ACUTE ENDOTHELIN-RECEPTOR INHIBITION DOES NOT ATTENUATE ACETYLCHOLINE-INDUCED CORONARY VASOCONSTRICTION IN EXPERIMENTAL HYPERCHOLESTEROLEMIA

Endothelin (ET) may mediate the enhanced coronary vasoconstriction ass ociated with hypercholesterolemia, We hypothesized that short-term inh ibition of ET receptors attenuates the coronary epicardial vasoconstri ctor response to acetylcholine in experimental hypercholesterolemia. E T-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 ri gs, ET-1 and acetylcholine were also infused with the specific ETA-rec eptor blocker FR-139317 (5 mu g.kg(-1).min(-1); group II, n=6; group I V, 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). Th e ETB-receptor agonist sarafotoxin 6c (5 ng.kg(-1).min(-1); n=4) was a lso 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%, respectivel y). FR-130317 did not attenuate the epicardial vasoconstrictor respons e 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 gro up I versus -14+/-6% for group II; P<.05). FR-139317 did not affect th e response to acetylcholine at baseline (%Delta CAD 5+/-2% for group I II 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-te rm ET-receptor inhibition in experimental hypercholesterolemia attenua ted the enhanced coronary epicardial vasoconstrictor effects of ET-1 b ut not acetylcholine-induced coronary epicardial vasoconstriction, sug gesting that acetylcholine-induced coronary epicardial vasoconstrictio n may not be mediated by ET receptors.