title: Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: role of bradykinin.
abstract: OBJECTIVE
  We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts.
  
  
  BACKGROUND
  Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts.
  
  
  METHODS
  In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery.
  
  
  RESULTS
  Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF.
  
  
  CONCLUSIONS
  The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.
authors.affiliation: Cardiovascular Division of Internal Medicine, National Cardiovascular Center, Osaka University Graduate School of Medicine, Suita, Japan. kitakaze@zf6.so-net.ne.jp
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Funaya
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ogita
authors.forename: Jiyoong
authors.initials: J
authors.lastname: Kim
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D013841:Thiazepines; D000804:Angiotensin II; C069156:temocaprilat; D009569:Nitric Oxide; C065679:icatibant; C437965:olmesartan; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester