Circulation, Vol 90, 1368-1385, Copyright © 1994 by American Heart Association
T Ehring, D Baumgart, M Krajcar, M Hummelgen, S Kompa and G Heusch
BACKGROUND: Attenuation of myocardial stunning by several angiotensin-
converting enzyme (ACE) inhibitors has been demonstrated. However, the
signal cascade mediating such protective effect has not been analyzed in
detail so far. METHODS AND RESULTS: In a first protocol, we addressed the
role of bradykinin and analyzed the effect of the ACE inhibitor ramiprilat
without and with added bradykinin B2 receptor antagonist HOE 140 on
regional myocardial blood flow (colored microspheres) and function
(sonomicrometry). Thirty-two enflurane/N2O- anesthetized open-chest dogs
were subjected to 15 minutes of occlusion of the left circumflex coronary
artery (LCx) and 4 hours of subsequent reperfusion. Eight dogs served as
placebo controls (group 1), and 8 dogs received ramiprilat (20
micrograms/kg IV) before LCx occlusion (group 2). Eight dogs received a
continuous intracoronary infusion of HOE 140 [0.5 ng/(mL.min) IC] during
ischemia and reperfusion (group 3), and in 8 dogs HOE 140 was infused
continuously during ischemia and reperfusion, starting 45 minutes before
the administration of ramiprilat (group 4). Mean aortic pressure was kept
constant with an intra-aortic balloon, and heart rate did not change
throughout the experimental protocols. Under control conditions and during
myocardial ischemia, posterior transmural blood flow (BF) and systolic wall
thickening (WT) were not different in the four groups of dogs. However, at
4 hours of reperfusion, WT was still depressed in groups 1 (-10 +/- 20% of
control [mean +/- SD]), 3 (-18 +/- 12% of control), and 4 (-12 +/- 21% of
control), whereas WT in group 2 had recovered to 55 +/- 20% of control (P
< .05 versus group 1). BF at 4 hours of reperfusion was not different in
the four groups of dogs. Thus, the beneficial effect of ramiprilat on the
functional recovery of stunned myocardium was obviously mediated by
bradykinin. Since bradykinin stimulates the formation of both
prostaglandins and nitric oxide, we tested in a second protocol which of
these mediators was further involved in the beneficial effects of
ramiprilat. Twenty-four additional dogs were subjected to 15 minutes of LCx
occlusion and 4 hours of reperfusion. Six dogs received the cyclooxygenase
inhibitor indomethacin (10 mg/kg IV) (group 5) and 6 dogs a combination of
indomethacin with ramiprilat (group 6) before LCx occlusion. Six dogs
received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl
ester (L-NAME) (20 mg/kg IV) (group 7) and 6 dogs a combination of L-NAME
with ramiprilat (group 8) before LCx occlusion. BF and WT before and during
myocardial ischemia were not different in groups 5 and 6 and groups 7 and
8. However, at 4 hours of reperfusion, WT was still depressed in groups 5
(-10 +/- 38% of control), 6 (-7 +/- 18% of control), and 7 (-12 +/- 14% of
control), whereas WT in group 8 had recovered to 47 +/- 28% of control (P
< .05 versus group 7). BF at 4 hours of reperfusion was not different in
the four groups of dogs. CONCLUSIONS: In summary, the attenuation of
stunning by the ACE inhibitor ramiprilat involves a signal cascade of
bradykinin and prostaglandins but not nitric oxide.
ARTICLES
Attenuation of myocardial stunning by the ACE inhibitor ramiprilat through a signal cascade of bradykinin and prostaglandins but not nitric oxide
Department of Pathophysiology, University of Essen Medical School, Germany.
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