ABSTRACT
BACKGROUND AND PURPOSE: The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA-cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495). EXPERIMENTAL APPROACH: Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function and metabolism before and after addition of vehicle, glucagon, ZP131 or ZP2495. Subsequently, cardiac levels of nucleotides and short-chain CoA esters were measured by HPLC. KEY RESULTS: Hearts from IR rats showed decreased rates of glycolysis and glucose oxidation, plus increased palmitate oxidation rates, although cardiac function and energy state (measured by ATP/AMP ratios) was normal compared with control rats. Glucagon increased glucose oxidation and glycolytic rates in control and IR hearts, but the increase was not enough to avoid AMP and ADP accumulation in IR hearts. ZP131 had no significant metabolic or functional effects in either IR or control hearts. In contrast, ZP2495 increased glucose oxidation and glycolytic rates in IR hearts to a similar extent to that of glucagon but with no concomitant accumulation of AMP or ADP. CONCLUSION AND IMPLICATIONS: Whereas glucagon compromised the energetic state of IR hearts, glucagon-GLP-1 dual-agonist ZP2495 appeared to preserve it. Therefore, a glucagon-GLP-1 dual-agonist may be beneficial compared with glucagon alone in the treatment of severe heart failure or cardiogenic shock in subjects with IR.
Subject(s)
Cardiotonic Agents/pharmacology , Glucagon-Like Peptide 1/agonists , Glucagon/pharmacology , Heart/drug effects , Insulin Resistance/physiology , Peptides/pharmacology , Adenosine Triphosphate/metabolism , Animals , Blood Pressure/drug effects , Glucose/metabolism , Glycolysis/drug effects , HEK293 Cells , Heart/physiology , Heart Rate/drug effects , Humans , Male , Oxidation-Reduction , Palmitates/metabolism , RatsABSTRACT
The efficiency of the samarium(II) iodide induced pinacol-type coupling for the construction of seven-membered cyclic amino alcohols has been investigated. With the acyclic carbonylhydrazones 6 and 16, good yields of the hexahydroazepines 22 and 23 were obtained (56-57%) with high trans-selectivity (= 10:1), which compares well with similar reactions generating the corresponding five- and six-membered carbocycles (Fallis, A. G.; Sturino, C. F. J. Am. Chem. Soc. 1994, 116, 7447). It is essential for ring formation that the strongly electron-donating ligand, hexamethylphosphoramide, be present, as in its absense intermolecular pinacol coupling forming the diols 27-30 is the dominant reaction. Hence, the role for HMPA appears not only to increase the rate of electron transfer but also to modulate rate constants for the subsequent reactions (cyclization and pinacol coupling) of the intermediate ketyl. This ring forming reaction has been applied to the construction of the fully functionalized hexahydroazepine ring of the PKC inhibitor, balanol. Initial attempts to develop an asymmetric version of this reaction indicate the use of chiral ligands based on the structure of HMPA.
