The effect of ranolazine, a novel anti-ischemic drug that stimulates the activity of pyruvate dehydrogenase, on hydrogen peroxide (H2O2)-induced mechanical and metabolic derangements was studied in isolated rat heart and compared with that of dichloroacetate (DCA), an activator of pyruvate dehydrogenase. The heart was perfused aerobically by the Langendorff's technique at a constant flow and driven electrically. H2O2 (600 microM) decreased the left ventricular developed pressure and increased the left ventricular end-diastolic pressure (i.e., mechanical dysfunction), decreased the tissue level of adenosine triphosphate (i.e., metabolic derangement), and increased the tissue level of malondialdehyde (MDA) (i.e., lipid peroxidation). These mechanical and metabolic derangements induced by H2O2 were significantly attenuated by ranolazine (10 or 20 microM). On the other hand, DCA (1 mM) was ineffective in attenuating the H2O2-induced mechanical and metabolic derangements. Ranolazine, however, did not modify the tissue MDA level, which was increased by H2O2. In the normal (H2O2-untreated) heart, ranolazine did not alter the mechanical function and energy metabolism. These results demonstrate that ranolazine attenuates mechanical and metabolic derangements induced by H2O2. It is suggested that the protective action of ranolazine against the H2O2-induced derangements is due to neither the energy-sparing, DCA-like, nor anti-oxidant effects.
The effect of lidocaine on the hydrogen peroxide (H2O2)-induced mechanical and metabolic changes was studied in the Langendorff rat heart, which was perfused aerobically at a constant flow rate and paced electrically. H2O2 (600 microM) increased the left ventricular end-diastolic pressure (i.e., mechanical dysfunction), decreased the tissue levels of ATP and creatine phosphate (i.e., metabolic change), and increased the tissue level of malondialdehyde (MDA). The mechanical and metabolic alterations induced by H2O2 were attenuated by lidocaine (50 or 200 microM). Lidocaine also attenuated the H2O2-induced increase in MDA. Nevertheless, lidocaine modified neither the myocardial ferrylmyoglobin level that was increased by H2O2 nor the H2O2 concentration in vitro and did not affect the mechanical function and energy metabolism of the normal heart. These results suggest that lidocaine attenuates both mechanical and metabolic changes induced by exogenous H2O2. The protective action of lidocaine on the H2O2-induced changes is due to neither energy-sparing nor H2O2-scavenging effect, but probably due to its effect to reduce the H2O2-induced lipid peroxidation.
Rats were treated with capsaicin (50 mg/kg, SC) either on the second day or on the second and third days of life. A significant attenuation of the responses to noxious stimuli was obtained in the capsaicin treated animals as measured by the hot-plate or paw pressure tests but not by the tail-flick test. Furthermore, neonatal capsaicin produced a significant reduction of response in the formalin test. Capsaicin reduced the reaction latency in rats with adjuvant arthritis as measured by the hot-plate and paw pressure tests, though capsaicin did not alter the overall time course of the response to Freund's adjuvant. Capsaicin also attenuated the weight loss or the decreased ambulatory and rearing behaviours which occurred in the control animals with adjuvant arthritis. It is suggested that neonatal treatment with capsaicin may relieve the responsiveness to long-lasting nociceptive stimuli by adjuvant in rats.
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