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 x kg[-1] x min[-1]) and acetylcholine (group III, n=7; 10[-6] to 10[-4] 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 microg x kg[-1] x 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 x kg[-1] x h[-1], group V, n=5). The ETB-receptor agonist sarafotoxin 6c (5 ng x kg[-1] x min[-1]; n=4) was also infused. The percentage change in coronary artery diameter (%deltaCAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %deltaCAD 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 (%deltaCAD -18+/-8% for group I versus -12+/-6% for group II; P=NS) but did at 10 weeks (%deltaCAD -77+/-14% for group I versus -14+/-6% for group II; P<.05). FR-139317 did not affect the response to acetylcholine at baseline (%deltaCAD 5+/-2% for group III versus 7+/-3% for group IV, P=NS) or at 10 weeks (%deltaCAD -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.
Hasdai
D
D
Division of Internal Medicine and Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn. 55905, USA.
Best
P J
PJ
Cannan
C R
CR
Mathew
V
V
Schwartz
R S
RS
Holmes
D R
DR
Lerman
A
A
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002784:Cholesterol / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D004036:Diet, Atherogenic; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000959:Antihypertensive Agents; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C079574:FR 139317; D002784:Cholesterol; D000109:Acetylcholine; D000077300:Bosentan