Creatine kinase kinetics studied by phosphorus-31 nuclear magnetic resonance in a canine model of chronic hypertension-induced cardiac hypertrophy

AbstractTo determine whether cardiac hypertrophy secondary to chronic renovascular hypertension is associated with altered in vivo myocardial metabolism, phosphorus-31 nuclear magnetic resonance saturation transfer techniques were used to study creatine kinase (CK) kinetics in six chronically hypertensive dogs with moderate cardiac hypertrophy and eight control dogs. The forward rate constant of CK and the flux of phosphocreatine to adenosine triphosphate were determined in both groups of dogs before and during norepinephrine administration (1 μg/kg per min), used to increase heart rate × systolic blood pressure (rate-pressure product), cardiac output and oxygen consumption.Baseline and norepinephrine-induced changes in rate-pressure product, cardiac output and oxygen consumption were similar in both groups of dogs, as were baseline forward rate constant and flux of phosphocreatine to adenosine triphosphate. However, the norepinephrine-induced changes in forward rate constant and flux were significantly less in hypertensive than in control dogs (p < 0.05) even though changes in hemodynamic and functional variables were similar in both groups.These data demonstrate that moderate myocardial hypertrophy is associated with altered CK kinetics, which do not appear to affect the heart's ability for global mechanical recruitment at this stage in the hypertensive process. It is possible that the changes in myocardial enzyme kinetics may contribute to diastolic dysfunction previously reported in this model and may be a precursor for ultimate development of heart failure if hypertension is maintained for prolonged periods.The data also suggest that the heart of moderately hypertensive animals may work less per gram muscle and that it may have greater metabolic efficiency because it can maintain lower adenosine diphosphate levels (as indicated by lower forward rate constant of CK) than those of control hearts. However, it appears that either the CK system has a large safety factor such that the lower forward rate constant and flux found in hypertensive dogs is sufficient to support normal global mechanical function or that the phosphocreatine shuttle is not a critical factor in maintaining mechanical function in the moderately hypertrophied heart

System identification to analyse changed kinetics of SERCA in intact rat heart

A mechanistic-based model has been derived of calcium handling in the intact heart. This model incorporates the quantitatively most important processes involved in beat-to-beat calcium homeostasis. Based on a priori physiological information the model has been reduced to yield (kinetic) parameters that could be estimated using time-series data of the free calcium concentration in the sarcoplasma. Observations of the dynamics of the overall system were translated into the underlying mechanisms. Experiments in which the most important calcium extrusion pump (Sarcoplasmic Reticulum Ca 2+ -ATPase, SERCA) was disturbed have been successfully analysed and interpreted using model and identification

System identification to analyse changed kinetics of SERCA in intact rat heart

\u3cp\u3e A mechanistic-based model has been derived of calcium handling in the intact heart. This model incorporates the quantitatively most important processes involved in beat-to-beat calcium homeostasis. Based on a priori physiological information the model has been reduced to yield (kinetic) parameters that could be estimated using time-series data of the free calcium concentration in the sarcoplasma. Observations of the dynamics of the overall system were translated into the underlying mechanisms. Experiments in which the most important calcium extrusion pump (Sarcoplasmic Reticulum Ca \u3csup\u3e2+\u3c/sup\u3e -ATPase, SERCA) was disturbed have been successfully analysed and interpreted using model and identification. \u3c/p\u3

Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling

The muscle Lim protein knock-out (MLP-KO) mouse model is extensively used for studying the pathophysiology of dilated cardiomyopathy. However, explanation is lacking for the observed long survival of the diseased mice which develop until adulthood despite the gene defect, which theoretically predestines them to early death due to heart failure. We hypothesized that adaptive changes of cardiac intracellular calcium (Ca (i) (2+) ) handling might explain the phenomenon. In order to study the progression of changes in cardiac function and Ca (i) (2+) cycling, myocardial Ca (i) (2+) -transients recorded by Indo-1 surface fluorometry were assessed with concomitant measurement of hemodynamic performance in isolated Langendorff-perfused hearts of 3- and 9-month old MLP-KO animals. Hearts were challenged with beta-agonist isoproterenol and the sarcoplasmic reticular Ca2+-ATPase (SERCA2a) inhibitor cyclopiazonic acid (CPA). Cardiac mRNA content and levels of key Ca2+ handling proteins were also measured. A decline in lusitropic function was observed in 3-month old, but not in 9-month old MLP-KO mice under unchallenged conditions. beta-adrenergic responses to isoproterenol were similar in all the studied groups. The CPA induced an increase in end-diastolic Ca (i) (2+) -level and a decrease in Ca2+-sequestration capacity in 3-month old MLP-KO mice compared to age-matched controls. This unfavorable condition was absent at 9 months of age. SERCA2a expression was lower in 3-month old MLP-KO than in the corresponding controls and in 9-month old MLP-KO hearts. Our results show time-related recovery of hemodynamic function and an age-dependent compensatory upregulation of Ca (i) (2+) handling in hearts of MLP-KO mice, which most likely involve the normalization of the expression of SERCA2a in the affected hearts