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Fares A Karamat, Inge Oudman, Yentl C Haan, Andre B P van Kuilenburg, Rene Leen, Jan A H Danser, Frank P J Leijten, Carrie Ris-Stalpers, Gert A van Montfrans, Joseph F Clark, Lizzy M Brewster
OBJECTIVE: Creatine kinase is reported to be a main predictor of blood pressure (BP) in the general population, with a strong correlation between resistance artery creatine kinase expression and clinical BP in humans. The enzyme rapidly regenerates ATP near cytoplasmic ATPases involved in pressor responses, including resistance artery contractility and renal sodium retention. Therefore, we assessed whether creatine kinase inhibition reduces BP. METHODS: We implemented the 'Animal Research: Reporting of In Vivo Experiments' guideline...
August 10, 2016: Journal of Hypertension
F A Karamat, D Horjus, Y Haan, L Van Der Woude, M Schaap, I Oudman, G Van Montfrans, R Nieuwland, J Clark, A Sturk, L Brewster
OBJECTIVE: There is increasing evidence that the ATP generating enzyme creatine kinase (CK) is involved in hypertension. The enzyme is central to the regeneration of ATP by using creatine phosphate and ADP, thereby forming creatine and ATP. We recently showed that beta-guanidinopropionic acid (GPA), a creatine analogue and competitive CK inhibitor, effectively and safely reduced blood pressure in the spontaneously hypertensive rat. This renders GPA to be potentially beneficial for blood pressure lowering...
September 2016: Journal of Hypertension
Fares A Karamat, Deborah L Horjus, Yentl C Haan, Lisa van der Woude, Inge Oudman, Gert A van Montfrans, Joseph F Clark, Lizzy M Brewster
BACKGROUND: Despite adequate treatment, up to 30% of treated antihypertensive patients with primary, uncomplicated hypertension remain uncontrolled. We proposed that high intracellular activity of the ATP regenerating enzyme creatine kinase (CK) increases pressor responses and hypertension risk. In line with this, we found that plasma CK activity after rest, a surrogate measure of tissue activity, is the main predictor of blood pressure levels and failure of antihypertensive therapy in the general population...
2015: Trials
Takuya Usui, Yoshiyuki Kubo, Shin-Ichi Akanuma, Ken-Ichi Hosoya
The supply of L-carnosine, a bioactive dipeptide of β-alanine and l-histidine, to the retina across the blood-retinal barrier (BRB) was studied. The in vivo and in vitro studies revealed low uptake activities for [(3)H]Gly-Sar, a representative dipeptide, suggesting that l-carnosine transport plays only a minor role at the BRB. The in vivo study using rats showed approximately 18- and 23-fold greater retinal uptake indexes (RUI) for [(3)H]β-alanine and [(3)H]l-histidine compared with that of a paracellular marker, respectively...
August 2013: Experimental Eye Research
Inge Oudman, Joseph F Clark, Lizzy M Brewster
BACKGROUND: Creatine kinase plays a key role in cellular energy transport. The enzyme transfers high-energy phosphoryl groups from mitochondria to subcellular sites of ATP hydrolysis, where it buffers ADP concentration by catalyzing the reversible transfer of the high-energy phosphate moiety (P) between creatine and ADP. Cellular creatine uptake is competitively inhibited by beta-guanidinopropionic acid. This substance is marked as safe for human use, but the effects are unclear. Therefore, we systematically reviewed the effect of beta-guanidinopropionic acid on energy metabolism and function of tissues with high energy demands...
2013: PloS One
Guy Vassort, Patrice Bideaux, Julio Alvarez
Despite its degradation by ectonucleotidases, a low ATP concentration is present in the interstitial space; moreover, its level can markedly increase during various physiopathological conditions. ATP and uridine 5'-triphosphate (UTP) releases correlate with the occurrence of ventricular premature beats and ventricular tachycardia. ATP facilitates several voltage-dependent ionic currents including the L-type Ca(2+) current. More recently, ATP and UTP were also shown to induce a poor voltage-dependent, long-lasting current carried by the heterotetrameric transient receptor potential (TRP) channels TRPC3/7...
2010: Experimental and Clinical Cardiology
Rajnish K Chaturvedi, Noel Y Calingasan, Lichuan Yang, Thomas Hennessey, Ashu Johri, M Flint Beal
We investigated the ability of AMP-activated protein kinase (AMPK) to activate PPARgamma coactivator-1alpha (PGC-1alpha) in the brain, liver and brown adipose tissue (BAT) of the NLS-N171-82Q transgenic mouse model of Huntington's disease (HD). In the striatum of the HD mice, the baseline levels of PGC-1alpha, NRF1, NRF2, Tfam, COX-II, PPARdelta, CREB and ERRalpha mRNA and mitochondrial DNA (mtDNA), were significantly reduced. Administration of the creatine analog beta guanidinopropionic acid (GPA) reduced ATP and PCr levels and increased AMPK mRNA in both the cerebral cortex and striatum...
August 15, 2010: Human Molecular Genetics
Rajnish K Chaturvedi, Peter Adhihetty, Shubha Shukla, Thomas Hennessy, Noel Calingasan, Lichuan Yang, Anatoly Starkov, Mahmoud Kiaei, Milena Cannella, Jenny Sassone, Andrea Ciammola, Fernando Squitieri, M Flint Beal
We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice...
August 15, 2009: Human Molecular Genetics
Mary Chebib, Navnath Gavande, Kit Yee Wong, Anna Park, Isabella Premoli, Kenneth N Mewett, Robin D Allan, Rujee K Duke, Graham A R Johnston, Jane R Hanrahan
GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5...
October 2009: Neurochemical Research
Linda Metzner, Madlen Dorn, Fritz Markwardt, Matthias Brandsch
The orally administered creatine analogue beta-guanidinopropionic acid (beta-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a beta-GPA induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been studied. We investigated whether the H(+)-coupled amino acid transporter PAT1, which is expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates...
May 2009: Molecular Pharmaceutics
Kristin E Pandke, Kerry L Mullen, Laelie A Snook, Arend Bonen, David J Dyck
Decreasing muscle phosphagen content through dietary administration of the creatine analog beta-guanidinopropionic acid (beta-GPA) improves skeletal muscle oxidative capacity and resistance to fatigue during aerobic exercise in rodents, similar to that observed with endurance training. Surprisingly, the effect of beta-GPA on muscle substrate metabolism has been relatively unexamined, with only a few reports of increased muscle GLUT4 content and insulin-stimulated glucose uptake/clearance in rodent muscle. The effect of chronically decreasing muscle phophagen content on muscle fatty acid (FA) metabolism (transport, oxidation, esterification) is virtually unknown...
September 2008: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Malin Lindbom, Truls Ramunddal, German Camejo, Finn Waagstein, Elmir Omerovic
BACKGROUND: The failing heart is characterized by disturbed myocardial energy metabolism and creatine depletion. The aims of this study were to evaluate in vivo the effects of creatine (Cr) depletion on 1) left ventricular (LV) function, morphology, and lipid metabolism and 2) to test whether functional, morphologic, and metabolic disturbances induced by Cr depletion are reversible. METHODS AND RESULTS: Male Balb/c mice approximately 20 g were used. Two groups were studied: the mice treated with creatine analogue beta-guanidinopropionic acid (BGP) (n = 30) and controls (n = 30)...
March 2008: Journal of Cardiac Failure
Malin Lorentzon, Truls Råmunddal, Entela Bollano, Bassam Soussi, Finn Waagstein, Elmir Omerovic
BACKGROUND: The failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI). METHODS AND RESULTS: Male rats weighing approximately 200 g were used...
April 2007: Journal of Cardiac Failure
Richard M Reznick, Haihong Zong, Ji Li, Katsutaro Morino, Irene K Moore, Hannah J Yu, Zhen-Xiang Liu, Jianying Dong, Kirsty J Mustard, Simon A Hawley, Douglas Befroy, Marc Pypaert, D Grahame Hardie, Lawrence H Young, Gerald I Shulman
Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha(2) activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and exercise was blunted in skeletal muscle of old rats...
February 2007: Cell Metabolism
Richard A Galbraith, Masaru Furukawa, Muyao Li
Cobaltic protoporphyrin IX (CoPP) is a synthetic heme analog which can elicit profound and prolonged decreases in appetite and body weight in several different animal species. Intracerebroventricular administration of CoPP in rats was found, by differential display and confirmed by Real-Time PCR, to result in an increase in expression of the creatine transporter when compared to vehicle-treated fed or vehicle-treated fasted control animals. In situ hybridization studies showed that creatine transporter mRNA concentrations were increased in several areas of the brain involved in the regulation of food intake, but creatine concentrations were decreased in hypothalamic homogenates in CoPP-treated animals compared to controls...
July 26, 2006: Brain Research
R Gatti, M G Gioia
The use of anisoin as pre-chromatographic reagent for LC analysis of guanidino compounds is proposed. The reagent reacts (5 min at 100 degrees C) with guanidino function and the resulting adducts can be chromatographed under reversed-phase conditions. A fluorescence detector (lambda(ex)=325 nm; lambda(em)=435 nm) was used to detect guanidino adducts. The derivatization and chromatographic conditions were optimised by a series of experiments. Application to the determination of arginine and creatine in pharmaceuticals and arginine, guanidine, methylguanidine, guanidinosuccinic acid, beta-guanidinopropionic acid, gamma-guanidinobutyric acid, guanidinoacetic acid and homoarginine in human urine is described...
September 11, 2006: Journal of Pharmaceutical and Biomedical Analysis
Jackie M Kinsella, Hilary A Laidlaw, Teresa Tang, Jenni Harvey, Calum Sutherland, Michael L J Ashford
BACKGROUND: 3-guanidinopropionic acid derivatives reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, the aminoguanidine carboxylate BVT.12777, opens KATP channels in rat insulinoma cells, by the same mechanism as leptin. RESULTS: BVT.12777 hyperpolarized CRI-G1 rat insulinoma cells by activation of KATP channels. In contrast, BVT.12777 did not activate heterologously expressed pancreatic beta-cell KATP subunits directly...
August 24, 2004: BMC Pharmacology
John Dominy, Jeffrey S Thinschmidt, Joanna Peris, Ralph Dawson, Roger L Papke
Perfusion with high millimolar levels of taurine evoked a long-lasting potentiation (LLP-TAU) of synaptic transmission in the Schaffer-collateral CA1 region of the rat hippocampus. Although LLP-TAU showed some correlations to increases in the total taurine content of hippocampal slices, it could not be blocked by the taurine transport inhibitor guanidinoethanesulfonic acid (GES), which was able to significantly reduce total slice taurine uptake. Inhibition of GABA transport by either nipecotic acid or beta-guanidinopropionate failed to abolish LLP-TAU and had no significant effect on taurine uptake...
June 2004: Journal of Neurochemistry
Yoshinobu Ohira, Fuminori Kawano, Roland R Roy, V Reggie Edgerton
The effects of chronically increasing (creatine-fed) or decreasing (beta-guanidinopropionic acid [beta-GPA]-fed) high-energy phosphates for up to 8 weeks on daily voluntary activity levels, swimming endurance capacity, electromyogram (EMG) activity, and the morphological and metabolic properties of single fibers in the soleus and extensor digitorum longus (EDL) muscles in young rats were determined. High-energy phosphate, voluntary activity, and soleus-integrated EMG levels were lower in beta-GPA-fed rats than in control rats...
December 2003: Japanese Journal of Physiology
Franziska Grafe, Wolfgang Wohlrab, Reinhard H Neubert, Matthias Brandsch
In the skin, taurine acts as an important osmolyte required for keratinocyte hydration. It has antioxidant effects, protects cells from UV-induced stress and has effects on cell proliferation, inflammation and collagenogenesis. This study was performed to find and characterize functionally a taurine transport system in keratinocytes and to establish a cell culture model for skin taurine transport studies. Uptake of [(3)H]taurine was studied both in the human adult low calcium high temperature (HaCaT) cell line and in human native epidermal keratinocytes...
March 2004: European Journal of Pharmaceutics and Biopharmaceutics
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