Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Injectable local drug delivery formulations-so-called microspheres have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson's disease.
Mol Chem Neuropathol
PMID:Dopamine fiber growth induction by implantation of synthetic dopamine-containing microspheres in rats with experimental hemi-parkinsonism. 135 53

Cells subjected to increases in temperature induce the expression of several proteins known as heat shock or stress proteins. This process enhances the cell's ability to overcome the effects of further stress. In this respect, the effects of heat stress have been reported to protect the hearts of rats following ischaemia and reperfusion. We have confirmed and extended this observation, not only using different indices of myocardial injury but also in another species, namely the rabbit. Animals were anaesthetized and the body temperature raised to 42 degrees C for a 15-min period. Controls were treated in the same way but without heating. Twenty-four hours later the rabbits were re-anaesthetized and the hearts removed for either heat stress protein analysis or perfusion with Krebs buffer using an isolated perfused heart apparatus. Hearts were subjected to 60 min of low flow (1 ml/min) ischaemia followed by 30 min of reperfusion. All hearts subjected to heat stress showed an enhanced recovery of function upon reperfusion as measured by improvements in developed pressure (27.3 +/- 3.6 vs 16.3 +/- 3.0 mmHg) and diastolic pressure (37.3 +/- 7.4 vs 54.7 +/- 3.1 mmHg). In addition, creatine kinase release, associated with reperfusion, was significantly reduced in the heat-stressed hearts (532 +/- 102 vs 1138 +/- 73 mU/min/g wet wt). Myocardial accumulation and release of oxidized glutathione, an index of oxidative stress, was significantly reduced in the heat-stressed group (0.003 +/- 0.003 vs 0.376 +/- 0.113 nmol/min/g wet wt). The improved metabolic status of the reperfused heat-stressed hearts was further demonstrated by a significant conservation in the levels of ATP (6.1 +/- 0.9 vs 2.8 +/- 0.8 mumol/g dry wt) and CP (36.9 +/- 6.4 vs 16.4 +/- 5.1 mumol/g dry wt). Finally, isolated mitochondrial function in terms of respiratory control index (RCI) was maintained in the heat-stressed hearts (9.2 +/- 0.9 vs 5.7 +/- 0.2) and overloading with calcium was reduced. These data extend the hypothesis that heat stress protects the heart following ischaemia and reperfusion in this in vitro model, in a way as yet undetermined.
J Mol Cell Cardiol 1992 Aug
PMID:The protective role of heat stress in the ischaemic and reperfused rabbit myocardium. 143 16

Repeated brief episodes of ischaemia "precondition" the myocardium and protect it during a subsequent period of sustained ischaemia. We subjected isolated rat hearts to sustained ischaemia with or without reperfusion after different schedules of preconditioning. We demonstrated that preconditioning with three 5 min periods of ischaemia separated by 10 min periods of reperfusion permits better functional recovery than preconditioning with three 2 min ischaemic periods separated by 10 min of reperfusion. Preconditioned hearts had creatine phosphate and adenine nucleotide levels comparable to those in the aerobically perfused controls, and showed good functional recovery. Although the mechanisms by which preconditioning protects the heart from subsequent ischaemic damage are unclear, we speculate that preservation of mitochondrial function and oxidative energy production is involved.
J Mol Cell Cardiol 1992 Sep
PMID:Effects of duration of ischaemia during preconditioning on mechanical function, enzyme release and energy production in the isolated working rat heart. 143 17

A significant reduction in the extent of cell necrosis or the incidence of reperfusion-induced arrhythmias can be achieved with ischaemic preconditioning. If preconditioning was also found to be effective in protecting against global ischaemia, then this may have significant implications for the preservation of the heart during cardiac surgery. We therefore investigated this phenomenon in relation to recovery of contractile function after global ischaemia in the isolated rat heart. Isolated working rat hearts (n = 6 per group) were perfused aerobically at 37 degrees C for 20 min and contractile function recorded. This was followed by 10 min of aerobic Langendorff perfusion (control hearts) or 5 min global ischaemia (37 degrees C) + 5 min Langendorff reperfusion (preconditioned hearts). The hearts were then subjected to 10, 15, 20 or 25 min of global ischaemia (37 degrees C) and reperfusion (15 min Langendorff + 20 min working) after which function was again assessed. Preconditioning improved functional recovery after all durations of ischaemia. Thus aortic flow after 10, 15, 20 and 25 min of ischaemia and 35 min of reperfusion recovered to 84, 58, 16 and 5%, respectively, in controls and 88, 74, 55 and 20%, respectively, in the preconditioned groups. To assess whether preconditioning was effective in a surgically relevant model of hypothermic ischaemia, the experiments were repeated with longer periods (45, 70, 90, 115, 135 and 160 min) of ischaemia at 20 degrees C. Under these conditions, normothermic preconditioning increase the post-ischaemic recovery of aortic flow after 115, 135 and 160 min of ischaemic (from 36, 20 and 10%, respectively, in controls to 57, 39 and 26%, respectively, in preconditioned hearts). There was no consistent correlation between tissue high energy phosphate content and enhanced post-ischaemic recovery. Thus, we have demonstrated that ischaemic preconditioning can improve contractile function after global ischaemia in the isolated rat heart, we have defined the duration of ischaemia for which it is operative, and we have shown that this protection is additive to that of hypothermia-induced protection during ischaemia. This may have clinical implications for cardiac surgery.
J Mol Cell Cardiol 1992 Oct
PMID:Ischaemic preconditioning and contractile function: studies with normothermic and hypothermic global ischaemia. 147 13

The vulnerability of the heart to injury during ischaemia and reperfusion and its responsiveness to various protective and pharmacological interventions are age-dependent. Using three independent indices of tissue injury (cardiac structure, contractile function and creatine kinase leakage), we compared the response of adult (60-90 days old) and neonatal (7 days old) isolated perfused rabbit hearts to global ischaemia and reperfusion. Prior to ischaemia, heart rate was significantly higher in neonatal hearts, as were control values for coronary flow, aortic flow and cardiac output when expressed on a dry wt basis. In experiments in which adult and neonatal hearts (n = 8 per group) were subjected to 2 min of cardioplegia and 45 min of ischaemia, the post-ischaemic recovery of all indices of cardiac function (when expressed as a percentage of pre-ischaemic control) was significantly higher in neonatal than in adult hearts. Thus, cardiac output recovered to 82.9 +/- 3.6% in the neonate but to only 57.9 +/- 6.7% in the adult (P < 0.05). The functional evidence of a greater resistance to ischaemia in the neonate was, however, contradicted by the levels of creatine kinase leakage which tended to be greater in the neonatal than in the adult heart (32.0 +/- 4.7 vs 20.0 +/- 3.1 IU/15 min/g dry wt). Morphological studies indicated that injury was comparable (moderate-to-severe in degree) in both groups. To assess further the relationship between the three indices, additional experiments were undertaken in which the duration of ischaemia in the neonate was extended to 60 min so that the post-ischaemic recovery of function was reduced to a level similar to that seen in the adult after 45 min of ischaemia. Under these conditions cardiac output recovered to 55.6 +/- 4.8% in the neonatal heart (P = NS when compared with the adult) and creatine kinase leakage increased to 88.2 +/- 13.9 IU/15 min/g dry wt--a value over four times greater than that measured in adult hearts with a comparable degree of functional injury. Morphological examination of tissue obtained after 15 min of reperfusion revealed a remarkable recovery of structure in both age groups. In conclusion, in functional terms the neonatal heart was more resistant to ischaemia than the adult; enzymic leakage, however, indicated the opposite and structural assessment revealed no differences. Thus, in comparing injury during ischaemia and reperfusion between different age groups, it is clearly important to employ several independent indices.
J Mol Cell Cardiol 1992 Oct
PMID:Developmental changes in tolerance to ischaemia in the rabbit heart: disparity between interpretations of structural, enzymatic and functional indices of injury. 147 15

Several biochemical and functional characteristics of immature myocardium suggest a diminished capacity to regulate intracellular Ca2+ during stress. In particular, cellular calcium overload has been postulated as an important pathogenetic mechanism accounting for suboptimal functional recovery following cardioplegia in immature myocardium. Using intracellular Fura-2 fluorescence as Ca2+ indicator, we measured cytosolic free calcium ([Cai]) in single myocytes and cell suspensions derived from both juvenile (4 weeks post-partum) and mature (6-12 months post-partum) New Zealand white rabbits. Resting [Cai] in juvenile heart cells (26 +/- 3 nM) were approximately 50% of that found in adult myocytes (55 +/- 5 nM). In addition, on exposure to increasing concentrations of extracellular potassium ([Kex]), adult but not juvenile myocytes exhibited increases in [Cai]. These two observations underscore developmental differences in intracellular Ca2+ homeostasis. Of particular clinical relevance is the [Cai] response to cardioplegia containing 16 mM [Kex]: neither group demonstrated the expected [Cai] increase in response to potassium depolarization. The lack of [Cai] response to cardioplegia was most likely due to the high levels of Mg2+ (32 mM) contained in cardioplegic solutions. We conclude that cellular calcium overload does not occur following exposure to cardioplegia alone. Accordingly, these findings do not account for recognized developmental differences in functional recovery from "myocardial protection".
J Mol Cell Cardiol 1992 Oct
PMID:Developmental differences in the response of cytosolic free calcium to potassium depolarization and cardioplegia in cardiac myocytes. 147 17

This overview is presented, in the main, to summarize the following aspects of lactate and cardiac fatty acid metabolism: 1. The utilization of exogenous carbohydrates and fatty acids by the heart. 2. The competition between lactate and fatty acids in cardiac energy metabolism. 3. The effect of lactate on endogenous triacylglycerol homeostasis. 4. Lactate-induced impairment of functional recovery of the post-ischemic heart. 5. The effect of lactate on lipid metabolism in the ischemic and post-ischemic heart. 6. The consequences of hyperlactaemia for cardiac imaging.
Mol Cell Biochem 1992 Oct 21
PMID:Interrelationship between lactate and cardiac fatty acid metabolism. 148 Jan 38

It was examined whether lactate influences postischaemic hemodynamic recovery as a function of the duration of ischaemia and whether changes in high-energy phosphate metabolism under ischaemic and reperfused conditions could be held responsible for impairment of cardiac function. To this end, isolated working rat hearts were perfused with either glucose (11 mM), glucose (11 mM) plus lactate (5 mM) or glucose (11 mM) plus pyruvate (5 mM). The extent of ischaemic injury was varied by changing the intervals of ischaemia, i.e. 15, 30 and 45 min. Perfusion by lactate evoked marked depression of functional recovery after 30 min of ischaemia. Perfusion by pyruvate resulted in marked decline of cardiac function after 45 min of ischaemia, while in glucose perfused hearts hemodynamic performance was still recovered to some extent after 45 min of ischaemia. Hence, lactate accelerates postischaemic hemodynamic impairment compared to glucose and pyruvate. The marked decline in functional recovery of the lactate perfused hearts cannot be ascribed to the extent of degradation of high-energy phosphates during ischaemia as compared to glucose and pyruvate perfused hearts. Glycolytic ATP formation (evaluated by the rate of lactate production) can neither be responsible for loss of cardiac function in the lactate perfused hearts. Moreover, failure of reenergization during reperfusion, the amount of nucleosides and oxypurines lost or the level of high-energy phosphates at the end of reperfusion cannot explain lactate-induced impairment. Alternatively, the accumulation of endogenous lactate may have contributed to ischaemic damage in the lactate perfused hearts after 30 min of ischaemia as it was higher in the lactate than in the glucose or pyruvate perfused hearts. It cannot be excluded that possible beneficial effects of the elevated glycolytic ATP formation during 15 to 30 min of ischaemia in the lactate perfused hearts are counterbalanced by the detrimental effects of lactate accumulation.
Mol Cell Biochem 1992 Dec 02
PMID:The nucleotide metabolism in lactate perfused hearts under ischaemic and reperfused conditions. 148 52

The present study was designed to evaluate the effects of POCA, a carnitine palmitoyltransferase I (CPT I) inhibitor, and pyruvate, a substrate inhibiting fatty acid (FA) oxidation, on post-ischemic cardiac FA accumulation on the one hand, and hemodynamic recovery and loss of cellular integrity on the other. To this end isolated, working rat hearts, receiving glucose (11 mM) as substrate, were subjected to 45 min of no-flow ischemia and 30 min of reperfusion. Hearts were perfused with or without POCA (10 microM) and/or pyruvate (5 mM). In the control group the FA content increased significantly during ischemia and remained elevated during reperfusion. Administration of POCA did not affect functional recovery and LDH release significantly, but resulted in about two-fold increased FA levels upon reperfusion as compared to glucose-perfused hearts. Pyruvate markedly improved functional recovery. Addition of this substrate did not affect lactate dehydrogenase (LDH) release, but enhanced FA accumulation during reperfusion. The combined administration of pyruvate and POCA nullified the positive effect of pyruvate on hemodynamic recovery, aggravated LDH release, and further enhanced the accumulation of FAs. The adenine nucleotide content of reperfused hearts was comparable for all groups investigated. In conclusion, during transient ischemia POCA and pyruvate markedly increased cardiac FA accumulation through inhibition of the oxidation of FAs released from endogenous lipid pools. No clear relation was found between the FA content of reperfused hearts and post-ischemic functional recovery.
J Mol Cell Cardiol 1991 Dec
PMID:Fatty acid accumulation during ischemia and reperfusion: effects of pyruvate and POCA, a carnitine palmitoyltransferase I inhibitor. 181 Oct 59

In the present investigation, we used electrolysis as a source of oxygen free radicals to test their possible role in norepinephrine release, as well as in the mechanism of cellular injury, cardiac dysfunction and arrhythmias. In the isolated rat heart perfused under constant pressure, according to the Langendorff technique, electrolysis of the Krebs-Henseleit solution (10 mA d.c. current for 1 min) produced myocardial irreversible dysfunction within 5 min. Fifteen minutes after electrolysis, significant falls in the left ventricular pressure (from 87.5 +/- 6.8 to 33.7 +/- 5.2 mmHg), dP/dt max (from 1230 +/- 90 to 375 +/- 59 mmHg/s), heart rate (from 287 +/- 18 to 119 +/- 13.5 beats/min) and coronary flow (from 14.8 +/- 9 to 3.4 +/- 1.7 ml/min) were observed, along with an increase in left ventricular end diastolic pressure from 10 to 50 +/- 3.5 mmHg (n = 8, P less than 0.01). AV conduction block and/or sinus bradycardia were noted in all preparations. An increase in norepinephrine washout from 298.5 +/- 84 at baseline to 610 +/- 110 pg/min/g 5 min after electrolysis was measured (n = 8, P less than 0.05) and a 44.8 +/- 9.2% and 35 +/- 7.5% reduction, respectively in right and left ventricular tissue norepinephrine content was also found at 30 min (n = 5, P less than 0.05). Pretreatment of the hearts 10 min before electrolysis and throughout the experimental period by superoxide dismutase (SOD; 100 U/ml), catalase (150 U/ml), a combination of SOD + catalase or mannitol (50 mM) partially blocked the deleterious effect of free radicals and permitted a functional recovery of 50 to 60%, mannitol being the more potent protective agent. Furthermore, these scavengers also significantly reduced norepinephrine washout.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1991 Mar
PMID:Myocardial dysfunction and norepinephrine release in the isolated rat heart injured by electrolysis-induced oxygen free radicals. 190 7


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