia. Twenty-one pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC), and HC diet plus ABT-627, a selective ETA receptor antagonist, (HC+ABT-627). After 12 weeks, cardiac electron beam computed tomography (EBCT) was performed before and during intravenous infusion of adenosine, and myocardial perfusion (ml/min per g) and coronary microvascular permeability index (arbitrary units) were calculated. Basal myocardial perfusion was similar in all groups (N: 0.91±0.10; HC: 0.95±0.08; HC+ABT-627: 1.03±0.09; P=0.64). Adenosine infusion led to a significant increase in myocardial perfusion in the N (1.32±0.15; P<0.001) but not in the HC (0.95±0.07) group. However, in the HC+ABT-627 group, adenosine also significantly increased myocardial perfusion (1.33±0.12; P=0.001). Basal permeability index did not differ between the groups (N: 1.56±0.13; HC: 1.34±0.19; HC+ABT-627: 1.62±0.10; P=0.38). Adenosine infusion significantly increased permeability index in HC pigs (2.29±0.22; P<0.001) but not in N (1.71±0.21) and HC+ABT-627 (1.82±0.08) pigs. We conclude that chronic selective ETA receptor antagonism preserves myocardial perfusion response and coronary microvascular integrity during episodes of increased myocardial demand in experimental hypercholesterolemia, indicating an important role for the endogenous endothelin system in this disorder.
KW - Endothelin
KW - Endothelin receptor antagonism
KW - Hypercholesterolemia
KW - Microvascular permeability
KW - Myocardial perfusion
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U2 - 10.1016/S0021-9150(03)00141-2
DO - 10.1016/S0021-9150(03)00141-2
M3 - Article
C2 - 12801621
AN - SCOPUS:0038511358
SN - 0021-9150
VL - 168
SP - 367
EP - 373
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -