Functional and energetic consequences of chronic myocardial creatine depletion by beta-guanidinopropionate in perfused hearts and in intact rats

Oral feeding with the creatine analogue beta-guanidinopropionate (beta-GP) reduces myocardial phosphocreatine and creatine concentrations by about 80% ; in vitro, this is accompanied by reduced contractile performance. We hypo thesized, thus, that beta-GP feeding leads to hemodynamic changes in vivo c haracteristic of heart failure. beta-GP was fed to Wistar rats for up to 8 weeks. In isolated hearts, function was measured isovolumically, myocardial energetics were followed with P-31-NMR spectroscopy. In vivo hemodynamics were measured with Millar-Tip-catheters and an electromagnetic flow probe. beta-GP feeding did not alter heart weight, In vitro, diastolic pressure-vo lume curves indicated structural left ventricular dilatation, and a 36% red uction of left ventricular developed pressure was found; phosphocreatine wa s reduced by similar to 80%, ATP unchanged and creatine kinase reaction vel ocity P-31-MR saturation transfer) decreased by similar to 90%. The total c reatine pool thigh-pressure liquid chromatography) was reduced by up to sim ilar to 70%. In contrast to in vitro findings, in vivo cardiac hemodynamics (including left ventricular developed pressure, dP/dt(max), cardiac output and peripheral vascular resistance) at rest and during acute volume loadin g showed no alterations after beta-GP feeding, The only functional impairme nt observed in vivo was a 14% reduction of maximum left ventricular develop ed pressure during brief aortic occlusion. In the intact rat, cardiac and/o r humoral compensatory mechanisms are sufficient to maintain normal hemodyn amics in spite of a 90% reduction of creatine kinase reaction velocity. How ever, chronic beta-GP feeding leads to structural left ventricular dilatati on. (C) 1999 Academic Press.