Assessment of the Efficacy of Interventions to Limit Ischemic Injury by Direct Measurement of Intramural Carbon Dioxide Tension after Coronary Artery Occlusion in the Dog

Hillis, L. David; Khuri, Shukri F.; Braunwald, Eugene; Kloner, Robert A.; Tow, Donald E.; Barsamian, Ernest M.; Maroko, Peter R.

doi:10.1172/jci109284

Cited by 38 publications

(12 citation statements)

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“…This suggests that flux through the pathways of ATP degradation to nucleosides and bases (ATP --~ ADP --~ AMP adenosine --~ inosine --~ hypoxanthine) was reduced during the second and third periods of ischemia. This is supported by observations by Hillis et al who measured intramyocardial carbon dioxide tension during repetitive 10-min occlusions and found that the increase in CO2 during the second and third periods of occlusion was significantly less than during the first occlusion (10). This suggests that the cellular processes responsible for ATP degradation and H + accumulation are slower or compensated for in the "stunned" myocardium.…”

Section: Discussionsupporting

confidence: 71%

Effects of recurrent ischemia on myocardial high energy phosphate content in canine hearts

et al. 1984

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Successive ischemic episodes are commonly seen in clinical and experimental cardiology. Although prolonged abnormalities of the canine myocardium have been described following a single ischemic episode, it is not known whether myocardial injury is cumulative following multiple ischemic episodes. Dogs were subjected to three 15-min left anterior descending coronary artery occlusions, each followed by 30 min of reperfusion. In vivo biopsies were obtained for biochemical analysis before and during the first occlusion and 30 min into each reperfusion period. ATP and creatine phosphate (CP) fell in the endocardium during occlusion by 24% and by 69% respectively (both p less than .0001). While CP recovered during each reperfusion period, ATP remained significantly depressed. Loss of membrane-permeable purine nucleotide synthesis precursors occurred with the first reperfusion period but not with the second and third reperfusion periods. Therefore, reperfusion following one 15-min coronary occlusion is associated with severe depression of myocardial high energy phosphates; however, two additional occlusions do not cause a further decrease of these substances when intermittent reperfusion is allowed for 30 min.

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Section: Discussionsupporting

confidence: 71%

Effects of recurrent ischemia on myocardial high energy phosphate content in canine hearts

et al. 1984

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“…However, studies in which this assumption is central to the interpretation of results require careful scrutiny. Pathologic investigations reveal no cellular necrosis after an ischemic event of this duration (24), and electrophysiological abnormalities and myocardial CO2 tension return to normal (25,26). Mechanical recovery, however, may be delayed for 24 hr (23).…”

Section: Methodsmentioning

confidence: 84%

“…After 90 min of reperfusion ATP concentrations remained depressed in the previously ischemic subendocardium 26.8 b 4.2 (P < 0.025 vs. nonischemic sites). After 72 hr of reperfusion, ATP was still depressed in the previously ischemic subendocardium at 29.2 ± 2.5 (P < 0.025 vs. nonischemic) and subepicardium (27.9 + 3.3, P < 0.05 vs. nonischemic).…”

mentioning

confidence: 88%

Prolonged derangements of canine myocardial purine metabolism after a brief coronary artery occlusion not associated with anatomic evidence of necrosis

DeBoer

Ingwall

Kloner

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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216

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Changes in myocardial purine metabolism were studied after temporary coronary artery occlusion and subsequent reperfusion in the dog. Sequential myocardial biopsies were performed to allow for measurements of ATP, adenine nucleotide, nucleoside, and base concentrations after 15 min of ischemia, and after 90 min and 72 hr of reperfusion following this period of ischemia. Control, nonischemic sites were also sampled. After 15 min of coronary occlusion, subendocardial ATP concentrations (reported in nmol/mg of protein; mean + SEM) were depressed in the ischemic zone at 19.9 + 3.5 compared to 38.1 ± 2.8 in the nonischemic zone (P < 0.001). Subepicardial ATP concentrations also were depressed at 27.0 ± 2.2 in ischemic sites compared to subepicardial nonischemic sites (40.0 + 4.0, P < 0.005). After 90 min of reperfusion ATP concentrations remained depressed in the previously ischemic subendocardium 26.8 b 4.2 (P < 0.025 vs. nonischemic sites). After 72 hr of reperfusion, ATP was still depressed in the previously ischemic subendocardium at 29.2 ± 2.5 (P < 0.025 vs. nonischemic) and subepicardium (27.9 + 3.3, P < 0.05 vs. nonischemic). Total purines were determined as the sum of ATP, ADP, AMP, adenosine, inosine, and hypoxanthine. After 15 min of occlusion, the total purine pool in the ischemic subendocardium tended towards being lower than in the nonischemic zone (42.0 + 5.9 vs. 53.8 + 5.2, not significant) but in the ischemic subepicardium the total purine pool was similar to that in the nonischemic zone. After 90 min of reperfusion the previously ischemic subendocardial purine pool was reduced compared to the nonischemic zone (39.0 + 4.8, P < 0.025). Total purines were also depleted in both the subendocardium and subepicardium of previously ischemic zones after 72 hr of reperfusion (44.5 + 2.9 and 40.0 + 4.4, respectively, P < 0.05). Histologic analysis of the previously ischemic tissue revealed no evidence of necrosis. Therefore, brief temporary coronary artery occlusions not associated with anatomic evidence of necrosis may result in prolonged abnormalities of ATP concentration and significant depletion of the total purine pool. It is generally assumed that the myocardium of patients who experience temporary myocardial ischemia, such as occurs in angina pectoris, and who recover from this event without developing electrocardiographic, enzymatic, or radioisotopic evidence of myocardial infarction, rapidly returns to normal. There are experimental studies that support this assumption. Thus, after temporary coronary artery occlusion in animals in which the myocardium is ischemic for less than 20 min, no necrosis develops when the coronary artery is released. Hence this myocardium has been considered to be reversibly injured (1). On the other hand, when the temporary coronary occlusion is maintained for a longer period of time (40-60 min), histologic evidence of necrosis develops in the subendocardium and, by definition, these cells may be considered to be irreversibly injured (1). Although brief coronary arter...

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“…Isoproterenol and glucagon, at doses that doubtlessly increased LV contractility, augmented ischemic zone ST-segment elevation during coronary artery occlusion.2 In these studies, atrial pacing produced less augmentation of ST-segment elevation than equichronotropic doses of isoproterenol, and the deleterious effects of glucagon were also partially mitigated when heart rate was maintained constant by atrial pacing.2 A study from our laboratory showed that dobutamine (20 ,g/kg/min) increased both heart rate and LV dP/dt in the anesthetized dog, and resulted in augmentation of ischemic zone epicardial ST-segment elevation during coronary occlusion; a lower dose of this agent (4 ,ug/kg/min), which raised heart rate only by [5][6][7][8][9][10] beats/min, did not augment ischemic damage despite a positive inotropic effect.' Ramanathan et al5 also showed that the inotropic stimulant dopamine, at doses that do not accelerate heart rate, does not augment ischemic zone ST-segment elevation., A dissociation of the deleterious effects of increases in heart rate and LV contractility was also noted by Vatner and Baig in conscious dogs subjected to coronary occlusion.2' Isoproterenol, in doses that increased heart rate and LV contractility, decreased ischemic zone segmental shortening and blood flow, while dobutamine and dopamine, at doses that increased LV dP/dt, did not further reduce ischemic zone contractile function or blood flow when heart rate was not increased.2' These investigators also found that ouabain given to chronically instrumented conscious dogs with temporary coronary occlusion led to an increase in LV dP/dt without a change in heart rate and improved systolic segment shortening, blood flow and ST-segment deviation in the ischemic zone.…”

Section: Discussionmentioning

confidence: 99%

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

et al. 1982

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SUMMARY The effect of i.v. dobutamine on acute myocardial ischemic injury was assessed in 22 anesthetized dogs subjected to serial 10-minute occlusions of the left anterior descending coronary artery. The severity of ischemic injury was determined by mass spectrometric measurement of the increase in intramural carbon dioxide tension (zAPmco2) in the ischemic zone. In the nine protocol 1 dogs, dobutamine, 20 ,ug/kg/min, infused between the control and final occlusion, significantly increased both heart rate (HR) and left ventricular (LV) dP/dt; APmco2 was significantly higher during the dobutamine infusion than during control occlusion (76 ± 21 vs 56 + 13 mm Hg,p < 0.01). The nine protocol 2 dogs were atrially paced at a HR of 20-30 beats/min above baseline values during the control occlusion and received dobutamine (12.6 ± 7.8 ugg/kg/min) at doses necessary to attain an equal HR (mean 149-154 beats/min) during the last occlusion.Although LV dP/dt was higher after dobutamine, APmco2 was similar during the two occlusions. Protocol 3 dogs (n = 4) received lower doses of dobutamine (5.6 ± 3.2 Ag/kg/min) to produce an increase in LV dP/dt, but not in HR compared with baseline values; APmco2 was similar during control and dobutamine occlusions. There were no major changes in arterial or left atrial pressures. Rate-pressure product, an indirect measurement of myocardial oxygen consumption, was increased only by the higher doses of dobutamine in protocol 1.Thus, inotropic stimulation with dobutamine during coronary occlusion does not cause important augmentation of acute myocardial ischemic injury in the nonfailing heart unless HR is increased simultaneously.THE SEVERITY of evolving acute myocardial ischemic injury can be influenced by interventions performed before or shortly after experimental coronary artery occlusion.' Pharmacologic agents and hemodynamic alterations can affect ischemic injury. Although most reports deal with interventions that lessen myocardial ischemic injury, certain interventions can intensify ischemia or increase infarct size.2 B Even though the role of specific therapy to protect ischemic myocardium in the patient with evolving acute myocardial infarction is not clear, it is widely held that interventions that augment ischemic injury in experimental animals should be avoided in patients with myocardial ischemic syndromes.0" 11 Most deleterious influences on evolving ischemic damage are thought to be mediated by further alterations in the relationship between myocardial oxygen supply and demand in ischemic tissue. An creasing heart rate, contractile state, or left ventricular (LV) wall tension.'1 Because many studies that showed augmentation of ischemic injury used interventions that simultaneously alter several determinants of myocardial oxygen demand or supply or both, we investigated whether deleterious effects on ischemic damage also result from more selective alterations in these hemodynamic variables.Methods Twenty-two mongrel dogs that weighed 17-44 kg were anesthetized with i.v. pen...

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Assessment of the Efficacy of Interventions to Limit Ischemic Injury by Direct Measurement of Intramural Carbon Dioxide Tension after Coronary Artery Occlusion in the Dog

Cited by 38 publications

References 46 publications

Effects of recurrent ischemia on myocardial high energy phosphate content in canine hearts

Effects of recurrent ischemia on myocardial high energy phosphate content in canine hearts

Prolonged derangements of canine myocardial purine metabolism after a brief coronary artery occlusion not associated with anatomic evidence of necrosis

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog.

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