phosphocreatinine and Myocardial-Ischemia

The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention.. To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease.. Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction.. Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery.. The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change.. Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia.. This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.

Topics: Cardiovascular Diseases; Creatine; Creatine Kinase; Heart Failure; Humans; Hypertension; Molecular Targeted Therapy; Myocardial Infarction; Myocardial Ischemia; Phosphocreatine

This study examined the changes in myocardial energy metabolism during myocardial ischemia after "remote preconditioning" and investigated the involvement of adenosine receptors in the mechanisms of this effect.. Recent studies have indicated that a brief period of ischemia and reperfusion (ischemic preconditioning, PC) in a remote organ reduces myocardial infarct size (IS) protecting against subsequent sustained myocardial ischemia. However, the mechanisms of "remote PC" remain unclear. We assessed myocardial energy metabolism during sustained myocardial ischemia and reperfusion after renal PC (RPC), in comparison with that after myocardial PC (MPC) in open-chest rabbits. It has been established that adenosine receptors are involved in the mechanisms of MPC.. Rabbits that had been anesthetized with halothane were divided into six groups. The control (CNT) group underwent 40-min coronary occlusion followed by 120 min reperfusion. Before the procedure, the MPC group underwent an additional protocol of 5 min coronary artery occlusion and 20 min reperfusion, and the RPC group received a 10 min episode of renal artery occlusion and 20 min reperfusion. In additional experimental groups, 8 sulfophenyl-theophylline (SPT, 10 mg/kg), an adenosine receptor inhibitor, was intravenously injected before the 40 min myocardial ischemia (SPT, MPC + SPT and RPC + SPT groups, respectively). Myocardial levels of phosphocreatine (PCr), ATP and intracellular pH (pHi) were measured by 31P-NMR spectroscopy.. RPC and MPC delayed the decreases in ATP levels, preserved pHi during 40-min myocardial ischemia and resulted in better recovery of ATP and PCr during 120 min reperfusion compared with the controls. SPT abolished the improvement in myocardial energy metabolism and the reduction in myocardial IS caused by MPC or RPC. Myocardial IS in the CNT (n = 8), MPC (n = 9), RPC (n = 9), SPT (n = 6), MPC + SPT (n = 8) and RPC + SPT (n = 8) groups averaged 42.8+/-3.5%, 18.2+/-1.8%*, 19.6+/-1.3%*, 44.9+/-5.0%, 35.6+/-2.7% and 34.8+/-3.6% of the area at risk (*p < 0.05 vs. CNT), respectively.. PC in a remote organ, similar to MPC, improved myocardial energy metabolism during ischemia and reperfusion and reduced IS in vivo by an adenosine-dependent mechanism in rabbits.

Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Hydrogen-Ion Concentration; Infusions, Intravenous; Intracellular Fluid; Ischemia; Ischemic Preconditioning, Myocardial; Kidney; Magnetic Resonance Spectroscopy; Male; Myocardial Ischemia; Myocardium; Phosphocreatine; Pilot Projects; Purinergic P1 Receptor Antagonists; Rabbits; Receptors, Purinergic P1; Theophylline

Fructose-1,6-diphosphate is a glycolytic intermediate that has been shown experimentally to cross the cell membrane and lead to increased glycolytic flux. Because glycolysis is an important energy source for myocardium during early reperfusion, we sought to determine the effects of fructose-1,6-diphosphate on recovery of postischemic contractile function.. Langendorff-perfused rabbit hearts were infused with fructose-1,6-diphosphate (5 and 10 mmol/L, n = 5 per group) in a nonischemic model. In a second group of hearts subjected to 35 minutes of ischemia at 37 degrees C followed by reperfusion (n = 6 per group), a 5 mmol/L concentration of fructose-1,6-diphosphate was infused during the first 30 minutes of reperfusion. We measured contractile function, glucose uptake, lactate production, and adenosine triphosphate and phosphocreatine levels by phosphorus 31-nuclear magnetic resonance spectroscopy.. In the nonischemic hearts, fructose-1,6-diphosphate resulted in a dose-dependent increase in glucose uptake, adenosine triphosphate, phosphocreatine, and inorganic phosphate levels. During the infusion of fructose-1,6-diphosphate, developed pressure and extracellular calcium levels decreased. Developed pressure was restored to near control values by normalizing extracellular calcium. In the ischemia/reperfusion model, after 60 minutes of reperfusion the hearts that received fructose-1,6-diphosphate during the first 30 minutes of reperfusion had higher developed pressures (83 +/- 2 vs 70 +/- 4 mm Hg, p < 0.05), lower diastolic pressures (7 +/- 1 vs 12 +/- 2 mm Hg, p < 0.05), and higher phosphocreatine levels than control untreated hearts. Glucose uptake was also greater after ischemia in the hearts treated with fructose-1,6-diphosphate.. We conclude that fructose-1,6-diphosphate, when given during early reperfusion, significantly improves recovery of both diastolic and systolic function in association with increased glucose uptake and higher phosphocreatine levels during reperfusion.

Topics: Adenosine Triphosphate; Animals; Calcium; Fructosediphosphates; Glucose; Immunologic Factors; Lactic Acid; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphocreatine; Phosphorus Isotopes; Rabbits

The aim was to examine the effect on cardiac function, energy metabolism, and calcium uptake of either prostaglandin I2 (PGI2, prostacyclin) or prostaglandin F2 alpha (both 28.6 nM) on the response of isolated rat hearts to 25 min of total global ischaemia with or without 30 min reperfusion.. Rat hearts were perfused by the Langendorff method and function assessed by left ventricular pressure. Energy metabolites were measured using enzymatic techniques and 45Ca2+ uptake determined by radioisotopic analysis.. Although there was no effect of either prostaglandin on contractile depression during ischaemia, both compounds accelerated the onset of and increased the magnitude of ischaemic contracture. High energy phosphate content at the end of the ischaemic period was not affected by prostaglandin treatment; however, tissue lactate levels were increased by PGI2 as was tissue calcium content. Under control conditions mean recovery of left ventricular developed pressure ranged from 66% to 83%. In the presence of PGI2 and PGF2 alpha, recovery of developed pressure was reduced to 20% and 38% of preischaemic values, respectively. The reduced recovery in developed pressure was accompanied by an approximately threefold increase in diastolic pressure (p < 0.05). The depression of functional recovery in reperfused hearts treated with prostaglandins was associated with various disturbances of cellular metabolism including depressed ATP and creatine phosphate content and increased tissue lactate and calcium following 30 min of reperfusion. A significant correlation was found between the changes in developed pressure and diastolic pressure during reperfusion and the reduction in ATP and creatine phosphate repletion. The deficit in recovery of ventricular function also correlated significantly with increased lactate and calcium accumulation in the reperfused heart.. Low concentrations of PGI2 and PGF2 alpha can depress contractile recovery of the globally ischaemic heart through a mechanism associated with altered cellular energy metabolism and increased calcium accumulation.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Calcium; Dinoprost; Energy Metabolism; Epoprostenol; In Vitro Techniques; Lactates; Lactic Acid; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Ventricular Function, Left