title: The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo.
abstract: Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may improve contractile function in heart failure. We tested whether application of two agents (etomoxir and NVP-LAB121) capable of inducing a substrate-switch reverts the onset of heart failure in rats with chronic pressure-overload. Hypertrophy was induced by aortic banding in rats for 1 or 15 weeks. Rats were treated for 10 days with the CPT-1-inhibitor etomoxir [29.5 micromol/(kg day)] or with NVP-LAB121 [60 micromol/(kg day)], a pyruvate-dehydrogenase-kinase-inhibitor, before assessment by echocardiography and perfusion as isolated working hearts. We also analyzed PDH- and CPT1-activity and expression of alpha- and beta-MHC by RT-PCR. Aortic banding increased heart-to-body-weight-ratio (g/kg) from 3.44 +/- 0.26 to 4.14 +/- 0.48 after 1 week and from 2.80 +/- 0.21 to 6.54 +/- 0.26 after 15 weeks. Ejection fraction was impaired after 15 weeks (57 +/- 11 vs. 73 +/- 8%, P < 0.05) and rats exhibited signs of heart failure. Total PDH activity was the same in all groups. CPT-1 activity was unchanged after 1 week but decreased after 15 weeks (P < 0.01). Neither etomoxir nor NVP-LAB121 affected cardiac function in vivo, but etomoxir improved function of the isolated heart. The drugs did not affect total PDH and CPT-1 activity, but increased PDH-activity status, prevented a decrease in PDK4 expression in heart failure, increased alpha and beta-MHC expression and shifted substrate oxidation toward glucose in the isolated working rat heart. In conclusion, pharmacologic induction of substrate-switching is associated with changes in myofibrillar isoform expression but does not reverse heart failure in vivo. The improvement of function in vitro deserves further investigation.
authors.affiliation: Department of Cardiac Surgery, University of Leipzig Heart Center, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarzer
authors.forename: Gloria
authors.initials: G
authors.lastname: Faerber
authors.forename: Tilmann
authors.initials: T
authors.lastname: Rueckauer
authors.forename: Daniel
authors.initials: D
authors.lastname: Blum
authors.forename: Gracjan
authors.initials: G
authors.lastname: Pytel
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Mohr
authors.forename: Torsten
authors.initials: T
authors.lastname: Doenst
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; C000594638:MYH7 protein, rat; C545274:NVP-LAB121; C000631440:Pdk4 protein, rat; D010879:Piperazines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases; D018995:Myosin Heavy Chains; D005947:Glucose; C054207:etomoxir