The hemodynamic and metabolic effects of acetate were studied in rats in vivo and in the isolated perfused heart. Hemodynamic parameters, myocardial phosphagens, inorganic phosphate, and adenosine were measured in vivo. Acetate uptake, coronary flow, O2 consumption, parameters of the cellular energy state, and hypoxanthine compounds and their washout were measured in heart perfusion experiments. Heart rate (HR), cardiac output, and the peak derivative of the left ventricular pressure rise (dP/dtmax) increased significantly during acetate infusion in vivo, but mean arterial pressure, systolic arterial pressure, and systemic vascular resistance decreased. Heart muscle ATP concentrations decreased after 7 min of acetate infusion. In vivo cardiac work load (HR.(peak left ventricular pressure] showed a positive correlation with tissue adenosine concentration and a negative correlation with phosphorylation potential. Acetate uptake in the perfused hearts was about 2.5 mumol/min per gram wet weight. Acetate perfusion increased O2 consumption and coronary flow concomitantly with a decrease in tissue ATP concentration. Tissue AMP and perfusate effluent adenosine concentration and adenosine output increased significantly, perfusate adenosine showing a non-linear positive correlation with coronary flow. The results demonstrate that acetate induces considerable changes in hemodynamics and metabolism in the heart.
Fish exposed to fluctuating oxygen concentrations often alter their metabolism and/or behaviour to survive. Hypoxia tolerance is typically associated with the ability to reduce energy demand by supressing metabolic processes such as protein synthesis. Arctic char is amongst the most sensitive salmonid to hypoxia, and typically engage in avoidance behaviour when faced with lack of oxygen. We hypothesized that a sensitive species will still have the ability (albeit reduced) to regulate molecular mechanisms during hypoxia. We investigated the tissue-specific response of protein metabolism during hypoxia. Little is known about protein degradation pathways during hypoxia in fish and we predict that protein degradation pathways are differentially regulated and play a role in the hypoxia response. We also studied the regulation of oxygen-responsive cellular signalling pathways [hypoxia inducible factor (HIF), unfolded protein response (UPR) and mTOR pathways] since most of what we know comes from studies on cancerous mammalian cell lines. Arctic char were exposed to cumulative graded hypoxia trials for 3 h at four air saturation levels (100%, 50%, 30% and 15%). The rate of protein synthesis was measured using a flooding dose technique, whereas protein degradation and signalling pathways were assessed by measuring transcripts and phosphorylation of target proteins. Protein synthesis decreased in all tissues measured (liver, muscle, gill, digestive system) except for the heart. Salmonid hearts have preferential access to oxygen through a well-developed coronary artery, therefore the heart is likely to be the last tissue to become hypoxic. Autophagy markers were upregulated in the liver, whereas protein degradation markers were downregulated in the heart during hypoxia. Further work is needed to determine the effects of a decrease in protein degradation on a hypoxic salmonid heart. Our study showed that protein metabolism in Arctic char is altered in a tissue-specific fashion during graded hypoxia, which is in accordance with the responses of the three major hypoxia-sensitive pathways (HIF, UPR and mTOR). The activation pattern of these pathways and the cellular processes that are under their control varies greatly among tissues, sometimes even going in the opposite direction. This study provides new insights on the effects of hypoxia on protein metabolism. Adjustment of these cellular processes is likely to contribute to shifting the fish phenotype into a more hypoxia-tolerant one, if more than one hypoxia event were to occur. Our results warrant studying these adjustments in fish exposed to long-term and diel cycling hypoxia.
Activation of peripheral delta2 opioid receptors increases cardiac tolerance to ischemia/reperfusion injury Involvement of protein kinase C, NO-synthase, KATP channels and the autonomic nervous system.
AIMS: This study aims to investigate the role of peripheral delta(2) opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, K(ATP) channels and the autonomic nervous system in delta(2) cardioprotection. MAIN METHODS: Deltorphin II and various inhibitors were administered in vivo prior to coronary artery occlusion and reperfusion in a rat model. The animals were monitored for the development of arrhythmias, infarct development and the effects of selected inhibitors. KEY FINDINGS: Pretreatment with peripheral and delta(2) specific opioid receptor (OR) antagonists completely abolished the cardioprotective effects of deltorphin II. In contrast, the selective delta(1) OR antagonist 7-benzylidenenaltrexone (BNTX) had no effect. The protein kinase C (PKC) inhibitor chelerythrine and the NO-synthase inhibitor L-NAME (N-nitro-L-arginine methyl ester) also reversed both deltorphin II effects. The nonselective ATP-sensitive K+ (K(ATP)) channel inhibitor glibenclamide and the selective mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoic acid only abolished the infarct-sparing effect of deltorphin II. Inhibition of tyrosine kinase (TK) with genistein, the ganglion blocker hexamethonium and the depletion of endogenous catecholamine storage with guanethidine reversed the antiarrhythmic action of deltorphin II but did not change its infarct-sparing action. SIGNIFICANCE: The cardioprotective mechanism of deltorphin II is mediated via stimulation of peripheral delta(2) opioid receptors. PKC and NOS are involved in both its infarct-sparing and antiarrhythmic effects. Infarct-sparing is dependent upon mitochondrial K(ATP) channel activation while the antiarrhythmic effect is dependent upon TK activation. Endogenous catecholamine depletion reduced antiarrhythmic effects but did not alter the infarct-sparing effect of deltorphin II.
BACKGROUND: Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide produced in the heart, but controversy persists regarding its cardiac effects. We explored the potential role of AM on cardiac function and remodeling by direct recombinant adenoviral AM gene delivery into the anterior wall of the left ventricle (LV). METHODS: AM was overexpressed in healthy rat hearts and in hearts during the remodeling process in response to pressure overload and myocardial infarction. The AM effects were analysed with echocardiography and in an isolated perfused rat heart preparation. The expression of AM and the activation of underlying signaling pathways were also investigated. RESULTS: AM mRNA increased by 20.9-fold (p
The levels of adrenomedullin (ADM), a newly discovered vasodilating and natriuretic peptide, are elevated in plasma and ventricular myocardium in human congestive heart failure suggesting that cardiac synthesis may contribute to the plasma concentrations of ADM. To examine the time course of induction and mechanisms regulating cardiac ADM gene expression, we determined the effect of acute and short-term cardiac overload on ventricular ADM mRNA and immunoreactive ADM (ir-ADM) levels in conscious rats. Acute pressure overload was produced by infusion of arginine8-vasopressin (AVP, 0.05 microg/kg/min, i.v.) for 2 h into 12-week-old hypertensive TGR(mREN-2)27 rats and normotensive Sprague-Dawley (SD) rats. Hypertension and marked left ventricular hypertrophy were associated with 2.2-times higher ir-ADM levels in the left ventricular epicardial layer (178 +/- 36 vs. 81 +/- 23 fmol/g, P
Laboratory of Biochemistry and Endocrinology of Aging, Institute of Children and Adolescent Health Protection, Academy of Medical Science, 50-Let VLKSM av., 52A, 61153, Kharkov, Ukraine. firstname.lastname@example.org
In order to investigate the possible reasons for age-related decrease in myocardium resistance to stress, we carried out a study of lipid peroxidation (LPO) stimulation features in the myocardium of adult (10-12 months) and aged (22-25 months) male Wistar rats during immobilization stress. In our studies of ascorbate-dependent LPO and induced chemiluminescence, we found that immobilization stress is accompanied by decreased efficiency in the induction of free radical processes in the heart of aged rats. An important cause of this phenomenon may be age-dependent changes in the catalytical properties of the cytosolic superoxide dismutase. The pathophysiological consequences of stress-related, age-dependent decreased efficiency of induction of free radical processes in the heart are discussed.
The purpose of this study was to determine whether aged myocardium exhibits decreased responsiveness to adenosine A1 and A(2a) receptor activation. Studies were conducted in adult (4-6 months) and aged (24-26 months) Fischer 344 x Brown Norway hybrid (F344 x BN) rats. Effects of the adenosine A1/A(2a) agonist AMP579 were measured in isolated hearts and in rats submitted to in vivo regional myocardial ischemia. Aged isolated hearts exhibited lower spontaneous heart rates and higher coronary resistance, as well as normal A1- and A(2a)-mediated responses. There was no difference in control infarct size between adult and aged rats; however, AMP579 treatment resulted in a 50% greater infarct size reduction in aged rats (18 +/- 4% of risk area) compared to adult rats (37 +/- 3%). These findings suggest that adenosine A1 and A(2a) receptor-mediated effects are not diminished in normal aged myocardium, and that aged hearts exhibit increased adenosine agonist-induced infarct reduction.