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

David Hasdai, Patricia J.M. Best, Charles R. Cannan, Verghese Mathew, Robert S. Schwartz, David R. Holmes, Amir Lerman

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR- 139317 (5 μg · 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 (%ΔCAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %ΔCAD 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 (%ΔCAD -18 ± 8% for group I versus -12 ± 6% for group II; P=NS) but did at 10 weeks (%ΔCAD -77 ± 14% for group I versus -14 ± 6% for group II; P<.05). FR-139317 did not affect the response to acetylcholine at baseline (%ΔCAD 5 ± 2% for group III versus 7 ± 3% for group IV, P=NS) or at 10 weeks (%ΔCAD -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.

Original languageEnglish (US)
Pages (from-to)108-113
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume18
Issue number1
DOIs
StatePublished - Jan 1 1998

Keywords

  • Acetylcholine
  • Endothelin
  • Endothelin receptor
  • Hypercholesterolemia
  • Pig

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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