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J Z Sun

Publications and source records attributed to J Z Sun.

At least 37 records · Page 2Linked to original sources
PubMed1997

Late preconditioning against stunning is not mediated by increased antioxidant defenses in conscious pigs.

Previous studies in conscious pigs have demonstrated that a sequence of ten 2-min coronary occlusion/2-min reperfusion cycles renders the heart relatively resistant to myocardial stunning 24 h later [late preconditioning (PC) against stunning] by an unknown mechanism. Since oxygen radicals contribute importantly to myocardial stunning and since antioxidant enzymes have been reported to be upregulated 24 h after PC in dogs and rabbits, we tested the hypothesis that late PC against stunning is related to an increase in endogenous antioxidant defenses. Chronically instrumented conscious pigs underwent a sequence of ten 2-min coronary occlusion/2-min reperfusion cycles (preconditioned group, n = 11) or received no intervention (control group, n = 5). Twenty-four hours later, pigs were killed and the myocardial levels of Mn superoxide dismutase (SOD), Cu-Zn SOD, catalase, glutathione (GSH) peroxidase, GSH reductase, GSH, GSH disulfide, alpha-tocopherol, and ascorbate were measured. There were no differences in any of the enzymatic or nonenzymatic antioxidants between the ischemic and nonischemic regions in the preconditioned group or between the control and the preconditioned group. Thus, when a marked protection against stunning was present (24 h after PC), no alteration in antioxidant defenses was observed. These results indicate that, in conscious pigs, late PC against myocardial stunning is not mediated by increased endogenous antioxidant defenses, thereby refuting one of the major current hypotheses regarding this phenomenon.

Animals↗
PubMed1997

The early and late phases of ischemic preconditioning: a comparative analysis of their effects on infarct size, myocardial stunning, and arrhythmias in conscious pigs undergoing a 40-minute coronary occlusion.

The effectiveness of the late phase of ischemic preconditioning (PC) in protecting against myocardial infarction and the concomitant contractile dysfunction after sustained ischemia remains unclear. The early and late phases of PC have not been compared using the same protocol in the same experimental model; furthermore, the late phase of PC has not been assessed in the conscious state in a large animal preparation. The goal of this study was to directly compare the effects of early and late PC on myocardial infarct size and postischemic dysfunction in chronically instrumented, conscious pigs. Four groups of pigs were subjected to a 40-minute coronary occlusion followed by 3 days of reperfusion. Group 1 (n=7) served as control. Group 2 (n=6) was subjected to ten 2-minute occlusion/2-minute reperfusion cycles 25 minutes before the 40-minute occlusion (early PC). Groups 3 (n=7) and 4 (n=4) were subjected to 10 and 25 cycles, respectively, of 2-minute occlusion/2-minute reperfusion 24 hours before the 40-minute occlusion (late PC). Infarct size averaged 45.1+/-5.9% of the region at risk in control pigs, was reduced by 79% (to 9.4+/-3.2%) in group 2, but did not differ in groups 3 (33.3+/-4.8%) and 4 (38.8+/-8.2%) versus group 1. Power analysis demonstrated that there was an 80% probability of detecting a 40% decrease in infarct size in groups 3 and 4 versus group 1. The recovery of systolic wall thickening (measured with ultrasonic crystals) after the 40-minute occlusion was poor in groups 1, 3, and 4 but markedly enhanced in group 2 throughout the 3 days of reperfusion; this beneficial effect could have been due to limitation of infarct size, alleviation of stunning, or both. Thus, a series of ten 2-minute coronary occlusions had a profound (approximately 80%) early infarct-limiting effect, which was associated with a marked functional benefit. This protection, however, disappeared 24 hours later and could not be reinstituted by increasing the number of PC coronary occlusions to 25. The incidence and duration of ventricular tachycardia after reperfusion was not changed by either early or late PC; no conclusions could be drawn regarding ventricular fibrillation or ischemia-induced ventricular tachycardia, since these arrhythmias did not occur in control animals. Taken together, the present results demonstrate striking differences between the early and late effects of PC: In conscious swine subjected to a sustained coronary occlusion, a PC protocol that induces powerful protection during the early phase of PC fails to induce any protection during the late phase, indicating either that a late protective effect of PC does not exist or that, if it exists, it must be weaker than the early protective effect.

Animals↗
PubMed1996

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3). On day 1, pigs received an i.v. infusion of a combination of antioxidants (superoxide dismutase, catalase, and N-2 mercaptopropionyl glycine; group II, n = 9), nisoldipine (group III, n = 6), or vehicle (group I [controls], n = 9). In the control group, systolic wall thickening (WTh) in the ischemic-reperfused region on day 1 remained significantly depressed for 4 h after the 10th reperfusion, indicating myocardial "stunning." On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 53% on day 2 and 56% on day 3 compared with day 1 (P < 0.01), indicating the development of a powerful cardioprotective response (late preconditioning against stunning). In the anti-oxidant-treated group, the total deficit of WTh on day 1 was 54% less than in the control group (P < 0.01). On day 2, the total deficit of WTh was 85% greater than that observed on day 1 and similar to that observed on day 1 in the control group. On day 3, the total deficit of WTh was 58% less than that noted on day 2 (P < 0.01). In the nisoldipine-treated group, the total deficit of WTh on day 1 was 53% less than that noted in controls (P < 0.01). On days 2 and 3, the total deficit of WTh was similar to the corresponding values in the control group. These results demonstrate that: (a) in the conscious pig, antioxidant therapy completely blocks the development of late preconditioning against stunning, indicating that the production of reactive oxygen species (ROS) on day 1 is the mechanism whereby ischemia induces the protective response observed on day 2; (b) antioxidant therapy markedly attenuates myocardial stunning on day 1, indicating that ROS play an important pathogenetic role in postischemic dysfunction in the porcine heart despite the lack of xanthine oxidase; (c) although the administration of a calcium-channel antagonist (nisoldipine) is as effective as antioxidant therapy in attenuating myocardial stunning on day 1, it has no effect on late preconditioning on day 2, indicating that the ability of antioxidants to block late preconditioning is not a nonspecific result of the mitigation of postischemic dysfunction on day 1. Generation of ROS during reperfusion is generally viewed as a deleterious process. Our finding that ROS contribute to the genesis of myocardial stunning but, at the same time, trigger the development of late preconditioning against stunning supports a complex pathophysiological paradigm, in which ROS play an immediate injurious role (as mediators of stunning) followed by a useful function (as mediators of subsequent preconditioning).

Animals↗
PubMed1996

Nisoldipine attenuates myocardial stunning induced by multiple coronary occlusions in conscious pigs and this effect is independent of changes in hemodynamics or coronary blood flow.

Recent studies suggest that calcium channel blockers attenuate reversible post-ischemic myocardial dysfunction (myocardial "stunning") in vivo. This beneficial effect, however, has been shown either in open-chest preparations, which are subject to the confounding influence of many unphysiological conditions, or in models in which treatment caused significant hemodynamic alterations. Furthermore, all of the studies have been conducted in the dog, and almost all of them have examined the effect of calcium antagonists after a single ischemic episode. The goal of the present investigation was to assess the effect of nisoldipine in a conscious pig model of repetitive ischemia, and to determine whether the drug exerts direct cardioprotection independent of hemodynamic changes. A total of 33 conscious pigs were used. Pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, and were randomly assigned to a treated group (n = 11), in which nisoldipine was infused at a rate of 0.5 microgram/kg/min from 15 min before the first coronary occlusion till 30 min after the last reperfusion, and a control group (n = 12), which received vehicle. Results showed that there were no significant differences between the two groups with respect to ischemic bed size or hemodynamic variables throughout the experiment. Collateral blood flow to the ischemic regions was virtually nil in both groups. During the sequence of coronary occlusions, systolic thickening fraction in the ischemic region decreased similarly in the two groups. After the 10th reperfusion, however, the recovery of wall thickening was markedly enhanced in treated compared to control pigs, with the differences being statistically significant at 5, 15, and 30 min and 1, 3, 4 and 5 h. The total deficit of wall thickening after the 10th reperfusion (an integrative assessment of post-ischemic dysfunction) was 51% less in the treated compared with the control group (P < 0.001). This study demonstrates that nisoldipine markedly attenuates myocardial stunning after multiple ischemic episodes in conscious pigs, the improvement is evident immediately after the end of the ischemic episodes and is sustained throughout the recovery phase. This beneficial effect is independent of any favourable hemodynamic changes, and therefore indicates a direct cardioprotective action of nisoldipine.

Animals↗
PubMed1996

Time course of late preconditioning against myocardial stunning in conscious pigs.

We have recently found in conscious pigs that a sequence of brief coronary occlusions induces severe myocardial stunning, but when the same sequence is repeated 24 hours later, the severity of stunning is markedly reduced (approximately 50%) ("late preconditioning against stunning"). As an initial step toward elucidating the mechanism and potential clinical significance of this powerful cardioprotective response, the present study was conducted to define the time course of late preconditioning against myocardial stunning. Conscious pigs underwent a sequence of ten 2-minute coronary occlusion/2-minute reperfusion cycles and then a second identical sequence at 6 hours (group I, n = 7), 12 hours (group II, n = 6), 24 hours (group III, n = 10), 3 days (group IV, n = 10), or 6 days (group V, n = 11) after the first. Systolic wall thickening (WTh) in the ischemic/reperfused region remained significantly depressed for at least 3 hours after the 10th reperfusion of the first sequence, indicating myocardial stunning. When the second sequence of coronary occlusions was performed 6 hours after the first (group I), the recovery of WTh was similar to the first. In contrast, when the second sequence was repeated 12 hours after the first (group II), the recovery of WTh was improved, though not consistently, and the total deficit of WTh decreased by 41% (P < .05) compared with the first sequence. When the second sequence was repeated 24 hours (group III) and 3 days (group IV) after the first, the recovery of WTh was substantially enhanced, with 52% and 49% reductions in the total deficit of WTh, respectively (P < .01 versus the first sequence). When the second sequence was repeated 6 days later (group V), the recovery of WTh was indistinguishable from the first sequence. Thus, late preconditioning against myocardial stunning requires > 6 hours to develop, lasts for at least 60 hours after its appearance (with the most effective protection present at 24 hours and 3 days), and disappears within 6 days after the preconditioning ischemia, a time course that is consistent with the synthesis and degradation of cardioprotective proteins. In view of its sustained duration, this endogenous cardioprotective mechanism is of potential clinical importance.

Animals↗
PubMed1996

[Effects of xinshuaikang granule on cardiac function and atrial natriuretic polypeptide levels in rabbits with experimental congestive heart failure].

Xinshuaikang (XSK) granule mainly consisted of Radix Ginseng, Aconifum carmichaeli, Ligustici wallichii, Semen Lepidii seu Descurainiae, etc. Thirty-five white rabbits of Japanese strain with big ears were used and five groups were divided randomly. The models of chronic heart failure (CHF) was made by injection of adriamycin through the marginal vein of rabbit's ear. Only one group without adriamycin injection was taken as blank group. After the making of models, Xinbao (XB) was used to treat one group which was regarded as control group, XSK was used to treat two model groups, one used higher dose, the other one used lower dose. Fifteen days was taken as a course of treatment. The results were: the body weight of all model groups was heavier than that without adriamycin. After a course of treatment, the body weight of the groups treated by XSK or XB decreased rapidly, the general conditions of the three groups were improved; the two drugs could reduce heart rate and enhance heart function, at the same time they reduced the level of atrial natriuretic polypeptide (ANP) in plasma. The best results was obtained in XSK group with higher dose, the effect of XSK group with lower dose was equivalent to that of XB group. Hence, XSK granule could enhance the CHF rabbits' heart function, improve their heart endocrine activity, this drug had a reliable effect on CHF.

Animals↗
PubMed1996

[Effects of high salt-loading on the regulation of angiotensin II receptor mRNA expression].

In the present study, the angiotensin II receptor subtype I-a (AT1a) and I-b (AT1b) mRNA levels in aortic smooth muscle (ASM), ventricular myocardium (VM) and adrenal from 12-week-old stroke-prone spontaneously hypertensive rats (SHRsp) and age-matched Wistar-Kyoto (WKY) rats with normal diet (control) and high salt-loading were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The results showed that: (1) The AT1a and AT1b mRNA levels in ASM and VM from SHRsp were lower than those from WKY rats (in ASM, 10% and 23%, while in VM, 23% and 40% lower, respectively). In contrast, both AT1a and AT1b mRNA levels in adrenal from SHRsp were higher (176% and 157%, respectively). (2) In the WKY rats with high salt-loading, the AT1a and AT1b mRNA levels in adrenal, as well as AT1b mRNA level in VM, increased significantly, as compared with the control (in adrenal, 167% and 401%, while in VM, 62%). However, the AT1a and AT1b mRNA levels in ASM, as well as AT1a mRNA level in VM, showed no obvious change. (3) In SHRsp with high salt-loading, the AT1b mRNA level in ASM, as well as AT1a and AT1b mRNA levels in VM, increased markedly (in ASM, 90%, while in VM, 590% and 200%); whereas the AT1a mRNA level in adrenal decreased significantly (58%). There was little influence on the regulation of AT1a (in ASM) and AT1b (in adrenal) receptor gene expression after high salt-loading. The results suggest that AT1a and AT1b receptors may be involved in the pathogenesis of salt-induced hypertension. The up-regulation of AT1b receptors in ASM may induce the remodeling of arterial wall, while that of AT1a and AT1b receptors in VM might contribute to ventricular hypertrophy in hypertension. Furthermore, there are certain differences between SHRsp and WKY rats with respect to the regulation of AT1a and AT1b receptor gene expression with or without external stimulation.

Adrenal Glands↗
PubMed1995

Import of subunit VII of the cytochrome bc1 complex into yeast mitochondrial.

The import of subunit VII, the so-called ubiquinol binding protein of the cytochrome bc1 complex of yeast mitochondria, has been investigated by subcloning the gene for subunit VII into the expression vector pSP64. The precursor to subunit VII synthesized in vitro by a transcription/translation system had the same molecular weight as the mature form of this protein present in mitochondria, confirming earlier reports that subunit VII does not contain a cleavable presequence. The subunit VII precursor was imported efficiently into a protease-resistant compartment of isolated yeast mitochondria in a reaction dependent upon a membrane potential and the presence of ATP both in the mitochondrial matrix and in the extramitochondrial space. After import, the radiolabeled subunit VII was bound to the mitochondrial inner membrane through protein-protein interactions and could not be detected in the matrix fraction or in the intermembrane space. Subunit VII was also imported into mitoplasts, where the protein was associated with the inner membrane facing the matrix side of the membrane. By contrast, after import into mitochondria obtained from yeast cells lacking cytochrome b, subunit VII was localized in the supernatant fraction, suggesting that the presence of cytochrome b may be required for the association of subunit VII with the inner mitochondrial membrane.

Adenosine Triphosphate↗
PubMed1995

Effect of the hydrophilic alpha-tocopherol analog MDL 74,405 on detection of hydroxyl radicals in stunned myocardium in dogs.

We have previously shown in dogs that the hydrophilic alpha-tocopherol analog, MDL 74,405, attenuates postischemic myocardial dysfunction ("stunning") and generation of free radicals as assessed with the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). However, we could not discern whether this drug acts on primary radicals (such as hydroxyl radical [.OH]) or on secondary radicals. The goal of this study was to directly determine whether the beneficial effects of MDL 74,405 result from actions against .OH. Open-chest dogs undergoing a 15-minute coronary artery occlusion and 3 hours of reperfusion received an intravenous infusion of either saline solution (control group, n = 7) or MDL 74,405 (n = 6) starting 30 minutes before coronary occlusion and ending 60 minutes after reflow at a dose of 0.3 mg/kg/hr. Formation of .OH was estimated by the technique of aromatic hydroxylation of phenylalanine. Phenylalanine was infused intravenously, and the plasma concentrations of the hydroxylated products ortho-, meta-, and para-tyrosines (o-, m-, and p-tyr) in the coronary venous effluent and in the arterial blood were measured with high-performance liquid chromatography. In the control group a dramatic increase in the myocardial release of o-, m-, and p-tyr was observed immediately after reperfusion; the release of tyrosines peaked at 1 minute of reflow and continued up to 10 minutes after reperfusion. MDL 74,405 abolished the release of o-tyr throughout the first 10 minutes of reperfusion but had a less pronounced effect on the production of m- and p-tyr. These results demonstrate that MDL 74,405 is effective in inhibiting .OH-initiated reactions in the postischemic stunned myocardium in the dog, suggesting that the anti-.OH action of MDL 74,405 is an important mechanism of action of this antioxidant.

Animals↗
PubMed1995

Effect of adenosine on myocardial 'stunning' in the dog.

Recent evidence suggests a cardioprotective effect of adenosine in myocardial ischemia and reperfusion. The present study was undertaken to determine (1) whether adenosine attenuates myocardial stunning, (2) if so, whether the beneficial effect of adenosine takes place during ischemia or after reperfusion, and (3) whether adenosine preconditions against myocardial stunning. A total of 93 dogs were used. In phase A of the study, open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion received an intracoronary infusion of either saline (group I [control], n = 14), 2 mg/min adenosine from 30 minutes before occlusion until 1 hour after reperfusion (group II, n = 10), or 2 mg/min adenosine from 2 minutes before reperfusion until 1 hour after reperfusion (group III, n = 11). Regional myocardial function (assessed as systolic wall thickening) was similar in the three groups at baseline and during ischemia. After reperfusion, dogs treated with adenosine before, during, and after ischemia (group II) demonstrated a significant improvement in the recovery of function that persisted throughout the 4 hours of reperfusion. In contrast, in dogs treated only during the reperfusion period (group III), the recovery of function was not statistically different from that in control dogs. The enhanced recovery effected by adenosine in group II could not be ascribed to differences in ischemic zone size, collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase B of the study, dogs received an intracoronary infusion of either saline (group IV [control], n = 6) or adenosine (4 mg/min from 40 to 10 minutes before occlusion [group V, n = 6]). Despite pretreatment with adenosine, the recovery of function in group V was indistinguishable from that in the control group. This study demonstrates that (1) continuous administration of adenosine before, during, and after ischemia results in a significant and sustained attenuation of myocardial stunning; (2) this improved recovery of function cannot be attributed to nonspecific variables, such as collateral flow during coronary occlusion, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective action of adenosine; (3) the protection against stunning is lost or markedly diminished if adenosine is given only at reperfusion; and (4) administration of adenosine before ischemia does not precondition the myocardium against the stunning induced by a 15-minute occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1995

Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs.

Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3 of stage I). The recovery of systolic wall thickening (WTh) after the 10th reperfusion was markedly improved on days 2 and 3 compared with day 1, indicating that the myocardium had become preconditioned against "stunning." 10 d after stage I, pigs underwent again a sequence of 10 2-min coronary occlusions for two consecutive days (days 1 and 2 of stage II). On day 1 of stage II, the recovery of WTh after the 10th reperfusion was similar to that noted on day 1 of stage I; on day 2 of stage II, however, the recovery of WTh was again markedly improved compared with day 1. Blockade of adenosine receptors with 8-p-sulfophenyl theophylline failed to prevent the development of preconditioning against stunning. Northern blot analysis demonstrated an increase in heat stress protein (HSP) 70 mRNA 2 h after the preconditioning ischemia; at this same time point, immunohistochemical analysis revealed a concentration of HSP70 in the nucleus and an overall increase in staining for HSP70. 24 h after the preconditioning ischemia, Western dot blot analysis demonstrated an increase in HSP70. This study indicates the existence of a new, previously unrecognized cardioprotective phenomenon. The results demonstrate that a brief ischemic stress induces a powerful, long-lasting (at least 48 h) adaptive response that renders the myocardium relatively resistant to stunning 24 h later (late preconditioning against stunning). This adaptive response disappears within 10 d after the last ischemic stress but can be reinduced by another ischemic stress. Unlike early and late preconditioning against infarction, late preconditioning against stunning is not blocked by adenosine receptor antagonists, and therefore appears to involve a mechanism different from that of other forms of preconditioning currently known. The increase in myocardial HSP70 is compatible with, but does not prove, a role of HSPs in the pathogenesis of this phenomenon.

Adaptation, Physiological↗
PubMed1995

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Open-chest dogs (total number used, 117) underwent 10 5-min coronary occlusions (O) interspersed with 10 min of reperfusion (R). When systolic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight additional loss during the next four cycles and no further loss during the last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained when the total deficit of wall thickening during the final 4-h R interval was measured. The total deficit was similar after one and three 5-min O (groups V and VI, respectively), indicating that the first ischemic episode did precondition against the next two episodes; however, it was approximately 2.5-fold greater after 10 O (group IV) than after 3, indicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th O, the preconditioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with alpha-phenyl N-tert-butyl nitrone (PBN) demonstrated a burst of free radical generation immediately after the 1st, 5th, and 10th R (group VIII). The total cumulative release of PBN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the 1st (P < 0.05) but did not differ significantly between the 1st and 10th R. When administered throughout the 10 O-R cycles, the .OH scavenger mercaptopropionyl glycine significantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the beneficial effects of mercaptopropionyl glycine were completely, or largely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles was sufficient to cause severe postischemic dysfunction, and (b) the cumulative injury caused by repetitive ischemic episodes is mediated by recurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of myocardial stunning after repetitive ischemia, and implicates .OH as a primary culprit. Taken together, the data indicate that recurrent brief ischemic episodes result in recurrent bouts of oxyradical-mediated injury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning.

Animals↗
PubMed1995

Inhibitory effect of a hydrophilic alpha-tocopherol analogue, MDL 74,405, on generation of free radicals in stunned myocardium in dogs.

A previous study has demonstrated that the hydrophilic (alpha-tocopherol analogue, MDL 74,405, attenuates postischemic myocardial dysfunction ("stunning") in dogs. The present study was undertaken to determine directly whether the salutary effect of this drug on myocardial stunning results from inhibition of the generation of oxygen-derived free radicals. Open-chest dogs undergoing a 15-min coronary artery occlusion and 3 h of reperfusion received an intravenous infusion of either saline (controls, n = 7) or MDL 74,405 (n = 6) starting 30 min before coronary occlusion and ending 60 min after reflow at a dose of 0.3 mg/kg/h. To measure free radical production, all dogs received an intravenous infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN) and local coronary venous plasma was analyzed by electron paramagnetic resonance (EPR). In control dogs, the myocardial production of PBN adducts exhibited an initial burst immediately after the onset of reflow and remained elevated until 10 min after reperfusion. Dogs treated with MDL 74,405 demonstrated a marked decrease in PBN adduct production. This effect of MDL 74,405 could not be attributed to nonspecific factors such as differences in ischemic zone size, collateral flow, arterial pressure, heart rate, coronary flow or other hemodynamic variables. These results demonstrate that the hydrophilic vitamin E analogue, MDL 74,405, inhibits free radical generation after myocardial ischemia-reperfusion in vivo. This finding provides direct evidence that the salutary effects of MDL 74,405 on myocardial stunning are due to attenuation of oxidative stress.

Animals↗
PubMed1993

Effect of transforming growth factor-beta 1 on myocardial stunning in the intact dog.

Previous studies have demonstrated that transforming growth factor-beta (TGF-beta) can accelerate wound healing, inhibit free radical formation and limit myocardial ischemia/reperfusion injury in a variety of experimental models. However, it is unknown whether exogenous TGF-beta 1 can attenuate the prolonged contractile dysfunction that is observed after a brief, reversible ischemic insult (myocardial stunning). Thus, open-chest dogs undergoing a 15-min left anterior descending coronary artery occlusion and 4 h of reperfusion were given TGF-beta 1 as an intravenous bolus (250 micrograms) at 24 h and again at 1 h before coronary occlusion (n = 5). Control dogs (n = 7) received equivalent amounts of vehicle. The two groups were similar with respect to occluded bed size, collateral blood flow and rate-pressure product. Fundamental physiological parameters, such as body temperature, arterial pH, PO2 and hematocrit, were within normal limits throughout the experiment. In control dogs, regional myocardial function (assessed as systolic thickening fraction) remained depressed throughout the 4 h reperfusion period, indicating severe myocardial stunning. TGF-beta 1 did not produce any significant improvement in the recovery of regional function; 4 h after reperfusion, paradoxical systolic thinning was still present in both treated and control groups, with thickening fraction being -22.5 +/- 6.1% and -31.0 +/- 5.3% of baseline, respectively (P = N.S.). These results demonstrate that a large dose of TGF-beta 1 given before ischemia fails to attenuate myocardial stunning in the open-chest dog, suggesting that this growth factor does not exert protective effects in the setting of reversible myocardial ischemia/reperfusion injury.

Acute Disease↗
PubMed1993

Effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury: an overview.

There are multiple mechanisms whereby ACE inhibitors could be beneficial during myocardial ischemia and reperfusion, including: i) reduced formation of angiotensin II, ii) decreased metabolism of bradykinin, iii) antioxidant activity, and iv) possibly other unknown mechanisms. Reduced formation of angiotensin II should be beneficial because this peptide exerts several actions that are potentially detrimental to the ischemic/reperfused myocardium, including vasoconstriction, increased release of norepinephrine, stimulation of phospholipase C and/or A2, and increased afterload with an attendant increase in oxygen demands. Reduced metabolism of bradykinin could be beneficial by increasing myocardial glucose uptake, by causing vasodilation, and by stimulating production of endothelium-derived relaxing factor and prostacyclin. Although earlier studies suggested that sulfhydryl-containing ACE inhibitors scavenge superoxide anions, recent data have shown that these drugs scavenge hydroxyl radical and hypochlorous acid with no effect on superoxide anion. Studies in isolated hearts have demonstrated that ACE inhibitors attenuate the metabolic, arrhythmic, and contractile dearrangements associated with ischemia and reperfusion, and have suggested that such beneficial effects are mediated by potentiation of bradykinin and/or increased synthesis of prostacyclin. Studies in models of myocardial stunning after brief (15-min) ischemia in vivo (anesthetized dogs) suggest that ACE inhibitors enhance the recovery of contractile function after a single brief ischemic episode. No data are available regarding the effect of these drugs on myocardial stunning after a prolonged, partly reversible episode, after multiple consecutive brief ischemic episodes, and after global ischemia. The mechanism for the salutary effects of ACE inhibitors on stunning remains a mystery. It may involve an antioxidant action (in the case of thiol-containing molecules) or potentiation of prostaglandins (in the case of non-thiol-containing molecules). What is clear is that the enhanced recovery of function effected by these drugs is not due to hemodynamic effects, inhibition of the converting enzyme per se, or an "antischemic" action (since the drugs were effective when given at the time of reperfusion). The effects of ACE inhibitors on myocardial infarct size remain controversial. Further studies will be necessary to conclusively establish whether ACE inhibitors can protect against the detrimental effects of myocardial ischemia and reperfusion. Nevertheless, the evidence provided thus far is encouraging and warrants an in-depth assessment of the role of these drugs in attenuating myocardial ischemia/reperfusion injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Effects of the spin trap alpha-phenyl N-tert-butyl nitrone on myocardial function and flow: a dose-response study in the open-chest dog and in the isolated rat heart.

Alpha-phenyl N-tert-butyl nitrone (PBN) is widely used in spin-trapping experiments, but its possible toxicity has not been systematically evaluated. The purpose of this study was to investigate the effects of different doses of PBN on cardiac function in vivo (open-chest dogs) and in vitro (isolated rat hearts). In open-chest dogs, PBN was infused intracoronarily to achieve coronary arterial concentrations ranging from 1.6 mM to 10.0 mM. At coronary arterial concentrations of 1.6 mM and 2.5 mM, PBN had no appreciable effect on regional myocardial function (assessed as systolic wall thickening). However, coronary arterial concentrations of PBN of 5.0 mM and 10.0 mM produced a marked reduction and, eventually, a complete loss of systolic wall thickening (53% of baseline values after 30 min at 5.0 mM and 14% after 30 min at 10.0 mM). Furthermore, PBN increased coronary blood flow by approximately 25% at 2.5 mM and by > 100% at 10.0 mM. In isolated rat hearts, perfusion with 2.5 and 5.0 mM PBN for 60 min did not significantly affect global myocardial function, assessed as developed pressure, rate-pressure product, and positive and negative dP/dt. At the 10.0 mM concentration, however, these variables were significantly decreased after 30 min (developed pressure: -77% vs. controls; rate-pressure product: -84%; +dP/dt: -60%; -dP/dt: -70%); two out of five hearts stopped beating within 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1993

Augmentation of endogenous adenosine attenuates myocardial 'stunning' independently of coronary flow or hemodynamic effects.

BACKGROUND: Mounting evidence suggests a protective effect of exogenous adenosine in myocardial ischemia and reperfusion. We tested the hypothesis that augmentation of endogenous adenosine levels, achieved by inhibiting adenosine catabolism and washout, is beneficial in postischemic myocardial dysfunction ("stunning"). METHODS AND RESULTS: In phase I of the study, open-chest dogs undergoing a 15-minute coronary artery occlusion and 4 hours of reperfusion received an intracoronary infusion of either saline (controls, n = 23) or 6-(4-nitrobenzyl)-mercapto: purine ribonucleoside (NBMPR, a selective nucleoside transport inhibitor) combined with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, a potent adenosine deaminase inhibitor) (EHNA + NBMPR, n = 15) starting 15 minutes before coronary occlusion and ending 15 minutes after the initiation of reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischemia. After reperfusion, however, the dogs treated with EHNA + NBMPR exhibited a significant improvement in the recovery of function, which was evident as early as 30 minutes after restoration of flow and was sustained throughout the rest of the reperfusion phase. The enhanced recovery effected by EHNA + NBMPR could not be attributed to nonspecific factors such as differences in collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase II of the study, the myocardial content of adenine nucleotides and nucleosides was measured by high performance liquid chromatography in myocardial biopsies obtained serially from open-chest dogs undergoing the same protocol used in phase I. There were no significant differences between control (n = 8) and treated (n = 9) dogs with respect to myocardial levels of adenosine triphosphate (ATP) at 30 and 60 minutes after reperfusion, indicating that the beneficial effects of EHNA + NBMPR cannot be ascribed to repletion of ATP stores. Compared with controls, dogs treated with EHNA + NBMPR exhibited a much larger increase in myocardial adenosine (6.07 +/- 1.47 vs 1.03 +/- 0.16 nmol/mg protein, P < .05) and a much smaller increase in inosine (0.52 +/- 0.27 vs 3.04 +/- 0.54 nmol/mg protein, P < .05) at the end of ischemia, such that the inosine-to-adenosine ratio noted in controls was completely reversed (approximately 6:1 vs approximately 1:6, respectively). In the treated group, adenosine levels remained markedly increased compared with controls up to 1 hour after reperfusion. CONCLUSIONS: This study demonstrates that (1) administration of an adenosine deaminase inhibitor plus a nucleoside transport blocker is remarkably effective in augmenting myocardial adenosine levels during regional ischemia and subsequent reperfusion in vivo, (2) this augmentation of adenosine results in a significant and sustained attenuation of myocardial stunning, and (3) the attenuation of stunning is not due to ATP repletion or to nonspecific actions on hemodynamic variables or coronary flow. These findings suggest that endogenous adenosine production during ischemia serves as an important pathophysiological mechanism that protects against myocardial stunning. The results also suggest that augmentation of endogenous adenosine (without exogenous adenosine administration) represents an effective therapeutic approach to the alleviation of reversible postischemic dysfunction.

Adenine↗