title: Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography.
abstract: BACKGROUND
  Heterogeneity of resting perfusion may be due in part to up-regulation of coronary vasoconstriction via endothelin (ET) type A receptors, as homogeneity increases during subsequent vasodilatory hyperemia. Therefore, we conducted a mechanistic study using an ET receptor antagonist to determine if it could alter the homogeneity of myocardial perfusion.
  
  
  METHODS
  Included subjects demonstrated a low myocardial perfusion homogeneity index (HI) compared to normal volunteers. Four serial cardiac positron emission tomography Rb-82 scans were performed 2 weeks apart. Before the middle two scans, subjects were randomized to receive either darusentan first then placebo or visa versa. Absolute flow and coronary flow reserve were quantified for each study. Rest flow was adjusted for the pressure-rate product (PRP).
  
  
  RESULTS
  We screened 37 subjects and randomized 20 who satisfied entry criteria. Rest HI increased significantly while taking darusentan (0.39 ± 0.10 vs 0.33 ± 0.04 on placebo, P = .030, compared to a normal range of 0.52 ± 0.10) without an increase in the PRP (6,859 ± 1,503 vs 6,976 ± 1,092, P = .79), leading to a higher adjusted flow at rest (0.69 ± 0.18 cc/minute/g at 7,000 PRP vs 0.59 ± 0.07 with placebo).
  
  
  CONCLUSIONS
  Antagonism of the type A ET receptor increases homogeneity of resting myocardial perfusion. The mechanism appears to be increased absolute rest flow without an increase in either the PRP or myocardial perfusion during hyperemia. Our translational results are consistent with one mechanism for the observed heterogeneity of myocardial perfusion in humans.
authors.affiliation: Weatherhead PET Center For Preventing and Reversing Atherosclerosis, Division of Cardiology, Department of Medicine, University of Texas Medical School and Memorial Hermann Hospital, 6431 Fannin St., Room 4.256 MSB, Houston, TX, 77030, USA, Nils.Johnson@uth.tmc.edu.
authors.forename: Nils P
authors.initials: NP
authors.lastname: Johnson
authors.forename: K Lance
authors.initials: KL
authors.lastname: Gould
mesh_terms: D000368:Aged; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000473:pathology; D018592:Cross-Over Studies; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D055414:Myocardial Perfusion Imaging; D010666:Phenylpropionates / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011312:Pressure; D011743:Pyrimidines / Q000737:chemistry*; D044022:Receptor, Endothelin A / Q000378:metabolism; D012414:Rubidium Radioisotopes; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000737:chemistry
chemical_list: D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; C107831:darusentan