Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers synergistically increase coronary blood flow in canine ischemic myocardium: role of bradykinin.
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.
Kitakaze
Masafumi
M
Cardiovascular Division of Internal Medicine, National Cardiovascular Center, Osaka University Graduate School of Medicine, Suita, Japan. kitakaze@zf6.so-net.ne.jp
Asanuma
Hiroshi
H
Funaya
Hiroharu
H
Node
Koichi
K
Takashima
Seiji
S
Sanada
Shoji
S
Asakura
Masanori
M
Ogita
Hisakazu
H
Kim
Jiyoong
J
Hori
Masatsugu
M
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
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