Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs.
BACKGROUND
Dihydropyridine calcium channel blockers protect endothelial cells against ischemia and reperfusion injury, suggesting that nifedipine may increase the in vivo cardiac NO level and thus coronary blood flow (CBF) in ischemic hearts. We tested this hypothesis.


RESULTS
In open-chest dogs, coronary perfusion pressure (CPP) was reduced in the left anterior descending coronary artery so that CBF decreased to one third of the control level, and thereafter CPP was maintained constant (103+/-8 to 43+/-3 mm Hg, n=9). We obtained fractional shortening (FS) and lactate extraction ratio (LER) as indices of regional myocardial contraction and metabolism. Both FS (26.4+/-2.1% to 6.7+/-2.0%, n=9, P<0.001) and LER (32+/-6% to -37+/-5%, n=9, P<0.001) showed a decrease when CPP was reduced. After intracoronary infusion of nifedipine (4 microgram. kg(-1). min(-1)), CBF increased from 30+/-1 to 48+/-4 mL. 100 g(-1). min(-1) (P<0.01) without a change of CPP (n=9). Both FS (14.0+/-1.9%, n=9) and LER (-9+/-7%, n=9) also increased (P<0.01). Nifedipine increased the difference in the level of metabolites of NO (nitrate+nitrite; 9+/-3 to 25+/-5 nmol/mL, n=9, P<0.01) and bradykinin (22+/-5 to 58+/-4 pmol/mL, n=9, P<0.01) between coronary venous and arterial blood. L-NAME (an NO synthase inhibitor) or HOE-140 (a bradykinin receptor antagonist) attenuated (P<0.05) the increase in CBF (29+/-3 and 35+/-2 mL. 100 g(-1). min(-1), n=5 each), FS (4.8+/-0.6% and 6.9+/-1.7%, n=5 each), LER (-47+/-8% and -35+/-9%, n=5 each), and nitrate+nitrite (3+/-2 and 8+/-4 nmol/mL, n=5 each) due to nifedipine infusion.


CONCLUSIONS
These results indicate that the calcium channel blocker nifedipine mediates coronary vasodilation and improves myocardial ischemia through both bradykinin/NO-dependent and -independent mechanisms.
Kitakaze
M
M
Department of Internal Medicine, Osaka University Graduate School of Medicine, Suita, Japan. kitakaze@medone.med.osaka-u.ac.jp
Asanuma
H
H
Takashima
S
S
Minamino
T
T
Ueda
Y
Y
Sakata
Y
Y
Asakura
M
M
Sanada
S
S
Kuzuya
T
T
Hori
M
M
D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects*; D006152:Cyclic GMP / Q000097:blood; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D009543:Nifedipine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D013599:Systole / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D002121:Calcium Channel Blockers; D009569:Nitric Oxide; D006152:Cyclic GMP; D009543:Nifedipine; D001920:Bradykinin