title: Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia.
abstract: BACKGROUND
  Experimental hypercholesterolemia is associated with coronary vasomotor dysfunction. This study was designed to test the hypothesis that experimental hypercholesterolemia is characterized by altered coronary vasomotor responses to endothelin and inhibition of the endogenous NO pathway.
  
  
  RESULTS
  Endothelin-1 (ET-1) at 5 ng x kg(-1) x min(-1) or N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthase (NOS), at 50 microg x kg(-1) x min(-1) was infused into the left anterior descending coronary artery in pigs before and after 10 weeks of cholesterol diet. There was a significant increase in serum cholesterol. At 10 weeks, ET-1 resulted in an accentuated decrease in coronary blood flow (CBF) and coronary artery diameter (CAD) compared with baseline (-88+/-6% versus -45+/-9%, P<.05, and -77+/-14% versus -18+/-8%, P<.05, respectively) and an increase in coronary vascular resistance (CVR) (242+/-18% versus 110+/-17%, P<.05); ET receptor density and binding affinity in epicardial coronary arteries were unchanged. The effect of L-NMMA on CBF, CAD, and CVR was attenuated at 10 weeks (-7+/-8% versus -48+/-4%, -2+/-3% versus -17+/-5%, and 16+/-10% versus 125+/-32%; each P<.05). Immunohistochemistry staining for constitutive NOS revealed a decrease in immunoreactivity in the coronary arteries of hypercholesterolemic pigs.
  
  
  CONCLUSIONS
  The present study demonstrates an enhanced coronary vasoconstrictive response to pathophysiological doses of endothelin and an attenuated response to the inhibition of endogenous NO activity, suggesting an alteration in coronary vascular reactivity in experimental hypercholesterolemia.
authors.affiliation: Division of Cardiovascular Diseases and Internal Medicine, Mayo Foundation, Rochester, Minn 55905, USA.
authors.forename: V
authors.initials: V
authors.lastname: Mathew
authors.forename: C R
authors.initials: CR
authors.lastname: Cannan
authors.forename: V M
authors.initials: VM
authors.lastname: Miller
authors.forename: D A
authors.initials: DA
authors.lastname: Barber
authors.forename: D
authors.initials: D
authors.lastname: Hasdai
authors.forename: R S
authors.initials: RS
authors.lastname: Schwartz
authors.forename: D R
authors.initials: DR
authors.lastname: Holmes
authors.forename: A
authors.initials: A
authors.lastname: Lerman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure; D002302:Cardiac Output; D002791:Cholesterol, Dietary / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003331:Coronary Vessels / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism; D013552:Swine; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D017466:Receptors, Endothelin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000109:Acetylcholine