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 [center dot] kg [center dot] min) and acetylcholine (group III, n = 7; 10 to 10 mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 micro gram [center dot] kg [center dot] min (); 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 [center dot] kg [center dot] h, group V, n = 5). The ETB-receptor agonist sarafotoxin 6c (5 ng [center dot] kg [center dot] min; 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 in all animals. Sarafotoxin 6c mildly reduced %Delta CAD at baseline and 10 weeks (-10 +/- 2% and -12 +/- 3%, respectively). FR-139317 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 group III versus -19 +/- 7% for group 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. (Arterioscler Thromb Vasc Biol. 1998;18:108-113.)