Studies of Langendorff-perfused rat hearts have revealed a biphasic response of the mitochondrial respiratory chain to global ischaemia. The initial effect is a 30-40% increase in the rate of glutamate/malate oxidation after 10 min of ischaemia, owing to an increase in the capacity for NADH oxidation. This effect is followed by a progressive decrease in these oxidative activities as the ischaemia is prolonged, apparently owing to damage to Complex I at a site subsequent to the NADH dehydrogenase component. This damage is exacerbated by reperfusion, which causes a further decrease in Complex I activity and also decreases the activities of the other complexes, most notably of Complex III. Perfusion for up to 1 h with anoxic buffer produced only the increase in NADH oxidase activity, and neither anoxia alone, nor anoxia and reperfusion, caused loss of Complex I activity. Perfusing for 3-10 min with anoxic buffer before 1 h of global ischaemia had a significant protective effect against the ischaemia-induced damage to Complex I.
The lipolytic response of isolated adipocytes from 1 ½-, 6-, 24- and 32-month-old rats to various doses of epinephrine was studied. Both the basal and the maximal stimulated glycerol release were largest in the mature rats (6 months old) which had the largest adipocytes. Expressing glycerol release per unit cell surface area (which was drastically reduced with age) eliminated the difference between mature and senescent rats both in absence of epinephrine and at high doses of the hormone. However, at low epinephrine doses the adipocytes of the very young and the very old rats showed an enhanced response per unit surface area. A simple pharmacodynamic analysis based on the occupancy theory of drug-receptor interaction suggests that the sensitivity of rat adipocyte receptors is increased during senescence; this increase may be related to the decreased surface of old adipocytes. On the other hand, the decreased maximal lipolytic response during senescence may be due in part to a reduced number of receptors and to a reduced sensitivity of the cellular enzymatic system underlying lipolysis.
Body weight, epididymal adipose tissue weight, fat cell size, and metabolic activity of fat depot were studied in 30-month-old Wistar rats and compared with rats aged 6 and 24 months old. In very old age a significant reduction of body weight was observed and was paralleled with a decline of adipose mass and a decrease in cell volume. In vitro metabolic studies, with and without insulin, showed a greater oxidation of D-U-14C glucose to 14CO2 and a greater incorporation into triglycerides than in the 24-month-old animals when the data were expressed per cell or per cm2 surface area. The resistance to insulin was elevated in spite of a significant decrease of adipocyte size in very old rats.
A diminished mitochondrial capacity to generate ATP after a period of ischaemia has been demonstrated in several perfused heart models in vitro. The cause of this apparent damage has been suggested to be free radicals [ 11, excessive Ca2 uptake upon reperfusion or the preferential uptake of Ca2+ rather than ATP-formation [2]. We were interested to examine the mitochondrial respiratory chain to determine if there was specific damage to the components of this system. Furthermore, we wanted to know whether such damage occurs during the ischaemic episode or is a consequence of reoxygenation, i.e. reperfusion damage.We studied the effects of global ischaemia, with and without reperfusion, and of anoxia on the function of mitochondrial fractions prepared from rat hearts perfused in a Langendorff apparatus with a Krebs-Henseleit buffer containin 11 mwglucose, continuously gassed with 0 2 / C 0 , (19:lf Aft er 15 rnin perfusion to equilibrate the tissue, one of the following protocols was imposed: continuous perfusion with oxygenated buffer for 15-60 rnin (Controls); global ischaemia induced for 6 0 rnin by clamping off the perfusate supply without reperfusion (Ischaemics) or with 5 rnin reperfusion with oxygenated buffer (Reperfused); 5 rnin perfusion with anoxic buffer to purge the tissue of oxygen before 6 0 min global ischaemia and 5 rnin reperfusion with anoxic buffer (N reperfused); or continuous perfusion for 60 rnin with anoxic buffer (Anoxic). Immediately after the end of each of the above treatments, the hearts were removed into ice-cold buffer and mitochondria prepared by a Nagarse digestion/Potter homogenization procedure. Oxygen uptake was measured in intact mitochondria with 5 mM-glutamate/S mwmalate as substrates and in lysed mitochondria (three freeze-thaw cycles) with 250 ,LAM-NADH as a substrate. The four respiratory chain complex activities were assayed using exogenous electron acceptors: ubiquinone-1 for complex 1; ubiquinone-1 and DCPIP for complex 11; ubiquinol-2 and cytochrome c for complex I11 and ascorbate/TMPD for complex IV ( polarographic). Specific mitochondrial marker enzyme activities, namely citrate synthase for the matrix, and NADH-ferricyanide reductase for the inner membrane, were also measured to compare the quality of the different preparations. All results are shown as the mean values of four to five hearts as a percentage of the mean control value ( n = 13).Ischaemia caused a marked decrease in state 3 glutamate/ malate oxidation (41% of controls) and 54% loss of NADH oxidase activity. This effect was worse in reperfused hearts (30% and 37%, respectively), suggesting some exacerbation of the damage by reoxygenation. This was indirectly supported by the effects of 'purging' the tissue of oxygen before the ischaemia, which protected against the effects of ischaemia alone (68% and 70% of controls, respectively). Furthermore, anoxia without ischaemia did not decrease these two activities. Rather, there was a slight stimulation in the activity of glutamate/malate ( 119'/0) and NADH (1 13...
The binding properties--binding capacity (MBC) and affinity (Ka)--of T3 nuclear receptors were analyzed in cortex, cerebellum and liver of rats aged 3, 6, 12 and 24 months. A slight but not significant decrease of Ka was observed in different tissues of normal rats. In hypothyroid animals the Ka in cortex at 24 months was significantly lower than at 3 months. During ageing the MBC of brain receptors decreased whereas hepatic receptors were not altered. Hypothyroidism did not further affect the MBC of the receptors. The data indicate that during ageing the T3 nuclear receptors behave differently in brain and liver. The difference in MBC suggests selectivity in organ sensitivity to thyroid hormones.
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