Protection of the ischemic dog myocardium with carnitine

In 25 open chest anestheslzed dogs, left anterior descending coronary arterial blood flow was measured with an electromagnetic flowmeter while aortic blood pressure and epicardlal electrocardiograms were recorded. Ischemia was produced in the left anterior descending arterial bed by decreasing mean flow to one third of control levels for a 5 minute period with a micrometer snare device. This produced an increase in S-T segment deviation greater than 4 mv in the ischemic bed. Control and ischemic left anterior descending arterial bed tissue samples were obtained by drill biopsy and were analyzed for adenosine triphosphate (ATP) and creatine phosphate levels and adenlne nucleotide translocase activity. The ATP levels decreased from 5.6 ± 1.2 to 3.6 ± 1.4 μmoles/g, and creatine phosphate decreased from 15.3 ± 4.6 to 5.8 ± 3.8 μmoles/liter. The adenine nucleotide translocase activity decreased from an average control value of 42,957 ± 9,480 to 29,100 ± 6,609 disintegrations per minute (dpm)/mg during the 5 minute period of ischemia. With the ischemia maintained, 100 mg/cc of L-carnitine was infused into the ischemic left anterior descending arterial bed at a rate of 1 cc/min for 5 minutes (17 dogs), and 80 mg/kg of D-L carnltine was given intravenously in 8 dogs. The epicardial S-T segment deviation decreased to approximately 2 mv after the carnltine infusion, with ischemia maintained. A third biopsy sample of the ischemic bed showed that the ATP level had increased to 5.2 ± 1.1 and the creatine phosphate to 10.8 ± 4.8 moles/g; the adenine nucleotide translocase activity had increased to 37,800 ± 7,210 dpm/mg. In 9 dogs ventricular fibrillation developed at this level of ischemia before infusion of carnitine, whereas only one dog had fibrillation at comparable levels of ischemia after infusion.

These results support the hypothesis that infusion of carnitine may benefit the ischemic myocardium by maintaining tissue levels of free carnitine, reversing inhibition of adenine nucleotide translocase by long chain acyl coenzyme A esters and in this manner restoring mitochondrial function.     

Protection of the myocardium during ischemic arrest: possible toxicity of carnitine in cardioplegic solutions

Carnitine has been suggested as an agent for the protection of the myocardium during regional ischemia and it might therefore be able to reduce tissue injury during surgically induced global ischemia. Using an isolated working rat heart model we have assessed the way in which various concentrations of carnitine infuence the efficacy of the St. Thomas' Hospital Cardioplegic Solution. Carnitine was found to exert a dose-dependent detrimental effect upon the ischemic myocardium, with high concentrations abolishing all the protective properties of the cardioplegic solution. Furthermore, this compound appeared to promote the occurrence of reperfusion dysrhythmias.     

Improved pacing tolerance of the ischemic human myocardium after administration of carnitine.

The possibility that DL-carnitine has a protective effect during myocardial ischemia was evaluated by performing two rapid coronary sinus pacing studies 15 minutes apart in 21 patients with coronary artery disease. Eleven patients received DL-carnitine (20 or 40 mg/kg) before the second pacing study. The treated group had a significant increase in mean heart rate (12.5 beats/min, P less than 0.001), pressure-rate product (1,912 units, P less than 0.01) and pacing duration (3.2 minutes, P less than 0.001) after the administration of carnitine. The treated group also had improvements in percent myocardial lactate extraction (8.8 percent increase, P less than 0.001) and left ventricular end-diastolic pressure (a decrease of 5.3 mm Hg, P less than 0.05). There was significantly less S-T segment depression during the second pacing period in both the untreated and treated groups. The results of this study suggest that in ischemic human hearts with reasonably well preserved left ventricular function, DL-carnitine may improve the tolerance for stress associated with an increase in heart rate and pressure-rate product.     

Effects of propranolol and diltiazem on carnitine derivatives and acyl CoA in ischemic myocardium

The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acid (FFA) has been suggested as a cause of cellular damage in ischemic myocardium. We investigated the effects of propranolol and diltiazem on carnitine metabolism in ischemic myocardium. Propranolol (0.2 mg/kg/min, i.v.) and diltiazem (0.1 mg/kg/min, i.v.) were administered for 5 min, the administration started 10 min before coronary occlusion. ECGs were continuously recorded throughout the experiment. Myocardial samples were prepared from both the non-ischemic and ischemic areas 40 min after coronary ligation. Adenosine triphosphate (ATP), free carnitine, long chain acyl carnitine and long chain acyl CoA were assayed. Propranolol reduced the decrease of ATP and the accumulation of long chain acyl CoA, induced by myocardial ischemia. Diltiazem reduced the decrease of ATP and free carnitine, and the accumulation of long chain acyl carnitine in the ischemic area. Propranolol and diltiazem significantly reduced the grade of ventricular arrhythmia. These results suggest that the protective mechanisms of propranolol and diltiazem on myocardium are based, at least in part, on their beneficial effects upon myocardial carnitine metabolism.     

肉毒硷对大鼠心肌抗氧化能力的影响

以ＶＤ造成心肌损害模型，以肉毒硷为影响因素，测定了实验性大鼠心肌损伤中谷光甙肽过氧化物酶（ＧＳＨ－Ｐｘ）活性及脂质过氧化物含量。结果表明：ＶＤ组的脂质过氧化物含量明显高于肉毒硷加ＶＤ组及对照组（Ｐ〈０．０１），而ＧＳＨ－Ｐｘ活性则比其余两组显著降低。结果提示肉毒硷有维持ＧＳＨ－Ｐｘ活性的作用。缓解自由基脂质过氧化对心肌的损害。     

Effects of carnitine on the ischemic arrested heart

Summary We investigated the effect of L-carnitine on the recovery of cardiac function after ischemic arrest in the perfused rat heart. L-carnitine was added to a cardioplegic solution, both as a free base and hydrochloride. The addition of L-carnitine as a free base to the solution had no effect on recovery of cardiac function. When L-carnitine HCl was added to the cardioplegic solution, it was necessary to adjust the pH of the solution to 7.4. The hearts arrested with this solution showed a greater incidence of reperfusion dysrhythmias than those in the control or the free base solution, but the overall recovery of cardiac function was the same as control. The hydrochloride of L-carnitine is strongly acidic, and these findings indicate that either the free base or a properly buffered solution must be used to study effects of carnitine upon cardiac function.Supported in part by the Research Service of Veterans Administration and NIH grant HL-17736.     

Protective role of intracoronary fatty acid binding protein in ischemic and reperfused myocardium

In this study, fatty acid binding protein was used to protect an ischemic heart from reperfusion injury. Isolated rat heart was preperfused in the presence of 1.4 microM liposome-bound fatty acid binding protein for 15 minutes, followed by 30 minutes of ischemia and 30 minutes of reperfusion. Our results indicated better preservation of myocardial high-energy phosphate compounds (including ATP and creatine phosphate), reduced creatine kinase and lactate dehydrogenase release from the heart, and improved coronary flow in hearts treated with fatty acid binding protein compared with untreated controls. Fatty acid binding protein enhanced reacylation of arachidonic acid into phospholipids, thereby preserving membrane phospholipids and reducing free fatty acid contents during ischemia and reperfusion. In addition, fatty acid binding protein-bound long-chain free fatty acids and their thioesters as well as carnitine esters were increased in the cytosolic compartment of the heart. These results suggest that fatty acid binding protein may be used as a possible therapeutic agent to improve myocardial function during reperfusion of ischemic heart.     

Autophagy in chronically ischemic myocardium

We tested the hypothesis that chronically ischemic (IS) myocardium induces autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which could protect against the consequences of further ischemia. Chronically instrumented pigs were studied with repetitive myocardial ischemia produced by one, three, or six episodes of 90 min of coronary stenosis (30% reduction in baseline coronary flow followed by reperfusion every 12 h) with the non-IS region as control. In this model, wall thickening in the IS region was chronically depressed by approximately 37%. Using a nonbiased proteomic approach combining 2D gel electrophoresis with in-gel proteolysis, peptide mapping by MS, and sequence database searches for protein identification, we demonstrated increased expression of cathepsin D, a protein known to mediate autophagy. Additional autophagic proteins, cathepsin B, heat shock cognate protein Hsc73 (a key protein marker for chaperone-mediated autophagy), beclin 1 (a mammalian autophagy gene), and the processed form of microtubule-associated protein 1 light chain 3 (a marker for autophagosomes), were also increased. These changes, not evident after one episode, began to appear after two or three episodes and were most marked after six episodes of ischemia, when EM demonstrated autophagic vacuoles in chronically IS myocytes. Conversely, apoptosis, which was most marked after three episodes, decreased strikingly after six episodes, when autophagy had increased. Immunohistochemistry staining for cathepsin B was more intense in areas where apoptosis was absent. Thus, autophagy, triggered by ischemia, could be a homeostatic mechanism, by which apoptosis is inhibited and the deleterious effects of chronic ischemia are limited.     

Calcium antagonists and the ischemic myocardium

Recent laboratory studies have shown that the calcium antagonists (slow channel blockers) can protect the myocardium against the consequences of experimentally induced ischemia and reperfusion. With one recent exception, however, clinical trials relating to the effectiveness of these drugs in the management of patients with myocardial infarction have been disappointing. This paper explores this apparent discrepancy.