Toshihiro Iwamoto

Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning.

BackgroundRecent studies implicated a key role for adenosine (ADO) receptor activation in the enhancement of ischemic tolerance by ischemic preconditioning. In this study, we aimed to test the hypothesis that dipyridamole, an ADO transport inhibitor, enhances the preconditioning effect. Methods and ResultsSix groups of rabbits underwent 30-minute coronary occlusion and 72-hour reperfusion. Infarct size (IS) and the area-at-risk (AR) were determined by histology and by use of fluorescent particles, respectively. IS expressed as the percentage ofAR (%IS/AR) was 46.5±3.4% (n=13) in control rabbits. Preconditioning with 2-minute ischemia tended to limit %IS/AR (%IS/AR, 35.5±3.5%, n=9), and that possible protection was abolished by pretreatment with 10 mg/kg 8-phenyltheophylline (8–PT), an ADO receptor antagonist (%IS/AR, 43.9±5.8%, n=9). Administration of dipyridamole (0.25 mg/kg) before the 2-minute preconditioning markedly limited %IS/AR to 13.8±2.6% (n=12), indicating the potentiation of the preconditioning effect by this agent. Furthermore, this enhancement of preconditioning effect by dipyridamole treatment was significantly attenuated by 8-PT (%IS/AR, 27.6±2.1%, n=11). Dipyridamole given before the 30-minute ischemia, without preconditioning, did not reduce %IS/AR (55.3±5.2%, n=7), and a previous study from this laboratory had demonstrated that the present dose of 8–PT alone did not modify IS in the rabbit. ConclusionsDipyridamole significantly potentiated the IS-limiting effect of preconditioning. This finding strongly supports the hypothesis that stimulation of ADO receptors by endogenous ADO, which builds up during preconditioning ischemia, mediates the increased ischemic tolerance afforded by preconditioning.

Myocardial infarct size-limiting effect of ischemic preconditioning was not attenuated by oxygen free-radical scavengers in the rabbit.

BackgroundThe limiting effect of ischemic preconditioning on infarct size has been reported in canine hearts, which contain considerable amounts of xanthine oxidase, a free radicalproducing enzyme. Furthermore, a recent study suggested that free radicals generated during preconditioning may contribute to the cardioprotective effect of preconditioning. The present study examined 1) whether preconditioning limits infarct size in rabbits, which, like humans, lack myocardial xanthine oxidase and 2) whether the cardioprotective effect of PC is mediated by free radicals. Methods and ResultsA branch of the circumflex coronary artery in rabbits was occluded for 30 minutes and then reperfused for 72 hours. Myocardial infarct size and area at risk were determined by histology and fluorescent particles, respectively. Five groups were studied: an untreated control group, a preconditioned group (PC group), a high-dose superoxide dismutase SOD) -treated preconditioned group (high-dose SOD-PC group), a low-dose SOD-treated preconditioned group (low-dose SOD-PC group), and a SOD-plus-catalase-treated preconditioned group (SOD/CAT-PC group). Preconditioning was performed with four episodes of 5 minutes of ischemia and 5 minutes of reperfusion. The free radical scavengers (30,000 units/kg SOD for high-dose SOD-PC group, 15,000 units/kg SOD for low-dose SOD-PC group, and 30,000 units/kg SOD plus 55,000 units/kg catalase for SOD/CAT-PC group) were infused intravenously over 60 minutes starting 20 minutes before preconditioning. Infarct size as the percentage of area at risk was 45.1 + 3.5% (mean ± SEM) in the control group (n =11), 13.3±3.0% in the PC group (n =12), 9.7±1.8% in the high-dose SOD-PC group (n =8), 11.9±2.2% in the low-dose SOD-PC group (n =6), and 9.6±2.3% in the SOD/CAT-PC group n =6) (p <0.05 versus control for the last four values). The differences in infarct size as the percent of area at risk among the PC, high-dose SOD-PC, low-dose SOD-PC, and SOD/CAT-PC groups were not significant. Conclusion.Ischemic preconditioning delays ischemic myocardial necrosis regardless of myocardial xanthine oxidase content. Free radicals are unlikely to have a major role in the mechanism of the preconditioning in rabbits. (Circulation 1991;83:1015–1022)

EFFECT OF NICORANDIL ON POST‐ISCHAEMIC CONTRACTILE DYSFUNCTION IN THE HEART: ROLES OF ITS ATP‐SENSITIVE K’ CHANNEL OPENING PROPERTY AND NITRATE PROPERTY

1. This study aimed to characterize the effect of nicorandil (NC) on myocardial stunning and the role of ATP‐sensitive K+ (Katp) channel opening property in its cardioprotective action.

SUPEROXIDE DISMUTASE ATTENUATED POST‐ISCHAEMIC CONTRACTILE DYSFUNCTION IN A MYOCARDIAL XANTHINE OXIDASE DEFICIENT SPECIES

1. We assessed the effect of polyethylene glycol conjugated superoxide dismutase (PEG‐SOD) on myocardial stunning in the rabbit heart in which xanthine oxidase level is extremely low.

Does verapamil limit myocardial infarct size in a heart deficient in xanthine oxidase

1. The delay of ischaemic myocardial necrosis by verapamil has been reported in the dog heart, which contains a high level of xanthine oxidase, a potential source of cytotoxic free radicals. To test whether the retardation of ischaemic myocyte death by verapamil is not an isolated phenomenon in the xanthine oxidase rich heart, we assessed the effect of verapamil in the rabbit heart, which lacks xanthine oxidase.