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A role for adenosine in ischemic preconditioning and hypoxic preconditioning (HP) has been established in several species but is controversial in rats, due in part to the inconsistency of the data from the different experimental design. Our objective was to investigate the role of adenosine in the protection of the ischemic myocardium by HP in rats. Methods: perfused hearts isolated from Sprague–Dawley rats were exposed to 5 min of hypoxic perfusion before 25 min of global ischemia followed by 20 min of reperfusion. The effects of adenosine receptor antagonist, 8-(p-sulfophenyl)-theophylline (8SPT) on HP-based changes in left-ventricular function, energy metabolites, and release of creatine kinase and lactate dehydrogenase were determined. To minimise non-specific effects of 8SPT, low concentrations of agent (0.5 or 1.0μmol/l) were used. Results: 8SPT alone had no deleterious effects on normoxically perfused hearts or on ischemic/reperfused hearts. HP improved the recovery of LV function and creatine phosphate, and reduced the release of enzymes during reperfusion. 8SPT (1.0μmol/l) ameliorated the beneficial effect of HP on cardiac function, but did not reverse the reduction in release of enzymes by HP completely. Conclusion: results suggest that the protective effect of HP on myocardial contractile function may be mediated by receptor(s) that can be inhibited by low concentrations of antagonist but may not have a primary role in the reduction of cellular damage by HP in rats.

Iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (123I-BMIPP) is widely used to detect myocardial metabolic changes, but the preferred energy substrates in the myocardium would be expected to be altered in the presence of metabolic disorders such as diabetes mellitus (DM). We investigated the metabolism of branched-chain fatty acids in the myocardium of rats with DM. Streptozotocin-induced DM rats were examined 48 h (acute; AD) and 6 weeks (chronic; CD) after injection of streptozotocin. Hearts were excised 15 min or 60 min after injection of 0.185 MBq of 125I-BMIPP, followed by homogenization in an EDTA-Tris buffer. The homogenates were subjected to differential centrifugation to obtain the mitochondrial (MF) and cytoplasmic (CF) fractions. Myocardial 125I uptake tended to increase in the AD group, but the change was not significant. Myocardial 125I uptake at 15 min was significantly lower in the CD group than in the control group, even in the insulin-treated rats [control (CC), 4.4±0.4; not treated (CDN), 3.3±0.5; insulin-treated (CDI), 3.4±0.4×104 cpm/g, p

While the ischemic tolerance of the myocardium has been reported to decrease with senescence, it is not known when and how this occurs. Our objectives were to determine whether the tolerance to myocardial ischemia in rats decreased before the onset of senescence and whether an increase in myocardial ionic imbalance was associated with an enhanced myocardial injury with aging. Hearts were isolated from Fischer 344 rats categorized as young (12 weeks old), mature adult (24 weeks), middle-aged (50 weeks) or senescent (100 weeks). Hearts were perfused isovolumically by the Langendorff procedure and subjected to 25 min of global ischemia followed by 30 min of reperfusion. In the 50- and 100-week-old rats, the recovery of ventricular function and high-energy phosphate levels was lower and there was increased incidence of ventricular fibrillation after 25 min of global ischemia followed by reperfusion. The release of creatine kinase and lactate dehydrogenase during reperfusion was greater in the 50-and 100-week-old rats than in the 12- and 24-week-old rats, indicating the irreversible myocardial damage due to ischemia-reperfusion increased by middle-age. Intracellular levels of Na+ and K+ before ischemia were higher in the 50- or 100-week-old rats than in the 12-week-old rats. The increase in intracellular Na+ at end of ischemia was greater in the older (50-week-old, 215% of the pre-ischemic value; 100-week-old, 232% of the pre-ischemic value) than in the younger rats (12-week-old, 158% of the pre-ischemic value). Results indicated that the rat heart becomes more vulnerable to ischemia in middle-age. This decrease in ischemic tolerance may be caused by an acceleration of myocardial ionic imbalance with aging.

Background Although both clinical and animal studies have shown that ischemic tolerance is reduced in the senescent myocardium, it has not been clarified when myocardium becomes more vulnerable to ischemia. Preconditioning protects the hearts of young adult animals of various species, but its effects are not identical in human studies. We investigated whether ischemic tolerance and the effect of preconditioning decreased in isolated hearts of middle-aged rats. Methods and Results The hearts of young adult rats (12 weeks old: group Y, n=44) and middle-aged rats (50 weeks old: group M, n=44) were subjected to global ischemia for 15, 20, or 25 minutes followed by reperfusion. Hearts were also subjected to preconditioning and then to 20 (group Y, n=22) or 15 (group M, n=22) minutes of ischemia followed by reperfusion. Left ventricular developed pressure (LVDP) was decreased by 40% to 60%, and the level of ATP was decreased by 60% to 70% in group M compared with group Y. Preconditioning increased LVDP (% LVDP, 40.5% to 72.4%) and levels of high-energy phosphates (ATP, 11.8 to 14.1; creatine phosphate, 17.0 to 23.1 μmol/g dry wt) and reduced left ventricular end-diastolic pressure (LVEDP, 32.8 to 10.3 mm Hg), creatine kinase release (257 to 132 U/g dry wt), and ryanodine-sensitive sarcoplasmic reticulum Ca 2+ release after ischemia in group Y. Preconditioning exerted opposite effects in group M (% LVDP, 45.9% to 15.8%; LVEDP, 21.0 to 28.5 mm Hg; ATP, 14.1 to 8.5 μmol/g dry wt; and CK release, 176 to 332 U/g dry wt). Preconditioning was associated with increases in the incidence of reperfusion-induced ventricular fibrillation (0% to 62.5%) and the rate of sarcoplasmic reticulum Ca 2+ release in group M. Conclusions These results indicate that hearts became more vulnerable to ischemia with age and that the beneficial effects of preconditioning were reversed in middle-aged rat hearts.

To clarify the roles of subclasses of alpha 1-adrenoreceptors in ischemic-reperfused myocardium, we compared the effect of the nonselective alpha 1-blocker bunazosin with that of the alpha 1A-blocker WB4101 and the alpha 1B-blocker chlorethylclonidine (CEC) in isolated rat hearts. After 30 min of preperfusion, Langendorff-perfused hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion. Hearts were randomly divided into 4 groups, with one of the following substances being added to the perfusate: buffer alone (control), 10(-6) mol/L bunazosin, 10(-7) mol/L WB4101, or 10(-7) mol/L CEC. Bunazosin had a negative inotropic effect and preserved the postischemic ATP content, reduced the postischemic increase in intracellular Na+ content and then enhanced postreperfusion recovery of creatine phosphate. Bunazosin also reduced myocardial 45Ca2+ uptake during reperfusion (control 5.2 vs bunazosin 2.5 mumol/g dry weight of tissue (dwt), p < 0.01). However, the recovery of left ventricular developed pressure (DP) was not improved when bunazosin was added to the perfusate during reperfusion. WB4101 had neither a negative inotropic nor an energy-sparing effect, but it improved the recovery of DP (control 43% vs WB4101 56% of preischemic value, p < 0.05) with no reduction in myocardial 45Ca2+ uptake. CEC had a negative inotropic and energy-sparing effect and then reduced myocardial 45Ca2+ uptake (CEC 3.1 mumol/g dwt, p < 0.05), but it did not improve the recovery of DP. These results suggest that the preischemic administration of an alpha 1B-adrenoreceptor subtype blocker protected ischemic-reperfused myocardium via reduction of Ca2+ overload, whereas the selective blockade of the alpha 1A-adrenoreceptor subtype reduced myocardial damage via mechanism(s) other than Ca2+ metabolism.

Some animal studies indicate that ischemic tolerance is decreased in the senescent myocardium. However, the results of cardiac operations in the elderly are compatible with those performed in middle-aged people. It is important to determine whether ischemic tolerance may be decreased in middle age. Hearts from young adult (12 weeks old) or the middle-aged (50 weeks old) Fischer 344 rats were subjected to 15, 20, or 25 minutes of global ischemia followed by reperfusion. The recovery of left ventricular function and high-energy phosphates was significantly lower in the hearts of middle-aged rats than in those of the young adult rats after any period of global ischemia. The increase in left ventricular end-diastolic pressure was also greater in the middle-aged rats, although there were no diferences in these indexes in the two age groups before the induction of ischemia. The incidence of reperfusion-induced ventricular fibrillation was significantly higher and the release of creatine kinase in the coronary effluent during reperfusion significantly greater in the middle-aged rats than in the young adult rats. Results indicate that rat hearts are more vulnerable to ischemia, even in middle age.

Apical hypertrophic cardiomyopathy (apical HCM) has been believed to be a special type of hypertrophic cardiomyopathy. It usually occurs in middle-aged or elderly men and the prognosis is thought to be good. However, recent reports suggest that approximately 10% of middle-aged patients with apical HCM have cardiac events and poor outcomes. We studied electrocardiograms and echocardiograms, the occurrence of cardiac events, and clinical characteristics in elderly patients with apical HCM (13 men and 7 women, 61 to 95 years old, mean age 74 +/- 7). Three of 20 patients (15%) had cardiac events (sudden death, 1; heart failure, 1; chest pain, 1), 2 had cerebral infarction with atrial fibrillation, and 2 died of non-cardiac causes. There were no differences in age, sex, medication, complications, or in initial values of electrocardiographic or echocardiographic variables between patients who had and did not have cardiac events. However, left ventricular end-systolic dimension (LVEDs) and left atrial diameter at the time of the last evaluation were larger in patients who had cardiac events than in those who did not (26 vs. 34 mm, p = 0.019, 33 vs. 38 mm, p = 0.1325, respectively). These results suggest that the prognosis for patients with apical HCM is not necessarily good, and that enlargement of the LVEDs might be used to predict cardiac events in elderly patients with apical HCM.

Protection of the ischemic myocardium by pretreatment with a high dose of 2,3-butanedione monoxime (BDM) is attributed to the enhancement of glycolytic ATP production rather than to the inhibition of contracture during mild ischemia. Our objective was to investigate whether the inhibition of contracture would protect the arrested heart during prolonged ischemia. Isolated perfused rat hearts were subjected to 30 min of low-flow ischemia followed by reperfusion. Ischemic hearts were treated with BDM (5 mmol/l) after beating stopped. BDM ameliorated the increase in intraventricular pressure after ischemia without significant changes in ATP levels and with a decreased accumulation of lactate. BDM treatment accelerated the recovery of function and high-energy phosphates with reduced myocardial Ca2+ overload. The results of this study suggested that inhibition of contracture can protect the heart from ischemia-reperfusion injury.