Role of bradykinin and eNOS in the anti-ischaemic effect of trandolapril.
1. Angiotensin converting enzyme (ACE) inhibitors are under study in ischaemic heart diseases, their mechanism of action being still unknown. 2. The anti-ischaemic effect of trandolapril and the possible involvement of a bradykinin-modulation on endothelial constitutive nitric oxide synthase (eNOS) in exerting this effect, were investigated. 3. Three doses of trandolapril, chronically administered in vivo, were studied in isolated perfused rat hearts subjected to global ischaemia followed by reperfusion. 4. Trandolapril has an anti-ischaemic effect. The dose of 0.3 mg kg(-1) exerted the best effect reducing diastolic pressure increase during ischaemia (from 33.0+/-4.5 to 14.0+/-5.2 mmHg; P<0.05 vs control) and reperfusion (from 86.1+/-9.4 to 22.2+/-4.1 mmHg; P<0.01 vs control), improving functional recovery, counteracting creatine phosphokinase release and ameliorating energy metabolism after reperfusion. 5. Trandolapril down-regulated the baseline developed pressure. 6. Trandolapril increased myocardial bradykinin content (from 31.8+/-6.1 to 54.8+/-7.5 fmol/gww; P<0.05, at baseline) and eNOS expression and activity in aortic endothelium (both P<0.01 vs control) and in cardiac myocytes (from 11.3+/-1.5 to 17.0+/-2.0 mUOD microg protein(-1) and from 0.62+/-0.05 to 0.80+/-0.06 pmol mg prot(-1) min(-1); both P<0.05 vs control). 7. HOE 140 (a bradykinin B(2) receptor antagonist) and NOS inhibitors counteracted the above-reported effects. 8. There was a negative correlation between myocyte's eNOS up-regulation and myocardial contraction down-regulation. 9. Our findings suggest that the down-regulation exerted by trandolapril on baseline cardiac contractility, through a bradykinin-mediated increase in NO production, plays a crucial role in the anti-ischaemic effect of trandolapril by reducing energy breakdown during ischaemia.
Cargnoni
A
A
Cardiovascular Research Center, Fondazione Salvatore Maugeri, IRCCS, Gussago, Brescia, Italy.
Comini
L
L
Bernocchi
P
P
Bachetti
T
T
Ceconi
C
C
Curello
S
S
Ferrari
R
R
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001920:Bradykinin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D017725:Ventricular Pressure / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001920:Bradykinin