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).

Norepinephrine-induced delayed cardioprotection against stunning is at the expense of a higher postischemic arrhythmia rate.

OBJECTIVE: alpha(1)-adrenoceptor activation confers myocardial protection from ischemic injury. We tested whether norepinephrine mediates delayed cardioprotection against stunning and whether this alters postischemic arrhythmias. METHODS: New Zealand White rabbits were assigned to three groups: Control-group (n=7): no drugs. Norepinephrine-group (n=7): 75 microg norepinephrine/kg bodyweight (bw). Norepinephrine/prazosin-group (n=7):75 microg norepinephrine and 15 microg prazosin/kg bw. After 24 h, hearts were excised, perfused with buffer and subjected to 20 min of ischemia followed by 120 min of reperfusion. RESULTS: (a) Developed pressures (dP) (P(syst)-P(diast)) at the end of reperfusion: C: 51.2+/-5.0%, NE: 71.7+/-5.1% (p<0.05 vs. C), NEP: 50.7+/-5.0%. (b) Ventricular extra beats (vebs) were detected throughout the experiments. C: 0.41+/-0.15 vebs/min, NE: 1.06+/-0.18 vebs/min (p<0.05 vs. C), NEP: 1.17+/-0.3 vebs/min. CONCLUSION: Norepinephrine confers delayed preconditioning against myocardial stunning via an alpha(1)-adrenoceptor mediated pathway. Norepinephrine-mediated preconditioning involves a beneficial effect towards stunning, but at the expense of a higher rate of postischemic ventricular arrhythmia.