A high level of fatty acid delays the recovery of pH(i) during reperfusion of ischemic hearts because of an increased H(+) production from glycolysis uncoupled from glucose oxidation. Improving the coupling of glucose metabolism by stimulating glucose oxidation accelerates the recovery of pH(i) and improves both mechanical function and cardiac efficiency.

We have produced a family of novel carriers enabling water solubilization of highly lipophilic molecules. The compound carriers were synthesized by conjugating polyethylene glycol to alpha-tocopherol, tocotrienols, beta-sitosterol or cholesterol via an alkanedioyl linker. These PEG- conjugates were amphiphilic and formed stable non-covalent complexes (nanomicelles) with a wide range of molecules including vitamins, carotenoids, ubiquinones, poly-unsaturated fatty acids and polyene macrolide antibiotics. The resulting formulations were water-soluble, non-toxic and had excellent stability. This solubilization method represents a major advance in the delivery of lipophilic molecules and could be used to reformulate drugs with near term patent expiry or those that have failed clinical trials due to low solubility. Furthermore, the technology could also be applied for delivery of active ingredients for dietary supplement, functional food, cosmetic and animal health industries.

1 The cardioprotective properties of inhibition of poly (ADP-ribose) synthetase (PARS) were investigated in the isolated perfused heart of the rat. Hearts were perfused in the Langendor mode and subjected to 23 min total global ischaemia and reperfused for 60 min. 2 Left ventricular function was assessed by means of an intra-ventricular balloon. High energy phosphates were measured by 31 P-NMR spectroscopy. Intracellular levels of NAD were measured by capillary electrophoresis of perchloric acid extracts of hearts at the end of reperfusion. 3 Reperfusion in the presence of the PARS inhibitor 1,5 didroxyisoquinoline (ISO, 100 mM) attenuated the mechanical dysfunction observed following 1 h of reperfusion; 27+13 and 65+8% recovery of preischaemic rate pressure product for control and 100 mM ISO, respectively. 4 This cardioprotection was accompanied by a preservation of intracellular high-energy phosphates during reperfusion; 38+2 vs 58+4% (P50.05) of preischaemic levels of phosphocreatine (PCr) for control and 100 mM ISO respectively and 23+1 vs 31+3% (P50.05) of preischaemic levels of ATP for control and 100 mM ISO respectively. 5 Cellular levels of NAD were higher in ISO treated hearts at the end of reperfusion; 2.56+0.45 vs 4.76+1.12 mmoles g 71 dry weight (P50.05) for control and ISO treated. 6 These results demonstrate that the cardioprotection a orded by inhibition of PARS activity with ISO is accompanied by a preservation of high-energy phosphates and cellular NAD levels and suggest that the mechanism responsible for this cardioprotection may involve prevention of intracellular ATP depletion.

Functional magnetic resonance imaging (fMRI) was used to examine the brain processing of capsaicin-induced painful stimulation in the ␣-chloralose anesthetized rat. Experiments were performed on a 9.4-T magnet (Magnex, UK) with Avance console (Bruker, Germany) using a surface coil tuned to 400.5 MHz centred over the rat forebrain. Gradient-echo images of two slices, with an echo time of 25 msec, repetition time of 70 msec, and 50 repetitions, were acquired per experiment. These images were analyzed using a fuzzy cluster analysis technique (EvIdent™). Activation of areas of the brain known to be associated with the processing of pain, namely the anterior cingulate (bilateral), frontal cortex (bilateral), and sensory motor cortex (contralateral), was found in all animals (N ‫؍‬ 6) following injection of 25 L of capsaicin (128 g/mL in 7.5% dimethylsulfoxide [DMSO]) into the dorsal forepaw. It is possible to reproduce the pain response in a given animal several times throughout the course of an experiment, provided that sufficient time is allowed between capsaicin injections. This acute phase of capsaicin-induced pain involving stimulation of C polymodal nociceptors was examined by functional imaging. There was a substantial initial increase in activation in regions of the brain associated with pain and there was a trend towards increasing activation with repeated stimulations. Treatment with morphine (3 mg/kg, intravenously) was found to substantially reduce, if not completely eliminate, the areas of functional activation associated with physiologic pain (anterior cingulate and frontal cortex) after C-nociceptor stimulation with capsaicin (N ‫؍‬ 6). FMRI involving capsaicin-induced painful stimulation could prove to be an effective tool for the study of novel analgesics and the central nervous system processing of pain.

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