Functional and Energetic Consequences of Chronic Myocardial Creatine Depletion by β -Guanidinopropionate in Perfused Hearts and in Intact Rats

Abstract

Oral feeding with the creatine analogue β -guanidinopropionate (β -GP) reduces myocardial phosphocreatine and creatine concentrations by about 80%in vitro, this is accompanied by reduced contractile performance. We hypothesized, thus, that β -GP feeding leads to hemodynamic changes in vivo characteristic of heart failure. β -GP was fed to Wistar rats for up to 8 weeks. In isolated hearts, function was measured isovolumically, myocardial energetics were followed with31P-NMR spectroscopy. In vivo hemodynamics were measured with Millar-Tip-catheters and an electromagnetic flow probe. β -GP feeding did not alter heart weight.In vitro , diastolic pressure–volume curves indicated structural left ventricular dilatation, and a 36% reduction of left ventricular developed pressure was found; phosphocreatine was reduced by ≈80%, ATP unchanged and creatine kinase reaction velocity (31P-MR saturation transfer) decreased by ≈90%. The total creatine pool (high-pressure liquid chromatography) was reduced by up to ≈70%. In contrast to in vitro findings, in vivo cardiac hemodynamics (including left ventricular developed pressure, d P/d tmax, cardiac output and peripheral vascular resistance) at rest and during acute volume loading showed no alterations after β -GP feeding. The only functional impairment observed in vivo was a 14% reduction of maximum left ventricular developed pressure during brief aortic occlusion. In the intact rat, cardiac and/or humoral compensatory mechanisms are sufficient to maintain normal hemodynamics in spite of a 90% reduction of creatine kinase reaction velocity. However, chronicβ -GP feeding leads to structural left ventricular dilatation.