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Direct and Noninvasive Measurement of Cerebral Metabolic Rate of ATP in Cat brain and its Physiological Implications

INTRODUCTION Adenosine triphosphate (ATP) production and utilization are fundamental biochemical processes for supporting the energy needs of all living species. In the brain, majority of ATP is formed in mitochondria through the oxidative phosphorylation of ADP and then utilized in cytosol for sustaining brain activity and normal function. In vivo P MRS in combine with the magnetization transfer (MT) approach had been applied to directly and non-invasively measure the cerebral metabolic rate of ATP (CMRATP) in human and rat brains at high field [1-3]. In principle, the cerebral ATP production (Pi → ATP) and utilization (ATP → Pi), with reaction rate constants of kf and kr, respectively, are regulated rigorously for maintaining a stable ATP level in the brain. The cerebral metabolic rate of ATP is defined as CMRATP = kf×[Pi]; and kr×[ATP] = kf×[Pi] in normal resting brain [2]. In this study, we apply the same approach to measure CMRATP in the isoflurane anesthetized cat brain at 9.4T. The results of the CMRATP measurement have been evaluated by comparing the CMRATP values obtained with different magnetization transfer techniques. At normal physiological condition, there should be a tight coupling between the cerebral oxidative phosphorylation and oxygen utilization. If the CMRATP value measured by the in vivo P MT experiment can truly reflect the oxidative phosphorylation rate, then it has to satisfy the simple relation of CMRATP ≈ 2×CMRO2×P:O ratio. Thus, we have compared the measured CMRATP with the estimated CMRATP derived from the CMRO2 previously obtained from the same cat model [4] and the P:O ratio of 2.5 taken from the literature [5]. In addition, the experimentally determined CMRATP in cat, as well as that in rat and human brain [1-3], are correlated with their corresponding CMRO2 values [4,6-8], respectively. This allows us for the first time to directly assess the P:O ratios in these three species in vivo, which would have profound physiological implications for understanding the dynamic relation of cerebral ATP metabolism, oxidative metabolism and brain function. METHODS All H images and P spectra were acquired with a home-built H-P dual RF surface coil probe on a 9.4T/30cm bore Magnex magnet equipped with Varian INOVA consoles. Female adolescent cats under gaseous anesthesia (0.9-1.2 % isoflurane in a mixture of 70% nitrous oxide and 30% oxygen) and artificial ventilation were used for this study. Progressive saturation of γ-ATP with varied saturation time (tsat ranging from 0.5 to 9.8s) under fully relaxed condition using an adequate pre-saturation delay (=12s) was performed for determining the intrinsic longitudinal relaxation time and the reaction rate constant kf in cat brain (n=5). A 90° adiabatic pulse of 300 μs was used for spin excitation, and the BISTRO pulse train was used for frequency-selective saturation of γ-ATP; and for collecting in vivo P MT spectra (spectral width=5,000 Hz and 64 averages). Steady-state MT experiments with multiple single-site saturation (MSS technique [2]) of γ-ATP, Pi and PCr, respectively, and a control (i.e. without saturation) were carried out on a separate group of cats (n=9) with TR of 16s and tsat of 9.8s to explicitly determine the reaction rate constants of kf and kr. The P spectra were processed with LB=10 Hz before Fourier transformation and analyzed using AMARES time domain spectra fitting algorithm in the JMRUI software package. All results were presented by mean±SD.