Acute endothelin-receptor inhibition does not attenuate acetylcholine-induced coronary vasoconstriction in experimental hypercholesterolemia

Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia, We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, n=5; 5 ng.kg(-1).min(-1)) and acetylcholine (group III n=7; 10(-6) to 10(-4) mol/L) were given by intracoronary infusion in rigs, ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 mu g.kg(-1).min(-1); group II, n=6; group IV, n=6), Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg.kg(-1).h(-1), group V, n=5). The ETB-receptor agonist sarafotoxin 6c (5 ng.kg(-1).min(-1); n=4) was also infused. The percentage change in coronary artery diameter (%Delta CAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet ill all animals. Sarafotoxin 6c mildly reduced %Delta CAD at baseline and 10 weeks (-10+/-2% and -12+/-3%, respectively). FR-130317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%Delta CAD -18+/-8% for group I versus -12+/-6% for group II; P=NS) but did at 10 weeks (%Delta CAD -77+/-14% for group I versus -14+/-6% for group II; P<.05). FR-139317 did not affect the response to acetylcholine at baseline (%Delta CAD 5+/-2% for group III versus 7+/-3% for group IV, P=NS) or at 10 weeks (%Delta CAD -23+/-12% for sour III versus -19+/-7% for soup IV; P=NS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. Short-term ET-receptor inhibition in experimental hypercholesterolemia attenuated the enhanced coronary epicardial vasoconstrictor effects of ET-1 but not acetylcholine-induced coronary epicardial vasoconstriction, suggesting that acetylcholine-induced coronary epicardial vasoconstriction may not be mediated by ET receptors.