guanosine-triphosphate and Coronary-Disease

Acute myocardial ischaemia frequently is complicated by ventricular tachyarrhythmias. These arrhythmias are in part due to an increased susceptibility of myocardial cells to adenylyl cyclase stimulation by catecholamines [1]. As adenylyl cyclase underlies an endogenous dual regulation by stimulatory and inhibitory receptor systems, adenylyl cyclase stimulation can be counteracted by the activation of receptors like the muscarinic M2 receptor [2]. Therefore, the effect of myocardial ischaemia on muscarinic receptor and "inhibitory" guanine nucleotide binding proteins (G(i)) mediated inhibition of adenylyl cyclase was studied. During 5 min of myocardial ischaemia, carbachol mediated inhibition of forskolin and isoproterenol stimulated adenylyl cyclase was reduced by 30% and 50%, respectively. Hormone independent inhibition of adenylyl cyclase by the nonhydrolyzable GTP-analogue guanosine 5'-[beta gamma-imido]triphosphate (Gpp(NH)p) was reduced by 46%. In contrast, the amount of G(i), as determined by pertussis toxin catalyzed ADP-ribosylation, remained constant during 15 min of ischaemia. The impaired function of muscarinic receptor linked signal transduction during early myocardial ischaemia could contribute to the occurrence of ischaemia induced tachyarrhythmias by a reduced ability to counteract adenylyl cyclase activation.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Carbachol; Colforsin; Coronary Disease; Dogs; GTP-Binding Proteins; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Isoproterenol; Receptors, Muscarinic

The effects of exogenous glutamate (20 mM) on myocardial energy metabolism and cardiac function during low-flow ischaemia and subsequent reperfusion were studied in isolated working rat hearts. Hearts were made severely ischaemic for 60 min by reducing the perfusion rate to 0.17 ml/min, and then reperfused for 30 min. Low-flow ischaemia resulted in a 50% reduction of myocardial ATP, a 70% reduction of both creatine phosphate (CP) and GTP, and a 250% rise in AMP. After reperfusion, CP was restored to normal levels but ATP and GTP remained significantly low. All hearts failed completely to recover cardiac pump function. The addition of glutamate to the perfusate during low-flow ischaemia had no significant effect on myocardial high-energy phosphates (HEP) but slightly increased succinate production. Subsequent reperfusion without added glutamate resulted in the recovery of 62% of pre-ischaemic aortic flow rate, as well as restoration of myocardial ATP and GTP to 70% of their control values and of creatine phosphate to supranormal levels. Reperfusion with added glutamate did not raise HEP levels any further but did increase recovery of cardiac function to 92% or more of pre-ischaemic values. Thus, by mechanism(s) which are not yet clear but which may include an increase in HEP via anaerobic succinate production, elevated levels of exogenous glutamate exert a highly beneficial effect on the post-ischaemic recovery of cardiac function.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Energy Metabolism; Glutamates; Glutamic Acid; Guanosine Triphosphate; Heart; Heart Rate; Male; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred Strains; Reference Values

We evaluated the effects of ischemic injury on the myocardial adenylate cyclase system, 5 h after ligation of the left anterior descending coronary in 5 anesthetized dogs. Crude cardiac membrane preparations were isolated from control and ischemic areas of ventricular myocardium and tested for: 1. L-(125I)iodocyanopindolol binding, in the absence and presence of +/- -isoprenaline and GTP, and 2. adenylate cyclase activity. The density of beta-adrenoceptors increased by 35% in membranes from ischemic areas while the proportion of receptors in a high affinity state for +/- -isoprenaline decreased from 43% to 20%. Adenylate cyclase activities in the basal state and under stimulation with NaF, forskolin, Gpp(NH)p, +/- -isoprenaline and VIP were all markedly and similarly reduced, being only about 30% of comparable activities in membranes from control areas. The +/- -isoprenaline subsensitivity of cardiac adenylate cyclase can, thus, be attributed to a defective enzymatic system and not to a reduction in the number of beta-adrenoceptors implying that the internal components of the system were more sensitive to acute ischemia than the outward oriented hormone receptors. It is tempting to ascribe this uncoupling to a functional depletion in the guanine nucleotide-binding regulatory protein Ns that might reflect a loss of high energy phosphate stores including GTP.

Topics: Adenylyl Cyclases; Animals; Binding, Competitive; Colforsin; Coronary Disease; Dogs; Guanosine Triphosphate; Guanylyl Imidodiphosphate; In Vitro Techniques; Isoproterenol; Male; Membranes; Myocardium; Receptors, Adrenergic, beta; Sodium Fluoride; Vasoactive Intestinal Peptide

Topics: Adenosine Triphosphate; Aminoimidazole Carboxamide; Animals; Coronary Disease; Cricetinae; Cytidine Triphosphate; Dogs; Guanosine Triphosphate; Heart; Imidazoles; Myocardium; Ribonucleosides

Langendorff perfused rat hearts show synchronous, statistically significant, systematic variations in ATP and ADP. Here we show that AMP and IMP also vary in register with ATP and ADP and we suggest that the synchronizing trigger for these oscillations may be ischaemia. Oscillations in the ATP/ADP ratio were found to be significantly correlated with creatine phosphate content but by contrast these quantities vary quite differently from the GTP/GDP ratio. Cyclic GMP oscillations showed a significant negative correlation with variations in ADP. Epinephrine raised mean cyclic AMP content and stabilized cyclic GMP oscillations, but had little other effect on the purine nucleotide variations.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Disease; Cyclic AMP; Cyclic GMP; Epinephrine; Guanosine Diphosphate; Guanosine Triphosphate; Heart; Inosine Monophosphate; Kinetics; Male; Myocardium; Perfusion; Purine Nucleotides; Rats; Rats, Inbred Strains

Increasing therapeutic use is made of purines for the treatment of ischemic heart disease, but little is known about regulatory mechanisms involved. Therefore we perfused isolated rat hearts with 0.02 mmol/l [8-14C]hypoxanthine or inosine. Under normoxic conditions about 1% is taken up by the heart and partially used for synthesis of ATP and GTP at a rate of 0.4 and 0.1 nmol X min-1 X g dry wt-1, respectively. After relatively mild ischemia (coronary flow reduction of 70% for 20 min), no increase in myocardial purine uptake is observed, but ATP and GTP synthesis rates are doubled (P less than 0.001). D-Ribose stimulates the hypoxanthine incorporation rate in normoxic perfused rat hearts to 1.1 and 0.5 nmol X min-1 X g dry wt-1 for ATP and GTP, respectively, which is further increased during postischemic perfusion. About 80% of the [8-14C]inosine or [8-14C]hypoxanthine passes through the heart unchanged, while 15% is converted to (hypo)xanthine and uric acid. We conclude from these experiments that inosine and hypoxanthine incorporation into ATP and GTP is at least partly regulated by the availability of 5-phosphoribosyl-1-pyrophosphate.

Topics: Adenosine Triphosphate; Animals; Coronary Disease; Guanosine Triphosphate; Hypoxanthine; Hypoxanthines; Inosine; Male; Phosphoribosyl Pyrophosphate; Rats; Rats, Inbred Strains; Uric Acid; Xanthine; Xanthines

During myocardial ischaemia the purine (ATP, GTP) and pyrimidine (CTP, UTP) nucleotide content of the myocyte falls. When the ischaemic episode resolves, many hours or even days are required for restoration of nucleotide pools. These observations suggest that repetitive episodes of ischaemia might produce progressive depletion of nucleotide pools. In order to determine the effect of repetitive episodes of brief ischaemia on nucleotide pools, open-chest dogs underwent three 12 min periods of occlusion of the left anterior descending coronary artery, with each occlusion followed by 10 min of reperfusion. During the first occlusion nucleotide pools decreased by 30% (ATP); 36% (GTP), 52% (CTP), and 48% (UTP). The subsequent two occlusions produced no further decrease in nucleotide pools. The myocardial content of adenine nucleotide catabolites (adenosine + inosine + hypoxanthine) tended to be greater during the first occlusion than during the subsequent occlusions, and substrate delivery (ie regional myocardial blood flow) was similar during each of the periods of ischaemia. These results indicate that a decrease in the rate of nucleotide degradation, rather than an increase in nucleotide synthesis, accounts for the maintenance of nucleotide content during subsequent ischaemic episodes after the initial ischaemic period. Thus repetitive episodes of regional ischaemia do not produce a cumulative decrease in the high energy phosphate content of the myocardium.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Disease; Cytidine Triphosphate; Dogs; Guanosine Triphosphate; Ligation; Myocardium; Perfusion; Phosphocreatine; Purine Nucleotides; Pyrimidine Nucleotides; Recurrence; Uridine Triphosphate

Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.

Topics: Adenine Nucleotides; Cardiomegaly; Coronary Disease; Guanosine Triphosphate; Humans; Myocardium; NAD; Nucleotides; Phosphocreatine; Pyrimidine Nucleotides

During ischemia, the myocardial content of the purine nucleotides ATP and GTP falls and remains depressed for hours to days. Prolonged depletion of ATP in the postischemic state is accompanied by functional and ultrastructural abnormalities. This report describes the successful use of the purine precursor 5-aminoimidazole-4-carboxamide riboside to selectively enhance the rate of repletion of the ATP and GTP pools in postischemic myocardium.

Topics: Adenosine Triphosphate; Aminoimidazole Carboxamide; Animals; Coronary Circulation; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Guanosine Triphosphate; Imidazoles; Myocardium; Ribonucleosides

Topics: Adenine Nucleotides; Aerobiosis; Animals; Coronary Disease; Guanosine Triphosphate; Heart; Hypoxia; Insulin; Male; Muscle Proteins; Myocardium; Perfusion; Phenylalanine; Rats; Tetrodotoxin

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Amino Acids; Animals; Coronary Disease; Guanosine Triphosphate; Hypoxia; Muscle Proteins; Myocardium; Perfusion; Phosphocreatine; Rats

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Disease; Guanosine Triphosphate; Hypoxia; Insulin; Myocardium; Phosphocreatine; Proteins