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PubMed1983

Regional measurements of blood-to-tissue transport in experimental RG-2 rat gliomas.

Regional measurements of blood-to-tissue transport were performed in transplanted RG-2 rat gliomas using [alpha- 14C]aminoisobutyric acid (AIB), quantitative autoradiography, and equations to express a unidirectional transfer constant. Thirty-eight intracranial tumors in ten rats were analyzed according to location; 23 intraparenchymal tumors, eight meningeal tumors, six fourth-ventricular tumors, and one third-ventricular tumor were studied. Except for the small third-ventricular tumor, the transfer constant (K) for AIB was similar in all groups and ranged from 0.031 to 0.038 ml/g/min. Within individual tumors, regional variation of K was also small, although some local variation could be correlated with histological features. The K for AIB decreased in brain around tumor and, at a distance of 300 microns from tumor edge, had returned to values similar to those of normal cortex (0.002 ml/g/min). An average extraction fraction (E) of 0.09 was calculated for AIB in the RG-2 tumors. The low E suggests that delivery of water-soluble chemotherapeutic drugs to RG-2 tumors should be limited more by capillary permeability or surface area than by blood flow. RG-2 is an ideal experimental tumor with which to test drug delivery and the methods that attempt to increase drug delivery in brain tumors.

Aminoisobutyric Acids↗
PubMed1998

Differential permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration on optimizing delivery of biologically diverse agents.

To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administration and tumor size on the distribution of three agents in a nude rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v., and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administration and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administration of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administration and BBBD.

Aminoisobutyric Acids↗
PubMed1997

Effects of hyperosmolar mannitol on regional oxygen supply and consumption in the newborn pig.

Previous work indicated that opening the blood-brain barrier with hyperosmotic mannitol decreased local venous O2 saturation and increased cerebral O2 consumption. This study was performed to assess the vascular effect of hypertonic mannitol on oxygen supply/consumption balance in the newborn pig and to determine the role of nitric oxide in mediating the effects of mannitol. Animals were anesthetized with alpha-chloralose and mechanically ventilated to maintain their blood gases within normal range. Retrograde catheterization of the right carotid artery was performed to inject 12 ml to 25% mannitol over a 30 sec interval. In one group of animals (n = 5), the blood-brain barrier transfer coefficient (Ki) to 14C-alpha aminoisobutyric acid or 14C-urea (n = 4) was measured 12 min after mannitol. In another group of animals (n = 9), regional cerebral blood flow and small vein O2 saturation was measured using 14C-iodoantripyrine and microspectrophotometry. Similar measurements were made in other groups of animals (n = 9) after pretreatment with 10 mg kg-1 i.v. of N-omega-nitro-L-arginine methyl ester (L-NAME), 20 min before mannitol injection. The mannitol injection did not increase Ki or local cerebral O2 consumption. It resulted in a decreased small vein O2 saturation in the ipsilateral cortex (46 +/- 3%) in comparison to the contralateral cortex (55 +/- 2%). The O2 supply/consumption ratio decreased in the ipsilateral cortex in the mannitol injected animals (2.14 +/- 0.23) in comparison to the contralateral cortex (2.76 +/- 0.28). Pretreatment with L-NAME abolished this effect of mannitol (small vein O2 saturation 59 +/- 2% in ipsilateral cortex and 58 +/- 2% in the contralateral cortex; O2 supply/consumption 2.68 +/- 0.17 in the ipsilateral cortex and 2.65 +/- 0.16 in the contralateral cortex). We conclude that hypertonic mannitol adversely affects O2 supply/consumption balance, without increasing blood-brain barrier transport, and this effect is blocked by L-NAME, a nitric oxide synthase antagonist.

Aminoisobutyric Acids↗
PubMed1976

Effects of growth hormone, thyroxine, and age on diaphragm muscle from dwarf mice.

The ability of GH in vitro to stimulate leucine incorporation into protein and the uptake of 2-aminoisobutyric acid (AIB) and 3-O-methyl-glucose (3-OMG) was studied in diaphragm muscle from dwarf (dw/dw) mice. Ovine GH (25 mug/ml) significantly enhanced the rate of protein synthesis in muscle from untreated dwarfs. In contrast, GH usually failed to stimulate transport, although occasionally a small increase in AIB uptake was seen. Insulin (50 muU/ml) readily stimulated both AIB transport and protein synthesis in muscle from untreated dwarfs. Dwarfs were treated for 4 days with thyroxine (T4) (0.3-5 mug/day) or 3,5,3'-triiodo thyronine (T3) (0.1 mug/day). This enhanced the responsiveness of the transport systems to GH and seemed to increase the basal transport rates for AIB and 3-OMG. After the T4-treatment 0.75 mug/ml GH stimulated AIB transport in mice aged 15 weeks; 25 mug/ml GH stimulated AIB transport in dwarfs aged 5 weeks-1 yr. and leucine incorporation into protein in dwarfs aged 5 weeks-2 yr. This last result suggests that response to GH does not cease merely due to increasing age. Synergism by T3/T4 was not permanent, and the maximum response to GH occurred 1 week after the last injection of T4. The possible mechanisms whereby thyroid hormones enhance responsiveness of the transport systems to GH are discussed.

Age Factors↗
PubMed1994

Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats.

There have been few investigations of brain edema formation after intracerebral hemorrhage (ICH), despite the fact that mass effect and edema are important clinical complications. The present study was designed to investigate the time course for the formation and resolution of brain edema and to determine how changes in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability are temporally related to edema formation following ICH. Anesthetized adult rats received a sterile injection of 100 microliters of autologous blood into the caudate nucleus. Water and ion contents were measured immediately, at 4 and 12 hours, and daily to Day 7 (10 time points, six rats at each time) after experimental ICH. The water content of the ipsilateral basal ganglia increased progressively (p < 0.002) over the first 24 hours, then remained constant until after Day 5, when the edema began to resolve. Edema was most severe in the tissue immediately surrounding the hemorrhage; however, it was also present in the ipsilateral cortex, the contralateral cortex, and the basal ganglia. Measurements of local CBF (using [14C]-iodoantipyrine) and BBB permeability (using [3H]-alpha-aminoisobutyric acid) were obtained in separate groups of six to eight rats at various time intervals between 1 and 48 hours after ICH. Cerebral blood flow was reduced to 50% of control at 1 hour, returned to control values by 4 hours, but then decreased to less than 50% of control between 24 and 48 hours after ICH. The BBB permeability increased significantly prior to the occurrence of significant edema in the tissue surrounding the clot. However, BBB permeability in the more distant structures remained normal despite the development of edema. These results demonstrate a time course for the formation and resolution of brain edema following ICH similar to that observed during focal ischemia. Brain edema forms in the immediate vicinity of the clot as a result of both BBB disruption and the local generation of osmotically active substances and then spreads to adjacent structures. While local ischemia, due to the mass effect of the hemorrhage, may play a role in producing cytotoxic and vasogenic edema, the release of toxic substances from the clot should also be considered. Since edema is nearly maximal by 24 hours after ICH, therapy directed at reducing edema formation must be instituted within the 1st day.

Aminoisobutyric Acids↗
PubMed2006

Effects of 17beta-estradiol on blood-brain barrier disruption during focal cerebral ischemia in younger and older rats.

This study was performed to compare the effects of 17beta-estradiol on blood-brain barrier disruption in focal cerebral ischemia between younger and older rats. Younger (three-month-old) and older (24-month-old) ovariectomized female Fischer 344 rats were studied. In one half of each age group, a 500 microg 17beta-estradiol 21-day release pellet and in another half, a vehicle pellet was implanted 21 days before the experiments. One hour after middle cerebral artery occlusion, the transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to examine the degree of blood-brain barrier disruption. In all four groups, the Ki in the ischemic cortex was higher than in the corresponding contralateral cortex. There was no significant difference in the Ki in both cortices among the groups. The volume of dextran distribution of the ischemic cortex was only greater than in the corresponding contralateral cortex in the older 17beta-estradiol-treated group, and the volume of that group was greater than the younger 17beta-estradiol-treated group (4.00 +/- 1.29 VS. 2.13 +/- 0.88 ml/100 g). After analyzing the difference in Ki between the ischemic cortex and the contralateral cortex in each animal, the difference was significantly greater in the older 17beta-estradiol-treated rats than the older vehicle-treated rats (3.40 +/- 2.10 VS. 1.26 +/- 1.44 microl/g/min). In the younger rats, however, 17beta-estradiol did not significantly affect the difference. Our data showed that 17beta-estradiol treatment failed to attenuate the BBB disruption in the cerebral ischemic cortex in the older or younger Fischer 344 rats. However, our data also suggest the possibility that 17beta-estradiol could aggravate the BBB disruption in older rats.

Aging↗
PubMed1990

Blood-brain barrier integrity during cardiopulmonary resuscitation in dogs.

Blood-brain barrier integrity during cardiopulmonary resuscitation may be important because of the potential effects of adrenergic agonists administered during arrest on cerebral metabolism and the cerebral vasculature. As an index of blood-brain barrier permeability to small molecules, we measured the brain uptake of [14C]alpha-aminoisobutyric acid during a 10-minute period in 25 anesthetized dogs. To correct for the amount of carbon-14 label in the plasma space, we administered [3H] inulin 2 minutes before death. The mean transfer coefficient in 14 brain regions of five control dogs ranged from 0.002 to 0.007 ml/g/min. After 8 (n = 15) or 15 (n = 5) minutes of cardiac arrest, external chest compression was instituted to maintain aortic blood pressure above 60 mm Hg. The transfer coefficient was not elevated during chest compression (n = 10), immediately following defibrillation (n = 5), or 4 hours after resuscitation (n = 5); in some brain regions the transfer coefficient decreased. However, the decrease in the transfer coefficient was proportional to the decrease in the cerebral plasma volume as measured by the ratio of the [3H]inulin concentration in the tissue to that in the plasma. Thus, it is unlikely that a decrease in capillary surface area masked an increase in blood-brain barrier permeability. Therefore, we found no evidence of blood-brain barrier disruption during or after cardiopulmonary resuscitation in dogs. Despite the large phasic increases in sagittal sinus pressure associated with external chest compression, concurrent increases in cerebrospinal fluid pressure apparently protect the microcirculation from increased transmural pressure.

Aminoisobutyric Acids↗
PubMed1980

Inhibition of proliferation of cloudman S91 melanoma cells by insulin and characterization of some insulin-resistant variants.

Insulin is a potent, reversible inhibitor of proliferation in Cloudman S91 mouse melanoma cells. The inhibition seems to be unique to the Cloudman line since five other cell lines, including the mouse B16 and hamster Greene melanomas, were unaffected by insulin under the same culture conditions. Variants of Cloudman S91 cells were isolated which differed from wild-type (WT) cells in their response to insulin. Most of these variants were resistant to insulin (INSres) and had the same generation time independent of the presence of the hormone. One line (INSdep) was found to require insulin for growth. This line was about 15 times more sensitive to the proliferative effects of insulin than the WT. Revertants of the INSdep line were selected for their ability to proliferate in the absence of insulin. Five out of five such revertants were insulin resistant, suggesting that the INSdep line arose as a results of at least two separate mutations. Both WT and INSdep cells showed enhanced uptake of 14C-alpha-aminoisobutyric acid (AIB) when exposed to insulin. Dose-response curves of the stimulation of AIB uptake in WT and INSdep cells were superimposable. Stimulation of AIB uptake and stimulation of proliferation by insulin were not under coordinate control since AIB uptake was increased equally in the wild-type cells when proliferation was inhibited and in INSdep cells when proliferation was enhanced. Binding of 125I-insulin was used to demonstrate the presence of specific, high affinity insulin receptors on the cells. INSres variants generally had fewer receptors than WT, but in no case did the magnitude of this effect appear to be sufficient to explain the insensitivity to insulin. The INSdep variant showed a greater than two-fold increase in the number of insulin receptors per cell, compared to WT. Revertants of the INSdep line had the same number of receptors as WT. The specificity for both binding and for the effects on proliferation were the same in WT and INSdep cells. Since the effects of insulin on proliferation were opposite in the two lines, we propose at least two distinct sites of insulin action on the cells. Further isolation and analyses of Cloudman lines with unusual responses to insulin should be useful for understanding the molecular basis of action of this hormone.

Aminoisobutyric Acids↗
PubMed1990

Decrease in perfusion of cerebral capillaries during incomplete ischemia and reperfusion.

The effect of unilateral, incomplete cerebral ischemia on CBF, unidirectional flux of alpha-aminoisobutyric acid (AIB) and sodium, and number of perfused capillaries during ischemia and reperfusion was measured in the cortex of gerbils with symptomatic ischemia. Three hours of unilateral carotid occlusion reduced the CBF to the ipsilateral cortex by 81%, with a smaller 30% decrease in the contralateral cortex. Following 11 min of reperfusion, CBF in the ipsilateral cortex returned to the preischemic value, while the contralateral blood flow decreased to 50% of control. The transfer constants for AIB and sodium in the ipsilateral cortex were reduced by 67 and 53%, respectively, after 3 h of ischemia, with no change in the contralateral cortex. The transfer constant for AIB remained decreased by 48% during the first 20 min of reperfusion, while that for sodium returned to its control value. The number of perfused capillaries was reduced 54% by 3 h of ischemia and remained decreased by 20% after 11 min of reperfusion. These data indicate that 3 h of unilateral carotid occlusion reduces the number of perfused capillaries in the ipsilateral cortex during the ischemic period. Further, the early reperfusion phase is characterized by a mismatch between capillary perfusion and CBF. Finally, early in the postischemic phase, sodium transport undergoes a selective stimulation, probably as a result of stimulation of ion transport.

Aminoisobutyric Acids↗
PubMed1996

Increased brain tumor microvessel permeability after intracarotid bradykinin infusion is mediated by nitric oxide.

Nitric oxide (NO), a free radical gas implicated in a wide variety of biological reactions, is a novel signaling molecule that may regulate vasodilation, cerebral blood flow, and vascular permeability. This study was performed to determine whether NO mediates the selective increase in brain tumor microvessel permeability after intracarotid infusion of bradykinin in the RG2 rat glioma model. Intracarotid infusion of bradykinin selectively increased the transport of radiolabeled alpha-aminoisobutyric acid and dextran into brain tumors. Transport into normal brain was not increased. The administration of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester, significantly inhibited the increased transport into tumors for both tracers. The inhibitory effect of NG-nitro-L-arginine methyl ester on the response to bradykinin was reversed by L-arginine. The expression of two NO synthase (NOS) isoforms in cultured RG2 glioma cell lines and intracerebral RG2 glioma was examined by immunohistochemistry and Western blot analysis. High levels of expression of neuronal NOS were detected in cultured and intracerebral RG2 cells but not in normal brain tissue, except in rare neuronal cells. The endothelial form of NOS was also expressed in cultured RG2 cells, but not as strongly as neuronal NOS expression. In intracerebral RG2 gliomas, expression of endothelial NOS in the tumor was detected at higher levels than in normal brain. These findings indicate that RG2 rat gliomas express high levels of NOS, which regulate the production of NO, compared with normal brain. We suggest that the selective permeability increase in brain tumor microvessels after bradykinin infusion is mediated by NO. Furthermore, the absence of high levels of NOS in normal brain may account for the attenuated permeability response to bradykinin in normal brain microvessels.

Aminoisobutyric Acids↗
PubMed2005

Effects of VEGF and nitric oxide synthase inhibition on blood-brain barrier disruption in the ischemic and non-ischemic cerebral cortex.

OBJECTIVES: This study was performed to compare the effects of exogenous vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) inhibition on blood-brain barrier (BBB) disruption in the ischemic cortex (IC) and non-ischemic contralateral cortex (CC) during the early stage of focal cerebral ischemia in rats. METHODS: A middle cerebral artery (MCA) was occluded after a craniotomy in each rat under isoflurane anesthesia. Two more craniotomies were performed over the contralateral non-ischemic hemisphere to expose cerebral cortex. For the control rats, the normal saline patches were applied to all three craniotomy holes (control group). To inhibit NOS, NG-nitro-L-arginine-methyl ester (L-NAME) (10 mg/kg) was administered i.v. 20 minutes after MCA occlusion (L-NAME group). In another group, VEGF (10(-10) M) was topically applied 30 minutes after MCA occlusion on the IC as well as one of the holes of the contralateral cortex (VEGF group). To investigate the effects of the combination of VEGF and L-NAME, both L-NAME and VEGF were administered as described above (L-NAME+ VEGF group). The transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid and the volume of 3H-dextran (70 000 Da) distribution were determined to measure the degree of BBB disruption at 1 hour after MCA occlusion. RESULTS: In the control group, Ki of the IC was significantly higher than the contralateral cortex (CC) (p<0.005). VEGF application increased the Ki of the IC further when compared with the control group (+51%, p<0.05%). L-NAME administration produced no significant decrease in the Ki of the IC when compared with the control group. With L-NAME+ VEGF administration, the Ki of the IC became significantly lower than that of the VEGF alone (-38%, p<0.005). Thus, L-NAME produced a much greater decrease in the Ki of the IC in the VEGF treated than the control animals (p<0.05). In the non-IC, VEGF, L-NAME, or their combination did not affect BBB disruption. The volume of dextran distribution followed a similar pattern to Ki. DISCUSSION: Our data suggest that even in the early stage of focal cerebral ischemia, the degree of BBB disruption in response to the exogenous VEGF is much greater in the ischemic than in the non-IC and that the mechanism of the increase of BBB disruption by VEGF in the IC involves the NOS pathway.

Administration, Topical↗
PubMed1983

Regional blood-to-tissue transport in ethylnitrosourea-induced brain tumors.

Regional blood-to-tissue transport, expressed as a unidirectional transfer rate constant (K), was measured in experimental brain tumors using alpha-aminoisobutyric acid (AIB) labeled with carbon 14 and quantitative autoradiography. A total of sixteen oligodendrogliomas, four mixed gliomas, three astrocytomas, two diffuse gliomatosis, one anaplastic astrocytoma, one ependymoma and four malignant schwannomas were studied in 9 rats. The mean Ks for all glioma classifications were similar, averaging 2.6 +/- 0.4 (standard error of the mean) ml . kg-1 . min-1, and were only slightly higher than those for nontumorous parietal cortex (2.1 ml . kg-1 . min-1), corpus callosum (0.9 ml . kg-1 . min-1), and a comparable region of brain tissue in the contralateral hemisphere (1.3 ml . kg-1 . min-1). Values of K varied minimally in the intracerebral gliomas and were marginally correlated with tumor cell morphology in only two tumors. In some (but not all) of the larger gliomas, increased vascularity, with or without endothelial proliferation, was associated with a 3- to 15-fold increase in K. Regional K values in malignant schwannomas were highly variable (4 to 207 ml . kg-1 . min-1) and generally were not correlated with specific histological features of the tumor, except in some regions with increased vascularity. Estimates of the average fractional extraction of AIB by the intracranial gliomas and malignant schwannomas were 0.01 and 0.2, respectively; average fractional extractions for nontumorous brain were approximately 0.003.

Aminoisobutyric Acids↗
PubMed1992

Metabolic actions of insulin-like growth factor II in cultured adult rat hepatocytes are not mediated through the insulin-like growth factor II receptor.

Short- and long-term regulation of hepatic carbohydrate metabolism by insulin-like growth factor II was studied in primary cultures of adult rat hepatocytes and compared to the metabolic potency of insulin. Insulin-like growth factor II stimulated glycogen synthesis from [14C]glucose, uptake of [3H]aminoisobutyric acid and [14C]lactate formation from [14C]glucose up to three-fold. Basal glycogenolysis was inhibited to about 10%, and glucagon-activated glycogenolysis was blocked completely. The enzymatic activity of glucokinase and pyruvate kinase was induced two-fold, the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was antagonized. Compared to insulin, half-maximal responses required up to 50 times higher insulin-like growth factor II concentrations ranging from 10-20 nmol/l. A similar difference was observed for binding affinity of insulin-like growth factor II to the insulin receptor. The interaction with the insulin-like growth factor II/mannose 6-phosphate (IGF-II/Man-6-P) receptor was examined by studying 125I-insulin-like growth factor II binding and uptake of lysosomal enzymes. The affinity of insulin-like growth factor II to the IGF-II/Man-6-P receptor was considerably higher than for the insulin receptor. Antibodies against the IGF-II/Man-6-P receptor did not affect metabolic responses to insulin-like growth factor II, while binding to its receptor and the receptor-mediated endocytosis of arylsulphatase A were strongly inhibited. Thus, in adult rat liver insulin-like growth factor II appeared to exert metabolic actions not via interaction with its own receptor but through low affinity binding to hepatic insulin receptors.

Aminoisobutyric Acids↗
PubMed1981

Interaction of the alkylating antitumor agent 2,3,5-tris(ethyleneimino)benzoquinone with the plasma membrane of Ehrlich ascites tumor cells.

The effect of the alkylating agent 2,3,5-tris(ethyleneimino)benzoquinone (Trenimon) on the uptake of 2-aminoisobutyric acid, 1-aminocyclopentane-1-carboxylic acid (cycloleucine), 3-O-methyl-D-glucose, and 86Rb was studied. All transport studies were performed at nonsaturating conditions where the specific transport system was rate limiting for the uptake. The activities of all systems are reduced after treatment with the alkylating agent. The impairment of the plasma membrane is expressed 30 sec after exposure to the drug, as measured by the 86Rb uptake, and lasts for at least 12 hr according to the reduced 3-O-methyl-D-glucose uptake. Inhibition of protein synthesis by cycloheximide for 2 hr does not affect the uptake of 86Rb. The short interval which is necessary before an inhibition of 86Rb uptake can be registered and the resistance of the 86Rb transport system to an inhibition of protein synthesis are considered as indicative for a direct alkylation of a membrane constituent. Treatment with the alkylating agent increases the cyclic adenosine 3':5'-monophosphate of the cells. This effect is not due to an effect on adenylate cyclase or the membrane-bound cyclic adenosine 3':5'-monophosphate phosphodiesterase. In view of the known correlations between plasma membrane functions and the regulation of cell division, it is proposed that the growth inhibition by Trenimon of Ehrlich ascites tumor cells may be caused by its interaction with the plasma membrane.

Alkylating Agents↗
PubMed1984

Modification of membrane function, protein synthesis, and heat killing effect in cultured Chinese hamster cells by glycerol and D2O1.

Glycerol and D2O can provide a protective effect to Chinese hamster V79 cells receiving heat treatment. The mechanism for this effect is assumed to be the ability of these agents to stabilize proteins which implies that one of the possible heat-killing mechanisms is the inactivation of a heat-sensitive molecule (protein?). In addition, we observed that heat can alter the membrane permeability rapidly, and glycerol can reduce the initial heat-induced membrane permeability changes (determined by aminoisobutyric acid uptake). Although not as effective as cycloheximide, glycerol and D2O can retard protein synthesis. These two processes can add to the protective effect of stabilizing cellular protein against heat killing. Since glycerol and D2O added during the heat-conditioning period can interfere with the appearance of thermotolerance, the mechanisms for the protective effect of glycerol and D2O are likely to be different from heat-induced thermotolerance. We propose that the heat-sensitive molecule protected by D2O or glycerol may also play a role in the triggering process of the thermotolerance phenomenon. If the conditioning heat treatment is sufficient to affect this molecule but not other cellular targets, thus allowing the cell to survive, thermotolerance may be observed in surviving cells in response to second or continued heat treatment. Depending on the severity of the heat effect, this heat-sensitive molecule may continue to exist after a conditioning heat treatment in medium containing glycerol or D2O, and therefore, the response of the cells to the challenging heat is altered little. This proposed mechanism is capable of explaining several thermotolerance experimental protocols. Since glycerol can also reduce the toxicity of vincristine, microtubule-related protein is probably one of the proteins stabilized by this agent. D2O also probably affects microtubule protein, because the cells heated in medium containing D2O show little topological changes.

Aminoisobutyric Acids↗
PubMed1983

Assessment of membrane damage in continuous cultures of mammalian cells.

The present studies were aimed at evaluating procedures for assessing the effect of chemicals on the integrity of the plasma membrane in continuous cell cultures. The degree of membrane damage was monitored by determining the 'leakage' of alpha-[3H]aminoisobutyric acid ([3H]AIB) and [14C]deoxy-2-fluoro-D-glucose ([14C]FdG) from the prelabelled cells. These parameters were compared to the loss of lactate dehydrogenase (LDH) from the cells and the decrease in the intracellular level of K+. Triton X-100, sodium dodecylsulfate (SDS), phospholipase C and nystatin which are known to affect membranes by different mechanisms served as test agents. In parallel, we monitored the effects of the chemicals on the viability of the cells. The following results were obtained: (1) The two radioactive markers [3H]AIB and [14C]FdG were found to be suitable to probe for damages of the plasma membrane in a variety of continuous cell lines which differ widely in their phenotype, rate of growth and degree of differentiation. (2) The leakage of the two markers could conveniently be monitored by double labelling techniques. (3) The loss from the cells of the 3 markers of smaller molecular size, K+, [3H]AIB, [14C]FdG, differed considerably depending on the test agent used. (4) Intracellular K+ level and [3H]AIB leakage generally appeared to follow a similar pattern, whereas [14C]FdG leakage may have shown a distinctly different response. (5) The leakage of LDH was an insensitive indicator for membrane damage. (6) No clear relationship was detectable between a particular leakage pattern of the markers and the loss of cellular viability.

Aminoisobutyric Acids↗
PubMed1986

Additive effects of prior exercise and insulin on glucose and AIB uptake by rat muscle.

After exercise of moderate intensity the ability of insulin to stimulate the uptake of glucose and alpha-aminoisobutyric acid (AIB) in perfused rat muscle is enhanced in a parallel fashion. The present study was designed to examine the effect of intense exercise on the subsequent uptake of these substrates. For this purpose, rats fed ad libitum were run on a treadmill for 50 min at high intensity and glucose and AIB uptake by muscle were then assessed in the isolated perfused hindquarter preparation. In confirmation of previous studies, 30 min after such exercise the absolute rate of glucose uptake in the presence of 20,000 microU/ml of insulin was greater due to additive effects of insulin and prior exercise. A novel finding was that 150 min postexercise the rate of glucose uptake was still increased in the presence of a supramaximal concentration of insulin, but entirely due to an increase in insulin responsiveness. The uptake of AIB and its response to insulin in general paralleled that of glucose. The results indicate that both glucose and AIB uptake by skeletal muscle in the presence of a supramaximal concentration of insulin are increased after intense exercise. They suggest that this is initially due to an additive effect of insulin and exercise and later due to an increase in insulin responsiveness. The findings are compatible with the notion that after exercise insulin is able to recruit or activate glucose (and possibly AIB) transporters in muscle, that it does not affect in the resting state.

Aminoisobutyric Acids↗
PubMed1984

The effect of graded hypertonic intracarotid infusions on drug delivery to experimental RG-2 gliomas.

The RG-2 brain tumor model was used to determine whether unidirectional transport of alpha-aminoisobutyric acid (AIB) into brain and tumor tissue was increased after an intracarotid infusion of one of six different hypertonic solutions of L-arabinose. Intracarotid infusion of hypertonic solutions that have been reported as subthreshold for normal brain were used to determine whether they would selectively increase blood-to-tissue transport in brain tumors. No increase in the transport rate constant (K) across RG-2 tumor capillaries resulted from the infusion of 0.8- to 1.4-osm solutions. Infusions of 1.6- and 1.8-osm solutions were also performed, and blood-to-tissue transport was measured under conditions that produce maximum blood-brain-barrier disruption; however, no increase in the transport rate across tumor capillaries was measured. In brain regions surrounding the tumor, there was a trend toward increasing K values associated with increasing osmolality of the infusate, but the magnitude of this increase was small. There was a progressive increase in the K of tumor-free brain regions. This increase correlated with increasing osmolality of the infusate (0.8 to 1.8 osm). We conclude that intracarotid infusion of hypertonic solutions of L-arabinose does not increase the rate of delivery of water-soluble drugs to experimental RG-2 brain tumors. In this situation, the use of hypertonic infusions may be counterproductive and result in a greater delivery to and exposure of surrounding and normal brain tissue to levels of chemotherapeutic drugs which are potentially neurotoxic.

Aminoisobutyric Acids↗