Delayed preconditioning via Angiotensin-converting enzyme inhibition: pros and cons from an experimental study.
1. Bradykinin B(2) receptor activation confers preconditioning from ischaemic injury. In the present study, we tested whether an angiotensin-converting enzyme (ACE) inhibitor (captopril) could mediate delayed preconditioning and, thus, cardioprotection. 2. New Zealand white rabbits received 15 mL infusion of either saline (control group; n = 7) or drugs (0.3 mg/kg captopril (CAP group; n = 7) or 0.3 mg/kg captopril + 0.1 mg/kg HOE 140 (CAPHOE group; n = 7)) via a marginal ear vein over 30 min. After 24 h, hearts were connected to a Langendorff apparatus and buffer perfused. The experimental protocol consisted of 20 min global normothermic hypoxia, followed by 120 min reperfusion. 3. Compared with baseline, the mean (SEM) contractile state (= dP/dt(max)) at 120 min reperfusion was decreased to 42 +/- ;23, 72 +/- ;16 (*P < 0.05 vs control) and 49 +/- ;22% in the control, CAP and CAPHOE groups, respectively. Early relaxation (= dP/dt(min)) was reduced to 55 +/- ;28, 73 +/- ;15 (*P < 0.05 vs control) and 52 +/- ;19% in the control, CAP and CAPHOE groups, respectively. The estimate for myocardial oxygen consumption (MVO(2)= rate-pressure product) was decreased to 52 +/- ;15, 69 +/- ;24 (*P < 0.05 vs control) and 56 +/- ;15% in the control, CAP and CAPHOE groups, respectively. Similarly, coronary flow was decreased in the control, CAP and CAPHOE groups to 49 +/- ;20, 67 +/- ;18 and 46 +/- ;19%, respectively. In contrast, ventricular extrasystoles during reperfusion were significantly elevated in both the CAP and CAPHOE groups (1.3 +/- ;0.2 and 1.1 +/- ;0.3 /min, respectively) compared with control (0.4 +/- ;0.2 /min). 4. Captopril confers delayed preconditioning against stunning via a B(2) receptor-mediated pathway. This pharmacological preconditioning protects against systolic and diastolic stunning, against vascular stunning and preserves cardiac metabolism. In addition to its accepted cardioprotective effects in early preconditioning, captopril should induce delayed preconditioning (e.g. for routine interventional cardiology or in elective cardiac surgery).
Marktanner
Ralph
R
Department of Thoracic and Cardiovascular Surgery, University Hospital Duesseldorf, Duesseldorf, Germany.
Nacke
Peter
P
Feindt
Peter
P
Hohlfeld
Thomas
T
Schipke
Jochen D
JD
Gams
Emmeran
E
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D015415:Biomarkers; D002216:Captopril / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D000860:Hypoxia / Q000209:etiology; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000401:mortality / Q000517:prevention & control*; D016276:Ventricular Function
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D002216:Captopril