The cardiac contractile failure induced by chronic creatine and phosphocreatine deficiency.
Rats were fed a diet containing beta-guanidinopropionic acid (GP), an inhibitor of creatine transport. After 6 to 8 weeks of feeding the myocardial creatine (Cr) and phosphocreatine (PCr) stores were severely depleted while ATP content was normal. Hearts of GP-treated rats perfused according to Neely's working heart model revealed clear cardiac contractile failure: the maximal work capacity at a stepwise increase in resistance as well as the maximal oxygen consumption were 32 to 40% less in the GP group. The cardiac failure in GP-treated working hearts was associated with a rise in the left ventricular diastolic pressure, which could cause a diminished cardiac output probably due to impaired LV filling. The extent of the contractile failure was found to depend on functional load and on the degree of Cr (PCr) substitution. The energy fluxes through creatine kinase measured by the 31P-NMR saturation transfer technique were diminished by a factor of two after substitution of 90% of creatine, but still exceeded the rate of ATP turnover. The results are compatible with the concept of phosphocreatine pathway for intracellular energy transport and show that PCr is an important high energy phosphate compound for cardiac contractile function.
Kapelko
V I
VI
USSR Research Center for Cardiology, Academy of Medical Sciences, Moscow.
Kupriyanov
V V
VV
Novikova
N A
NA
Lakomkin
V L
VL
Steinschneider AYa
Severina MYu
Veksler
V I
VI
Saks
V A
VA
D000818:Animals; D002302:Cardiac Output; D003401:Creatine / Q000172:deficiency* / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006323:Heart Arrest / Q000139:chemically induced*; D006339:Heart Rate; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010725:Phosphocreatine / Q000172:deficiency* / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D006146:Guanidines; D011422:Propionates; D010725:Phosphocreatine; D003401:Creatine; C005775:guanidinopropionic acid