TY - JOUR
T1 - Enhanced endothelin-B-receptor-mediated vasoconstriction of small porcine coronary arteries in diet-induced hypercholesterolemia
AU - Hasdai, David
AU - Mathew, Verghese
AU - Schwartz, Robert S.
AU - Smith, Leslie A.
AU - Holmes, David R.
AU - Katusic, Zvonimir S.
AU - Lerman, Amir
PY - 1997
Y1 - 1997
N2 - The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (<481±25 μm in diameter) to cumulative concentrations (10-10 to 10-6 mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86±7% versus 47±7%, P=.001) and hypercholesterolemic (77±6% versus 37±7%, P<.001) pigs. At 10-10 mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23±6% versus 8±3%, P=.02) and S6c (17±5% versus 4±2%, P=.02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR- 139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10-10 mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.
AB - The coronary vasoconstrictor effects of endothelins, mediated by both endothelin ETA and ETB receptors, may be differentially altered in pathophysiological states associated with endothelial dysfunction and elevated endothelin levels. Experimental hypercholesterolemia is associated with coronary endothelial dysfunction and increased circulating endothelin concentrations. These studies were designed to test the hypothesis that experimental hypercholesterolemia is characterized by a differentially altered coronary contractile response to ETA- and ETB-receptor stimulation, in vitro. Pigs were fed either a normal or a high-cholesterol diet for 10 to 13 weeks. Changes in the intraluminal diameter of pressurized small coronary arteries (<481±25 μm in diameter) to cumulative concentrations (10-10 to 10-6 mol/L) of endothelin-1 (ET-1), and sarafotoxin 6c (S6c), a specific ETB-receptor agonist, were measured using a video dimension analyzer. The maximal contraction attained with ET-1 was greater than with S6c in both normal (86±7% versus 47±7%, P=.001) and hypercholesterolemic (77±6% versus 37±7%, P<.001) pigs. At 10-10 mol/L, vessels from hypercholesterolemic pigs manifested greater contraction to both ET-1 (23±6% versus 8±3%, P=.02) and S6c (17±5% versus 4±2%, P=.02). Incubation of arteries from hypercholesterolemic pigs with BQ-788 (ETB-receptor antagonist), but not FR- 139317 (ETA-receptor antagonist), altered the contractile response to ET-1 at 10-10 mol/L. Removal of the endothelium abolished the difference in response to S6c between normal and hypercholesterolemic pigs. These studies demonstrate that experimental hypercholesterolemia is characterized by enhanced coronary vasoconstriction to endothelins in vitro, the mechanism of which is mediated mainly through the ETB receptor. Thus, the ETB receptor has a role in regulation of coronary artery tone in both the steady-state and pathophysiological states.
KW - Endothelin
KW - Endothelium
KW - Hypercholesterolemia
KW - Pigs
KW - Receptors
KW - Sarafotoxin
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U2 - 10.1161/01.ATV.17.11.2737
DO - 10.1161/01.ATV.17.11.2737
M3 - Article
C2 - 9409250
AN - SCOPUS:0031439532
SN - 1079-5642
VL - 17
SP - 2737
EP - 2743
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 11
ER -