guanosine-triphosphate and Myocardial-Ischemia

Ischemia-reperfusion injury, a clinical problem during cardiac surgery, involves worsened adenosine trisphosphate (ATP) generation and damage to the heart. We studied carbon monoxide (CO) pretreatment, proven valuable in rodents but not previously tested in large animals, for its effects on pig hearts subjected to cardiopulmonary bypass with cardioplegic arrest. Hearts of CO-treated pigs showed significantly higher ATP and phosphocreatine levels, less interstitial edema, and apoptosis of cardiomyocytes and required fewer defibrillations after bypass. We conclude that treatment with CO improves the energy status, prevents edema formation and apoptosis, and facilitates recovery in a clinically relevant model of cardiopulmonary bypass surgery.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Apoptosis; Carbon Monoxide; Cardiopulmonary Bypass; Cardiotonic Agents; Edema; Electric Countershock; Energy Metabolism; Female; Guanosine Triphosphate; Heart; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; NAD; NADP; Oxidation-Reduction; Sus scrofa

The sulfonylurea glibenclamide (Glib) abolishes the cardioprotective effect of ischemic preconditioning (IP), presumably by inhibiting mitochondrial K(ATP) channel opening in myocytes. Glimepiride (Glim) is a new sulfonylurea reported to affect nonpancreatic K(ATP) channels less than does Glib. We examined the effects of Glim on IP and on the protection afforded by diazoxide (Diaz), an opener of mitochondrial K(ATP) channels.. Rat hearts were Langendorff-perfused, subjected to 35 minutes of regional ischemia and 120 minutes of reperfusion, and assigned to 1 of the following treatment groups: (1) control; (2) IP of 2x 5 minutes each of global ischemia before lethal ischemia; or pretreatment with (3) 30 micromol/L Diaz, (4) 10 micromol/L Glim, (5) 10 micromol/L Glib, (6) IP+Glim, (7) IP+Glib, (8) Diaz+Glim, or (9) Diaz+Glib. IP limited infarct size (18.5+/-1% vs 43.7+/-3% in control, P<0.01) as did Diaz (22.2+/-4.7%, P<0.01). The protective actions of IP or Diaz were not abolished by Glim (18.5+/-3% in IP+Glim, 22.3+/-3% in Diaz+Glim; P<0.01 vs control). However, Glib abolished the infarct-limiting effects of IP and Diaz. Patch-clamp studies in isolated rat ventricular myocytes confirmed that both Glim and Glib (each at 1 micromol/L) blocked sarcolemmal K(ATP) currents. However, in isolated cardiac mitochondria, Glim (10 micromol/L) failed to block the effects of K(ATP) opening by GTP, in contrast to the blockade caused by Glib.. Although it blocks sarcolemmal currents in rat cardiac myocytes, Glim does not block the beneficial effects of mitochondrial K(ATP) channel opening in the isolated rat heart. These data may have significant implications for the treatment of type 2 diabetes in patients with ongoing ischemic heart disease.

Topics: Animals; Diazoxide; Glyburide; Guanosine Triphosphate; Heart; Heart Ventricles; Hemodynamics; Hypoglycemic Agents; In Vitro Techniques; Intracellular Membranes; Ischemic Preconditioning, Myocardial; Male; Membrane Potentials; Membrane Proteins; Mitochondria, Heart; Myocardial Infarction; Myocardial Ischemia; Patch-Clamp Techniques; Potassium Channels; Rats; Rats, Sprague-Dawley; Sulfonylurea Compounds; Ventricular Function

In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase activity in right and left atria and left ventricles and on left ventricular contractility in six potential heart transplant donors (nonfailing hearts; NFHs) and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated adenylyl cyclase was significantly diminished, whereas NaF-activated (involving only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl cyclase was unaltered. Left ventricular positive inotropic responses to beta1- (noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2-receptor (histamine) stimulation were significantly reduced. The extent of reduction was not different for each agonist in ICM and DCM. We conclude that in DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is similarly reduced.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Adult; Cardiomyopathy, Dilated; Female; GTP-Binding Proteins; Guanosine Triphosphate; Heart Atria; Heart Transplantation; Heart Ventricles; Histamine; Humans; Iodocyanopindolol; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia; Pindolol; Receptors, Adrenergic, beta; Serotonin; Tissue Donors

Topics: Adenine Nucleotides; Animals; Creatine; Cytidine Triphosphate; Guanine Nucleotides; Guanosine Triphosphate; Hot Temperature; Male; Myocardial Ischemia; Myocardium; NAD; NADP; Phosphocreatine; Rats; Rats, Wistar; Ribonucleotides; Stress, Physiological; Uridine Triphosphate

Topics: Adenine Nucleotides; Animals; Cold Temperature; Creatine; Diastole; Guanosine Triphosphate; Heart; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion; NAD; Nucleotides; Organ Preservation; Phosphocreatine; Rats; Rats, Wistar; Time Factors

Topics: Adenosine; Adenosine Triphosphate; Animals; Cytidine Triphosphate; Guanosine Triphosphate; Heart; In Vitro Techniques; Kinetics; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Purines; Pyrimidines; Rats; Rats, Wistar; Time Factors; Uridine Triphosphate

Topics: Adenine Nucleotides; Animals; Animals, Newborn; Cell Hypoxia; Cells, Cultured; Energy Metabolism; Guanosine Triphosphate; Heart; Heart Rate; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; NAD; Oxygen; Partial Pressure; Phosphocreatine; Rats

It was examined whether lactate influences postischaemic hemodynamic recovery as a function of the duration of ischaemia and whether changes in high-energy phosphate metabolism under ischaemic and reperfused conditions could be held responsible for impairment of cardiac function. To this end, isolated working rat hearts were perfused with either glucose (11 mM), glucose (11 mM) plus lactate (5 mM) or glucose (11 mM) plus pyruvate (5 mM). The extent of ischaemic injury was varied by changing the intervals of ischaemia, i.e. 15, 30 and 45 min. Perfusion by lactate evoked marked depression of functional recovery after 30 min of ischaemia. Perfusion by pyruvate resulted in marked decline of cardiac function after 45 min of ischaemia, while in glucose perfused hearts hemodynamic performance was still recovered to some extent after 45 min of ischaemia. Hence, lactate accelerates postischaemic hemodynamic impairment compared to glucose and pyruvate. The marked decline in functional recovery of the lactate perfused hearts cannot be ascribed to the extent of degradation of high-energy phosphates during ischaemia as compared to glucose and pyruvate perfused hearts. Glycolytic ATP formation (evaluated by the rate of lactate production) can neither be responsible for loss of cardiac function in the lactate perfused hearts. Moreover, failure of reenergization during reperfusion, the amount of nucleosides and oxypurines lost or the level of high-energy phosphates at the end of reperfusion cannot explain lactate-induced impairment. Alternatively, the accumulation of endogenous lactate may have contributed to ischaemic damage in the lactate perfused hearts after 30 min of ischaemia as it was higher in the lactate than in the glucose or pyruvate perfused hearts. It cannot be excluded that possible beneficial effects of the elevated glycolytic ATP formation during 15 to 30 min of ischaemia in the lactate perfused hearts are counterbalanced by the detrimental effects of lactate accumulation.

Topics: Adenosine; Adenosine Triphosphate; Animals; Energy Metabolism; Glucose; Glycogen; Guanosine Triphosphate; Heart; Hypoxanthine; Hypoxanthines; In Vitro Techniques; Inosine; Inosine Monophosphate; Kinetics; Lactates; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphocreatine; Pyruvates; Rats; Rats, Inbred Lew; Time Factors; Xanthine; Xanthines