ABSTRACT
In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.
Subject(s)
Coronary Vessels/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Cyclic GMP/metabolism , Endothelium, Vascular/metabolism , Heart Failure/metabolism , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/metabolism , Vasodilation , Acetylcholine/pharmacology , Animals , Bradykinin/pharmacology , Coronary Circulation , Coronary Vessels/drug effects , Coronary Vessels/enzymology , Coronary Vessels/physiopathology , Disease Models, Animal , Dogs , Endothelium, Vascular/drug effects , Endothelium, Vascular/enzymology , Endothelium, Vascular/physiopathology , Gene Expression Regulation, Enzymologic , Heart Failure/enzymology , Heart Failure/genetics , Heart Failure/physiopathology , Male , Myocardial Contraction , Myocardium/metabolism , Nitric Oxide Synthase Type III/genetics , Nitroglycerin/pharmacology , Phosphoproteins/metabolism , Phosphorylation , RNA, Messenger/metabolism , Recovery of Function , Signal Transduction , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Ventricular Function, LeftABSTRACT
The design and synthesis of dual PPAR gamma/delta agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}propionic acid is described. This compound dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats and produced less weight gain relative to rosiglitazone at an equivalent level of glucose control.