Adenine Nucleotide Biosynthesis Research Articles

Identification of Protective Amino Acid Metabolism Events in Nursery Pigs Fed Thermally Oxidized Corn Oil.

Feeding thermally oxidized lipids to pigs has been shown to compromise growth and health, reduce energy digestibility, and disrupt lipid metabolism. However, the effects of feeding oxidized lipids on amino acid metabolism in pigs have not been well defined even though amino acids are indispensable for the subsistence of energy metabolism, protein synthesis, the antioxidant system, and many other functions essential for pig growth and health. In this study, oxidized corn oil (OCO)-elicited changes in amino acid homeostasis of nursery pigs were examined by metabolomics-based biochemical analysis. The results showed that serum and hepatic free amino acids and metabolites, including tryptophan, threonine, alanine, glutamate, and glutathione, as well as associated metabolic pathways, were selectively altered by feeding OCO, and more importantly, many of these metabolic events possess protective functions. Specifically, OCO activated tryptophan-nicotinamide adenosine dinucleotide (NAD+) synthesis by the transcriptional upregulation of the kynurenine pathway in tryptophan catabolism and promoted adenine nucleotide biosynthesis. Feeding OCO induced oxidative stress, causing decreases in glutathione (GSH)/oxidized glutathione (GSSG) ratio, carnosine, and ascorbic acid in the liver but simultaneously promoted antioxidant responses as shown by the increases in hepatic GSH and GSSG as well as the transcriptional upregulation of GSH metabolism-related enzymes. Moreover, OCO reduced the catabolism of threonine to α-ketobutyrate in the liver by inhibiting the threonine dehydratase (TDH) route. Overall, these protective metabolic events indicate that below a certain threshold of OCO consumption, nursery pigs are capable of overcoming the oxidative stress and metabolic challenges posed by the consumption of oxidized lipids by adjusting antioxidant, nutrient, and energy metabolism, partially through the transcriptional regulation of amino acid metabolism.

Meta‐analysis of cancer incidence in folic acid supplementation trials

It has been suggested by several research groups that folate is procarcinogenic. Data in the 1940s of folate supplementation indicated that it enhanced the proliferation of cancer cells. Folate is a unique vitamin because its coenzymes are required for de novo adenine, guanine, and thymine nucleotide biosynthesis; therefore, it is essential for DNA synthesis and repair, and RNA synthesis, and structurally related folate analogs, such as methotrexate, are used as anticancer agents. Using a meta‐analysis weighted for the duration of folic acid (FA, pteroylglutamic acid) supplementation, we analyzed the cancer incidence of 5 published large prospective FA supplementation trials that lasted 1 year or more involving men and women. These articles were selected from over 1,100 identified by a PubMed search that was done in June 2009, and skin cancer was excluded by the original investigators or by us. Our data suggest that cancer incidence was higher in the FA supplemented groups than the non‐FA supplemented groups (relative risk = 1.26 [95% confidence interval: 1.05–1.51]). FA supplementation trials should be performed with careful monitoring of cancer incidence by investigators, and funding agencies should provide long‐term support. In the US, solid monitoring systems to detect side effects, such as increased cancer risk, should have been established before the food FA fortification mandate.

Cerulenin-mediated apoptosis is involved in adenine metabolic pathway

Cerulenin, a fatty acid synthase (FAS) inhibitor, induces apoptosis of variety of tumor cells. To elucidate mode of action by cerulenin, we employed the proteomics approach using Schizosaccharomyces pombe. The differential protein expression profile of S. pombe revealed that cerulenin modulated the expressions of proteins involved in stresses and metabolism, including both ade10 and adk1 proteins. The nutrient supplementation assay demonstrated that cerulenin affected enzymatic steps transferring a phosphoribosyl group. This result suggests that cerulenin accumulates AMP and p-ribosyl- s-amino-imidazole carboxamide (AICAR) and reduces other necessary nucleotides, which induces feedback inhibition of enzymes and the transcriptional regulation of related genes in de novo and salvage adenine metabolic pathway. Furthermore, the deregulation of adenine nucleotide synthesis may interfere ribonucleotide reductase and cause defects in cell cycle progression and chromosome segregation. In conclusion, cerulenin induces apoptosis through deregulation of adenine nucleotide biosynthesis resulting in nuclear division defects in S. pombe.

Preparation of 5‐amino‐4‐imidazole‐N‐succinocarboxamide ribotide, 5‐amino‐4‐imidazole‐N‐succinocarboxamide riboside and succinyladenosine, compounds usable in diagnosis and research of adenylosuccinate lyase deficiency

The enzyme adenylosuccinate lyase (ADSL) intervenes twice in the biosynthesis of adenine nucleotides. ADSL deficiency is an inherited metabolic disease characterized by various degrees of psychomotor retardation and accumulation of dephosphorylated enzyme substrates 5-amino-4-imidazole-N-succinocarboxamide riboside (SAICAr) and succinyladenosine (SAdo) in body fluids. Severity of symptoms seems to correlate with residual activity of mutant enzyme and with SAdo/SAICAr concentration ratio in cerebrospinal fluid. To better understand the pathogenetic mechanisms of the disease symptoms, studies of catalytic properties of mutant enzymes together with in vitro and in vivo experiments utilizing SAICAr and SAdo must be performed. Such studies require availability of both ADSL substrates, 5-amino-4-imidazole-N-succinocarboxamide ribotide (SAICAR) and succinyladenosine 5'-monophosphate (SAMP) and their dephosphorylated products in sufficient amounts and purity. Except for SAMP, none of these compounds is commercially available and they must therefore be synthesized. SAICAR was prepared by recombinant human ADSL-catalysed reaction of AICAR (5-aminoimidazole-4-carboxamide) with fumarate and isolated by thin-layer chromatography. SAICAr and SAdo were prepared by calf intestine alkaline phosphatase-catalysed dephosphorylation of SAICAR and SAMP and isolated on cation- and anion-exchange resin columns. The procedures described are easily scalable and provide high yields of sufficiently pure products for use in experiments related to studies of pathogenetic mechanisms in ADSL deficiency.

Significance of the 5-phosphoribosyl-1-pyrophosphate pool for cardiac purine and pyrimidine nucleotide synthesis: studies with ribose, adenine, inosine, and orotic acid in rats.

Several experimental approaches have been applied to examine the significance of the available pool of 5-phosphoribosyl-1-pyrophosphate (PRPP) for purine and pyrimidine nucleotide metabolism in the rat heart. In a series of studies including some pentoses and pentitols, in particular ribose, it was shown that these sugars were all capable of elevating the cardiac PRPP pool and stimulating the rate of adenine nucleotide biosynthesis. In several pathophysiological situations that were characterized by a decrease in ATP content, the increase in adenine nucleotide biosynthesis elicited by ribose was of such magnitude that the ATP level was replenished partially or completely in a considerably shorter period of time than that without any intervention. In two experimental models, in cardiac hypertrophy induced by aortic constriction with additional isoproterenol administration and in the noninfarcted rat heart after permanent coronary artery ligation, there was also an improvement in global heart function under the influence of ribose. The myocardial cell damage induced by isoproterenol was prevented by ribose. Combination of ribose with adenine or inosine led to an even quicker ATP normalization in the isoproterenol-stimulated rat heart than with either intervention alone. Ribose had no functional effects on the cardiovascular system, whereas adenine, inosine, and orotic acid were demonstrated to have different hemodynamic influences. Adenine and inosine had negative chronotropic and inotropic effects in the intact rat, whereas orotic acid had a positive influence both on the left and right rat heart. On the basis of these experimental studies, a new therapeutic strategy is suggested in which elevation of the available PRPP plays a key role. Once this has been elevated by ribose, additional substrates, such as adenine, inosine, and orotic acids, should be included. This would exploit the full potential of a therapeutic approach that corrects a natural metabolic deficiency of the heart that is the low capacity of the oxidative pentose phosphate pathway in which PRPP is generated.

Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression.

The effect of beta- and alpha-adrenergic stimulation on cardiovascular function and development of cardiac hypertrophy was studied in rats by measuring the heart weight/body weight and cardiac RNA/DNA ratios. Beta-receptor stimulation with isoproterenol over 3 days induced an increase in the biosynthesis of cardiac adenine nucleotides, myocardial protein synthesis, and the heart weight/body weight ratio. The isoproterenol-induced metabolic effects were prevented by simultaneous beta-adrenergic blockade with propranolol. Alpha-adrenergic stimulation with norfenephrine for 3 days induced an increase in heart rate, total peripheral resistance, the myocardial RNA/DNA, and left ventricular weight/body weight ratio. The calcium antagonist verapamil prevented the hemodynamic changes but did not influence the development of cardiac hypertrophy. The alpha-adrenergic blocker prazosin reversed the norfenephrine-induced functional changes and prevented cardiac hypertrophy. Norepinephrine was infused into isolated perfused working rat hearts to elucidate some molecular biological changes that precede the development of cardiac hypertrophy. It increased transiently and sequentially the mRNA of c-fos and c-myc. This enhancement occurred at about the same time as that induced by elevation of pre- and afterload but was more pronounced. These findings were compared with those obtained in other studies assessing the effects of catecholamines on proto-oncogene expression. Combination of norepinephrine with pre- and afterload elevation induced the c-fos mRNA signal to appear earlier, to be more pronounced, and to persist for a longer period of time. Similar results were obtained in regard to the c-myc mRNA. These findings indicate that the combination of two hypertrophy-inducing stimuli which may cause a higher degree of cardiac hypertrophy in vivo induce an earlier, more pronounced, and longer lasting expression of the proto-oncogenes c-fos and c-myc.

Radiochemical assay of adenylosuccinase: Demonstration of parallel loss of activity toward both adenylosuccinate and succinylaminoimidazole car☐amide ribotide in liver of patients with the enzyme defect

A radiochemical assay for adenylosuccinase, an enzyme which intervenes twice in the biosynthesis of adenine nucleotides, has been developed. The two substrates of the enzyme, succinylaminoimidazole car☐amide ribotide (SAICAR) and adenylosuccinate (S-AMP), were synthesized in radioactive form by incubating [2,3- 14C]fumarate and, respectively, AICAR and AMP with partially purified adenylosuccinase from yeast. Enzyme activities were determined by measuring the release of labeled fumarate after its separation from the substrate by chromatography on polyethyleneimine thin-layer plates. The ratio of the activity of adenylosuccinase measured with SAICAR compared to that with S-AMP was about 1 in crude extracts of rat liver and muscle and around 0.5 in human liver. In rat and human liver, but not in rat muscle, 20 to 40% of both activities of adenylosuccinase were lost after freezing at −80°C followed by thawing. In the liver of patients with adenylosuccinase deficiency, in whom the deficiency had hitherto been measured only with S-AMP, the activity of the enzyme toward S-AMP and SAICAR was found to be lost in parallel. This is in accordance with the finding that both SAICA-riboside and succinyladenosine accumulate in adenylosuccinase-deficient patients.

Beta-adrenergic agonists stimulate the oxidative pentose phosphate pathway in the rat heart.

The oxidative pentose phosphate pathway is poorly developed in the rat heart compared with other organs, since the activity of glucose-6-phosphate dehydrogenase (G-6-PDH), the first and rate-limiting enzyme of the oxidative pentose phosphate pathway, is low. As a consequence, the available pool of 5-phosphoribosyl-1-pyrophosphate and the rate of adenine nucleotide biosynthesis are limited. Isoproterenol, 24 hours after subcutaneous administration at 0.1, 1, and 25 mg/kg, stimulated the activity of G-6-PDH in whole hearts dose-dependently from 4.3 +/- 0.16 (control) to 6.6 +/- 0.35, 10.3 +/- 0.82, and 11.5 +/- 0.56 units/g protein, respectively. The activity of 6-phosphogluconate dehydrogenase, another of the enzymes in the oxidative pentose phosphate pathway, remained unchanged. G-6-PDH activity started to increase 12 hours after isoproterenol application, when the glycogenolytic and functional response was over, and reached a peak value between 24 and 48 hours. This stimulating effect was also demonstrated in cardiac myocytes that were isolated 28 hours after isoproterenol application. beta-receptor blockade with atenolol reduced the isoproterenol-induced increase in cardiac G-6-PDH activity by 90%. Cycloheximide, which inhibits translation, and actinomycin D, which interferes with transcription, attenuated it by 83% and 78%, respectively. These results indicate that cardiac beta-adrenergic receptors and enzyme protein synthesis are involved in this effect. Other beta-sympathomimetic agents such as dopamine, dobutamine, fenoterol, salbutamol, and terbutaline also stimulated myocardial G-6-PDH activity in a time- and dose-related manner. The calcium antagonist D 600 (gallopamil) reduced the isoproterenol-elicited stimulation by 65%, and verapamil blunted the fenoterol-induced increase by 50%. This suggests that Ca2+ ions also contribute to the stimulation of the cardiac oxidative pentose phosphate pathway.

Recovery of postischemic myocardial ATP levels and hexosemonophosphate shunt activity

Recovery of myocardial ATP levels after a period of ischemia is slow, requiring several days to return to normal. The biochemical limitation for ATP recovery appears to be the availability of the adenine nucleotide (AN) precursor, phosphoribosylpyrophosphate (PRPP), which is produced by the phosphorylation of ribose in the hexosemonophosphate shunt (HMP). In fact, ATP precursors, in particular ribose, have been shown to enhance the rate of postischemic ATP recovery. Infusion of exogenous ribose bypasses the rate-limiting steps in the HMP and speeds up adenine nucleotide (AN) biosynthesis. I propose another method for augmenting the rate of postischemic ATP recovery; increase the flux of substrate through the HMP. This would have the effect of making more PRPP available for AN biosynthesis. Effective physiologically and biologically tolerable means for enhancing HMP activity are presently available. These may be of significant utility in facilitating postischemic myocardial energy recovery.

Reduction of adenine nucleotide content of clone 4 mdck cells: Effects on multiplication, protein synthesis, and morphology

The antitumor agent hadacidin (N-formyl-hydroxyamino-acetic acid), at 4 mM, inhibited the multiplication of clone 4 Madin Darby canine kidney (MDCK) cells within 24 hr. Growth resumed rapidly upon replacement of hadacidin with aspartate, an observation consistent with the drug's action as a competitive inhibitor of adenylosuccinate synthetase, an enzyme in adenine nucleotide biosynthesis. Data indicate that the drug-treated cells were arrested in S phase of the cell cycle. Accompanying inhibition of multiplication was a 16-fold increase in the area occupied by the cells and a refractoriness to release by treatment with trypsin. None of these changes occurred when 0.5 mM adenosine was included in the incubation mixture containing the inhibitor. Hadacidin decreased the adenosine triphosphate (ATP) and cyclic adenosine monophosphate (cAMP) content of the cells as well as the rate at which 3H-leucine was incorporated into protein. In the presence of 1 mM dibutyryl cAMP and theophylline, the drug had no effect on cell division and protein synthesis. The data suggest that, in clone 4 MDCK cells, the effects of hadacidin are mediated by diminishing the level of cAMP.

Myocardial infarction in rats: effects of metabolic and pharmacologic interventions

Myocardial infarction was induced in rats by ligation of the descending branch of the left coronary artery. The time course of changes in heart function was recorded within the first nine days. There was a progressive decline in LVSP, in LV dP/dtmax and in the pressure-rate-product. LVEDP was elevated. Cardiac output and stroke volume index were depressed after two days. The ATP content in the nonischemic region was lower than control, but recovered spontaneously toward the normal value within the first four days. Three metabolic and pharmacologic interventions known to affect cardiac adenine nucleotide metabolism were applied. Continuous i.v. administration of ribose which stimulates further adenine nucleotide biosynthesis attenuated the fall and promoted the restoration of ATP in the nonischemic myocardium within four days after coronary artery ligation. The elevation of LVEDP was attenuated with ribose after two and four days. The calcium antagonist gallopamil administered as i.v. infusion for two days led to a further reduction of all parameters of left heart function, but did not influence the increase in adenine nucleotide and protein synthesis that occurred in the nonischemic heart. Coenzyme Q10 had only slight effects on LVSP, LVEDP, and LV dP/dtmax, but attenuated significantly the fall in cardiac output and stroke volume index after two days following coronary artery ligation. Thus, all interventions affected differently the infarct-induced changes in heart and circulatory function. An improvement was observed with ribose and with coenzyme Q10.

62 ISOZYME SHIFT OF ADENYLOSUCCINATE SYNTHASE IN RATS AND HUMAN NEOPLASMS

The distribution of two isozymes of adenylosuccinate synthase was measured in rat transplantable tumors, human tumors, and their corresponding normal tissues. The two isozymes, the acidic and basic enzymes, were separated by DEAE cellulose column and the proportions of each fraction were guantitatively compared. In rat liver, the activity was distributed 47% in the passed fraction of basic enzyme and 53% in the adsorbed fraction of acidic enzyme. In hepatoma 3924A, however, 99% of activity was found in the adsorbed fraction. Adenylosuccinate synthase in rat skeletal muscle was entirely basic enzyme, whereas sarcoma consisted of 99% acidic enzyme and 1% basic enzyme. The distributions of acidic enzyme in human liver and colon mucosa were 24% and 62%, respectively. On the other hand, the values increased in human hepatocellular carcinoma and colon carcinoma to 86% and 96%, respectively. These results suggest that the isozyme pattern of adenylosuccinate synthase shifts into a predominance of the acidic enzyme in malignant tissues. The increase in adenylosuccinate synthase activity in neoplastic tissues reported earlier (Jackson, R.C., Morris, H.P., and Weber, G., Cancer Res. 37: 3057, 1977) and the shift to the acidic isozyme with a lower Km for IMP indicate an increased capacity for adenine nucleotide biosynthesis in cancer cells. These observations are in line with the isozyme shift identified for other enzymes in hepatomas (Weber, G., Cancer Res. 43: 346, 1983). (Supported by Outstanding Investigator Grant CA-42510 to G.W.)

Metabolic recovery following temporary regional myocardial ischemia in the rat

The restoration of the cardiac ATP content after an ischemic insult takes a long period of time. Ribose, via stimulation of adenine nucleotide biosynthesis, accelerated the replenishment of the adenine nucleotide pool in the heart, in the kidney, however, it had no effect. In the myocardium, the ribose-mediated restoration of the adenine nucleotide content was dependent on the duration of the previous ischemic period and was not influenced by the beta-receptor blocker atenolol.

Correlation between haemodynamic and metabolic changes in three models of experimental cardiac hypertrophy.

Three models of cardiac hypertrophy (aortic constriction, application of isoproterenol, daily injections of triiodothyronine) were characterized in haemodynamic and in metabolic terms. Heart function was evaluated in closed-chest rats after catheterization of the left ventricle with an ultraminiature catheter pressure transducer. Heart rate (HR), left ventricular systolic pressure (LVSP), and the maximal rate of rise of left ventricular pressure (LV dP/dtmax) were measured. The metabolic parameters determined included the levels of cardiac cyclic AMP and the rates of the biosynthesis of myocardial adenine nucleotides. During the first 72 h after aortic constriction, HR was decreased, whereas LVSP and LV dP/dtmax were both elevated. Within 12 h after administration of isoproterenol, HR and LV dP/dtmax were markedly increased, while LVSP was depressed. In triiodothyronine-treated animals, all haemodynamic parameters were elevated during the first 72 h. Comparison with the time course of changes in metabolic parameters revealed that the rise in cardiac contractility measured as LV dP/dtmax occurred at about the same time as the increase in the content of myocardial cyclic AMP in the isoproterenol- and triiodothyronine-models. In hypertrophy due to aortic constriction, cardiac cyclic AMP was elevated only moderately, and this elevation did not correlate with the enhancement of contractility. Beta-receptor-blockade with propranolol prevented entirely the increase of myocardial adenine nucleotide biosynthesis in the isoproterenol- and triiodothyronine- but not in pressure-induced hypertrophy.

Ribose accelerates the repletion of the ATP pool during recovery from reversible ischemia of the rat myocardium

It is a characteristic feature of the myocardium that the derangement in function [6] and the depletion of the ATP pool [1, 2, 9] that occur subsequent to oxygen deficiency persist when blood flow is restored. Of renewed interest is the inability of the heart to replenish rapidly its adenine nucleotide pool once it has been diminished during a brief period of regional ischemia [2, 9]. A hypothesis that could explain this metabolic insufficiency of the myocardium is that the biosynthesis of adenine nucleotides is very slow in the normal heart and is increased only moderately during postischemic recovery [15] so that the replenishment of adenine nucleotides is not affected appreciably. To substantiate such a hypothesis it is necessary to provide evidence that the restitution of the ATP pool can be accelerated by stimulation of this biosynthetic process. In previous studies ribose has been recognized as a substrate that enhances markedly adenine nucleotide biosynthesis in the rat heart [11, 12]. We now demonstrate that continuous i.v. infusion of ribose during recovery from a 15-min period of myocardial ischemia in rats leads to restoration of the cardiac ATP pool within 12 h, whereas 72 h are needed for ATP normalization without any intervention.

Adenine nucleotide biosynthesis in cardiac muscle: regulation and intervention.

It is well established that cardiac ATP breaks down when there is a discrepancy between energy production and energy demand. This occurs in situations such as myocardial ischemia or extreme cardiac overload. In those conditions the breakdown of ATP via ADP and AMP proceeds further to adenosine, inosine and hypoxanthine1. These degradation products are permeable, are washed out from the myocardium and thus are not available for restitution of ATP via the “salvage pathways” during the recovery period. The restitution of ATP is therefore largely dependent on the de novo formation (= biosynthesis) of adenine nucleotides from small molecular precursor substances. In contrast to the salvage pathways, the de novo synthesis of adenine nucleotides can be measured quantitatively. Utilizing 1-14C-glycine as precursor substance to which rats were usually exposed for 60 min, the total radioactivity of adenine nucleotides was measured and related to the mean specific activity of the tissue glycine precursor pool thus yielding rates of adenine nucleotide biosynthesis2. Using this approach, adenine nucleotide synthesis was determined not only in the normal rat heart but also in the myocardium under various pathophysiological conditions such as recovery from oxygen deficiency2, cardiac hypertrophy3, and stimulation with catecholamines4. In all these situations, myocardial adenine nucleotide biosynthesis turned out to be enhanced quite considerably. As far as the mechanisms for this stimulation is concerned, there are essentially two major possibilities. 1. Regulation via an ATP-dependent feedback mechanism directed at the first and rate-limiting enzyme of adenine nucleotide biosynthesis, 5-phosphoribosyl-1-pyrophosphate amidotransferase (EC 2.4.2.14), 2. availability of 5-phosphoribosyl-1-pyrophosphate.

Ribose prevents the propranolol-induced reduction of myocardial adenine nucleotide biosynthesis.

Blockade of myocardial ß-adrenergic receptors with high doses of propranolol has been shown to be accompanied by a marked reduction in cardiac adenine nucleotide biosynthesis1. It was therefore of interest to examine whether this reduction may be prevented by another intervention in adenine nucleotide biosynthesis. An experimental approach which seemed to be most promising for reaching that goal is the administration of ribose. This pentose which bypasses the hexose monophosphate shunt has been demonstrated to elevate the available pool of 5-phosphoribosyl-1-pyrophosphate and to stimulate adenine nucleotide biosynthesis in the normal rat heart in vivo2. Furthermore, ribose potentiates the enhancement of myocardial adenine nucleotide biosynthesis during development of cardiac hypertrophy3 and during recovery from oxygen deficiency4. Ribose was therefore administered as continuous i.v. infusion in rats that were treated with a high dose of propranolol, and myocardial adenine nucleotide biosynthesis was then determined.KeywordsAdenine NucleotideLeft Coronary ArteryAortic ConstrictionVentricular Free WallNucleotide BiosynthesisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Effects of ribose on cardiac metabolism and function in isoproterenol-treated rats.

Continuous iv infusion of ribose for 5 h in unanesthetized and unrestrained rats treated with isoproterenol (25 mg/kg sc) further enhanced the available pool of 5-phosphoribosyl-1-pyrophosphate and the biosynthesis of adenine nucleotides in the myocardium. The increase in adenine nucleotide biosynthesis was of such an extent that the isoproterenol-induced decline of the ATP level (mumol/g) was attenuated after 5 h (isoproterenol + ribose infusion 4.0 +/- 0.2, n = 10; isoproterenol + NaCl infusion 3.5 +/- 0.1, n = 23; control 4.5 + 0.1, n = 38) and prevented after 24 h (isoproterenol + ribose infusion 4.6 +/- 0.3, n = 5; isoproterenol + NaCl infusion 3.2 +/- 0.1, n = 9). Ribose, however, did not affect the isoproterenol-elicited elevation of the adenosine 3',5'-cyclic monophosphate (cAMP) and glucose 6-phosphate content nor did it influence the decline in glycogen. Thus ribose acts primarily via elevation of the cardiac 5-phosphoribosyl-1-pyrophosphate pool. Measurements of hemodynamic parameters with an ultraminiature catheter pressure transducer in intact rats anesthetized with thiobutabarbital sodium revealed that ribose infusion for at least 3 h further enhanced the isoproterenol-elicited increase in left ventricular dP/dtmax by about 20% but did not influence appreciably the rise in heart rate and the fall in left ventricular systolic pressure. Since ribose did not affect the immediate hemodynamic alterations induced by isoproterenol, it appears that it exerts its hemodynamic effects via the pronounced influence on cardiac adenine nucleotide metabolism.

Normalization of depressed heart function in rats by ribose.

Severe constriction of the abdominal aorta and simultaneous injection of isoproterenol in rats induced depression in heart function and reductions in cardiac adenosine triphosphate and total adenine nucleotides. When ribose was continuously infused for 24 hours, biosynthesis of cardiac adenine nucleotides was stimulated to such an extent that the reductions in adenosine triphosphate and total adenine nucleotides were prevented and left ventricular hemodynamic parameters were normal. These results support the hypothesis that adenosine triphosphate is primarily responsible for depression in myocardial contractility and that ribose is cardioprotective through its pronounced effects on adenine nucleotide metabolism in heart muscle.

Ribose enhances the isoproterenol-elicited positive inotropic effect in rats in vivo

Ribose has recently been shown to have a pronounced and specific effect on myocardial adenine nucleotide metabolism. It elevates the available pool of 5-phosphoribosyl-1-pyrophosphate and thereby stimulates the biosynthesis of adenine nucleotides [ 12]. In rats treated with isoproterenol, this stimulation is of such a degree that the decline in cardiac adenine nucleotides is prevented and the development of focal myocardial cell lesions significantly reduced [ 15]. However, no information is as yet available as to whether the ribose-induced normalization of myocardial adenine nucleotide levels may have functional consequences. Therefore, the effect of ribose on the hemodynamics of the normal and the isoproterenol-stimulated heart was examined. Utilizing a recently developed Mikro-tip ® pressure transducer catheter, the function of the rat heart in vivo was evaluated and correlated with some parameters of myocardial metabolism such as the cyclic AMP level, the biosynthesis of adenine nucleotides and the ATP content. This study shows that ribose itself has no hemodynamic effect. However, when it is administered as continuous i.v. infusion in isoproterenol-treated rats, the positive inotropic effect is enhanced concomitant with the normalization of the ATP level.