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P H Sugden

Publications and source records attributed to P H Sugden.

At least 19 recordsLinked to original sources
PubMed1992

Stimulation of cardiac protein synthesis by insulin-like growth factors.

The effects of the insulin-like growth factors (IGF)-1 and -2 on the rates of protein synthesis in freshly isolated cardiac myocytes from adult rats were compared with those of insulin. At concentrations of 50-100 nM, each agent stimulated protein synthesis by about 70%. There was no additional stimulation upon combination of insulin with IGF-1 or IGF-2 at these high concentrations. When compared over a range of concentrations, the relative response to each agent was insulin greater than IGF-1 greater than or equal to IGF-2. Concentrations of 1 nM-IGF-1, 1 nM-IGF-2 or 0.2 nM-insulin enhanced the rates of protein synthesis by 36%, 30% or 34% respectively. A combination of 0.2 nM-insulin and 1 nM-IGF-1 or 1 nM-IGF-2 increased the stimulation of protein synthesis to 46%. In contrast, the effects of 1 nM-IGF-1 and 1 nM-IGF-2 were not additive. The possible mechanistic basis for this difference is discussed. At a concentration of 50 nM, epidermal growth factor (EGF), fibroblast growth factor and platelet-derived growth factor were each without effect on protein synthesis. In anterogradely perfused rat heart preparations, 2 nM-IGF-1 or 2.4 nM-IGF-2 increased protein synthesis and lactate production, but 9.2 nM-EGF did not. From a consideration of the plasma free concentrations of IGF-1 and IGF-2, we suggest that these factors may contribute to the maintenance of rate of cardiac protein synthesis in vivo.

Animals↗
PubMed1992

The effects of the exogenous provision of lactate and the endogenous production of lactate on protein synthesis in the heart.

We have investigated the effects of exogenous addition of lactate and of the stimulation of endogenous production of lactate on protein synthesis in the anterogradely perfused rat heart. In the absence of exogenous lactate, hearts release lactate into the perfusate. At lactate concentrations of 0.2 mM and greater, the heart takes up lactate. The best fit for lactate uptake plotted against exogenous lactate concentration is a rectangular hyperbola with a maximal rate of 220 mumol/2 h per heart (wet wt. about 1 g). Uptake is half-maximal at about 1.3 mM-lactate. The stimulation of protein synthesis also exhibits a rectangular-hyperbolic dependence on exogenous lactate concentration, with maximal stimulation being about 38%. Half-maximal stimulation occurs at about 0.9 mM-lactate. We stimulated endogenous lactate production by perfusion with 2-cyanocinnamate (an inhibitor of mitochondrial pyruvate transport) at concentrations up to 70 microM. Cardiac outputs, intracellular pH and the concentrations of phosphocreatine and the adenine nucleotides were not altered. Atrial protein-synthesis rates were unchanged, but ventricular rates were decreased. We conclude that endogenous lactate production is unlikely to stimulate protein synthesis and that the stimulation of protein synthesis by exogenous lactate is related to its uptake.

Adenine Nucleotides↗
PubMed1991

Correlations between cardiac protein synthesis rates, intracellular pH and the concentrations of creatine metabolites.

We have examined in detail the correlations between protein synthesis rates, intracellular pH (pHi) and the concentrations of creatine metabolites in the rat heart perfused anterogradely in vitro. Using perfusion buffers ranging from pH 7.2 to 8.2 at 37 degrees C, we were able to manipulate pHi from between 7.24 to 7.66, i.e. from the slightly acidotic to the alkalinotic as compared with the physiological values of pHi (about pH 7.29). The dependence of pHi on extracellular pH (pHo) was linear, with the value of delta pHi/delta pHo being 0.4-0.5. Protein synthesis rates were significantly stimulated when pHi was increased above its physiological value, and they were strongly correlated with pHi. They were also strongly correlated with phosphocreatine concentrations (and with creatine concentrations and phosphocreatine/creatine concentration ratios). Adenine nucleotide (ATP, ADP and AMP) concentrations and the ATP/ADP concentration ratio were not systematically altered by manipulating pHi, and protein synthesis rates showed only a relatively weak dependence on these variables. Since creatine kinase catalyses a reaction that is close to equilibrium in the perfused heart, and since phosphorylation of creatine involves release of a proton, we argue that the changes in phosphocreatine and creatine concentrations are manifestations of alterations in pHi. In this regard, we show that [log[( phosphocreatine]/[creatine]) + log [( ADP]/[ATP])] [the value of which gives [pHi--log (mass action ratio)]] is positively correlated with pHi, although the slope of the line is 0.7, as opposed to the ideal value of unity. We discuss three hypotheses to account for our observations: (i) protein synthesis rates are influenced directly by pHi, (ii) pHi affects the concentrations of creatine metabolites, which in turn affect protein synthesis rates, and (iii) pHi affects the value of an unidentified co-variable, which in turn affects protein synthesis.

Adenine Nucleotides↗
PubMed1991

Acute alpha 1-adrenergic stimulation of cardiac protein synthesis may involve increased intracellular pH and protein kinase activity.

In the presence of 5 microM-DL-propranolol and in HCO3(-)-containing buffers, 1 microM-adrenaline acutely stimulated protein synthesis by about 25% in the anterogradely perfused rat heart. This stimulation was opposed by low (1-10 nM) concentrations of prazosin, but not by similar concentrations of yohimbine, suggesting involvement of the alpha 1-adrenoceptor. Under the same conditions, adrenaline raised intracellular pH (pHi) by about 0.1 unit. The increase in pHi induced by adrenaline was prevented by 5 nM-prazosin, but not by 5 nM-yohimbine, again suggesting involvement of the alpha 1-adrenoceptor. Since an increase in pHi stimulates protein synthesis in the heart [Sugden & Fuller (1991) Biochem. J. 273, 339-346], the increase in pHi induced by adrenaline may be involved in its stimulation of protein synthesis. Adrenaline also increased phosphocreatine concentrations. As discussed, the increase in pHi induced by adrenaline may be responsible for this effect. Using second-order polynomial regression analysis, we showed that rates of protein synthesis were significantly correlated (P less than 0.0001) with phosphocreatine concentrations. We discuss two possible reasons for this correlation: (i) increases in pHi stimulate protein synthesis and separately raise phosphocreatine concentrations, or (ii) the increase in protein synthesis rates is a consequence of the raised phosphocreatine concentrations induced by the increase in pHi. Rates of protein synthesis were not significantly correlated with ATP/ADP concentration ratios, nor with any of the following: ATP, ADP, AMP or total adenine nucleotide concentrations. In freshly isolated adult rat cardiomyocytes, the protein kinase inhibitor staurosporine (1 microM) prevented stimulation of protein synthesis by 0.3 microM-adrenaline (and by 1 microM-phorbol 12-myristate 13-acetate or 1 m-unit of insulin/ml). The results are discussed within a mechanistic framework initiated by stimulation of the hydrolysis of membrane phospholipids by alpha 1-adrenergic agonists.

Adrenergic alpha-Agonists↗
PubMed1990

Protein synthesis in liver and extra-hepatic tissues after partial hepatectomy.

Effects of partial hepatectomy on protein synthesis were defined in liver and extra-hepatic tissues of the mature rat. Studies were performed at 24 h and 48 h after surgery in the absence of the dietary input. Protein accretion in the regenerating liver preceded mitosis, but was accompanied by increases in RNA content and fractional rates of protein synthesis (ks). A positive relationship existed between protein-synthetic capacity and ks over the period of study. Increases in ks also bore a positive relationship with increases in translational efficiency. Extra-hepatic tissues showing decreased rates of protein synthesis after liver resection included kidney, striated muscles and brain. Effects were observed mainly at 24 h after surgery and resulted from decreased translational efficiency. Partial hepatectomy increased ks in diaphragm and tibia at both 24 h and 48 h after surgery. In diaphragm, there was net protein accretion, and, as in liver, increases in ks were due to increases in both protein-synthetic capacity and efficiency.

Animals↗
PubMed1990

Effects of catecholamines on protein synthesis in cardiac myocytes and perfused hearts isolated from adult rats. Stimulation of translation is mediated through the alpha 1-adrenoceptor.

Protein-synthesis rates in freshly isolated cardiac myocytes from adult rats were acutely stimulated by 20-30% by 1 microM-adrenaline, by 1 microM-noradrenaline or by 1 microM-phenylephrine, but were not stimulated by 1 microM-isoprenaline. Stimulation by 1 microM-adrenaline was completely prevented by 100 nM-prazosin. Yohimbine was much less effective in preventing stimulation, and 20 microM-DL-propranolol was completely ineffective. The stimulation of protein synthesis by adrenaline was still observed after inhibition of transcription by actinomycin D. None of these manipulations affected myocyte ATP contents. In anterogradely perfused hearts, protein-synthesis rates were stimulated by 1-2 microM-adrenaline in the presence of 10 microM-DL-propranolol (to decrease the beta-adrenergic effects of adrenaline). ATP contents were not altered, but phosphocreatine contents were increased. These observations lead us to conclude that cardiac protein synthesis can be stimulated acutely at the level of translation by alpha 1-adrenergic stimulation. We discuss possible roles for protein kinase C and intracellular alkalinization in the mediation of this effect.

Adrenergic beta-Agonists↗
PubMed1990

Stimulation of protein synthesis by raised extracellular pH in cardiac myocytes and perfused hearts.

Protein synthesis was stimulated in freshly-isolated rats cardiac myocytes by increasing the extracellular pH of Hepes-buffered Tyrode's solutions over the range pH 7.4-8.4. The maximal stimulation was about 45%. Protein synthesis in anterogradely-perfused rat hearts was stimulated by 11% by increasing the pH of the bicarbonate-containing perfusion medium from pH 7.4 to 7.8. This manoeuvre increased intracellular pH by 0.12 units. A concomitant increase in phosphocreatine concentration was observed. These findings are consistent with the hypothesis that intracellular pH may exert profound effects on tissue protein synthesis rates.

Adenine Nucleotides↗
PubMed1989

Protein synthesis in rat cardiac myocytes is stimulated at the level of translation by phorbol esters.

12-O-Tetradecanoylphorbol 13-acetate acutely stimulated the rate of protein synthesis maximally by about 43% in terminally differentiated myocytes freshly isolated from adult rat hearts. Stimulation was rapidly expressed (within 20 min). The relative effects of four phorbol esters on protein synthesis was consistent with a specific effect on protein kinase C. Inhibition of transcription with actinomycin D had no effect on the absolute stimulation of the protein synthesis rate by 12-O-tetradecanoylphorbol 13-acetate. We conclude that protein kinase C may be involved in the regulation of the translational process.

Animals↗
PubMed1989

Effects of increasing extracellular pH on protein synthesis and protein degradation in the perfused working rat heart.

Increasing the extracellular pH over the range pH 7.4-8.9 stimulated protein synthesis by about 60% in the rat heart preparation anterogradely perfused in vitro. Protein degradation was inhibited by this pH increase. The magnitudes of the effects at pH 8.9 on protein synthesis and degradation were similar to those of high concentrations of insulin. Cardiac outputs were increased, as were cardiac phosphocreatine contents, indicating that the alterations in extracellular pH did not adversely affect the physiological viability of the preparation. ATP contents were unaltered. The creatine kinase equilibrium was used to assess the magnitude of the change in intracellular pH induced by these treatments. The increase in intracellular pH was about 0.2 for a 1-unit increase in extracellular pH. Thus small changes in intracellular pH have dramatic effects on cardiac protein turnover.

Adenine Nucleotides↗
PubMed1989

The effects of fasting or hypoxia on rates of protein synthesis in vivo in subcellular fractions of rat heart and gastrocnemius muscle.

We measured rates of protein synthesis in vivo in subcellular fractions (soluble, myofibrillar and stromal fractions) of the heart and the gastrocnemius from rats after fasting or under hypoxic conditions (i.e. atmospheres containing 5% or 10% O2). Such interventions are known to inhibit protein synthesis under some circumstances. The recovery of tissue protein after fractionation was 80-100%. The proportions of protein present in the soluble and stromal fractions were different in the two muscles. The rates of protein synthesis in the myofibrillar and stromal fractions were less than those for total mixed tissue protein, whereas the rate for soluble protein was greater. Both fasting and moderate hypoxia (10% O2 for 24 h) inhibited protein synthesis in the gastrocnemius. In this tissue, the synthesis of the myofibrillar fraction was apparently the most sensitive to inhibition, and this resulted in some significant increases in the soluble-fraction/myofibrillar-fraction protein-synthesis rate ratios. In the heart, fasting inhibited protein synthesis, but moderate hypoxia (10% O2 for 24 h) did not. The rate of protein synthesis in the cardiac myofibrillar fraction was again more sensitive to fasting than were the rates in the other fractions, but it was not as sensitive as that in the gastrocnemius. Under severely hypoxic conditions (5% O2 for 1 or 2 h), protein synthesis was decreased in all fractions in both tissues. These results suggest that the rates of protein synthesis in these relatively crude subcellular fractions vary.

Animals↗
PubMed1988

The effects of surgical stress and short-term fasting on protein synthesis in vivo in diverse tissues of the mature rat.

1. We measured fractional rates of protein synthesis, capacities for protein synthesis (i.e. RNA/protein ratio) and efficiencies of protein synthesis (i.e. protein-synthesis rate relative to RNA content) in fasted (24 or 48 h) or fasted/surgically stressed female adult rats. 2. Of the 15 tissues studied, fasting caused decreases in protein content in the liver, gastrointestinal tract, heart, spleen and tibia. There was no detectable decrease in the protein content of the skeletal muscles studied. 3. Fractional rates of synthesis were not uniformly decreased by fasting. Rates in striated muscles, uterus, liver, spleen and tibia were consistently decreased, but decreases in other tissues (lung, gastrointestinal tract, kidney or brain) were inconsistent or not detectable, suggesting that, in many tissues in the mature rat, protein synthesis was not especially sensitive to fasting. 4. In fasting, the decreases in fractional synthesis rate resulted from changes in efficiency (liver and tibia) or from changes in efficiency and capacity (heart, diaphragm, plantaris and gastrocnemius). In the soleus, the main change was a decrease in capacity. 5. Surgical stress increased fractional rates of protein synthesis in diaphragm (where there were increases in both efficiency and capacity) by about 50%, in liver by about 20%, in spleen by about 40%, and possibly also in the heart. In liver and spleen, capacities were increased. In other tissues (including the skeletal muscles), the fractional rates of protein synthesis were unaffected by surgical stress.

Animals↗
PubMed1988

Acute inhibition of rat heart protein synthesis in vitro during beta-adrenergic stimulation or hypoxia.

In the anterogradely perfused rat heart with glucose as fuel, 1 microM isoproterenol (ISO) inhibited the insulin (INS) plus adenosine deaminase (AdoDA) stimulation of ventricular protein synthesis by 72%. ISO (1 microM) alone had no effect on ventricular protein synthesis but inhibited atrial protein synthesis by 20%. The concentration dependence of the ISO inhibition was similar to the stimulation of glucose uptake by ISO. Inhibition could not be overcome by increasing INS concentrations. The effects of ISO were diminished by propranolol and could be partially mimicked by forskolin (FSK) or 8-(4-chlorophenylthio-)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). The stimulation of protein synthesis by noncarbohydrate fuels was antagonized by ISO. Hypoxia (PO2 = 50%) also antagonized the INS stimulation of ventricular protein synthesis but did not affect basal rates. ATP contents were decreased by ISO but not by a PO2 of 50%. Both manipulations increased lactate output. The inhibition of protein synthesis by ISO could possibly be explained by indirect effects of ISO on cardiac "energy status." Furthermore, inhibition may thus represent purely an in vitro phenomenon and may not occur in vivo. However, the possibility that there are more direct effects of ISO on the machinery of protein synthesis has not been excluded. The inhibition of protein synthesis by hypoxia cannot be explained by changes in energy status and may result from intracellular lactoacidosis.

Adenosine Deaminase↗