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PubMed1994

The influence of picolines on glutathione transferase activity and subunit composition in human liver derived Hep G2 cells.

Hep G2 cells, an established cell line derived from a human hepatoma, have retained a number of hepatocytic phase I and II reactions. The influence of picolines (2-, 3- and 4-methylpyridine), related compounds and some classical enzyme inducers on specific glutathione transferase (GST) activity and its subunit composition in Hep G2 cells was investigated. Increased GST activity was observed for rifamycin, phenobarbital, pyrazine and the picolines, of which the 4-isomer was the strongest inducer. The GST subunits were analysed by HPLC. GSTP1, GSTM1a, GSTA1 and GSTA2 were present in control Hep G2 cells. GSTM1a disappeared or was strongly reduced under the influence of the test chemicals. All GST increases were due to augmented GSTA1 expression. Thus, picolines stimulate GST activity in Hep G2 cells by influencing the class alpha GSTA1.

Enzyme Induction↗

PubMed1993

Quinolinate potentiates the neurotoxicity of excitatory amino acids in hypoxic neuronal tissue in vitro.

Excitatory amino acids (EAAs) in the central nervous system are involved in both neurotransmission and neurotoxicity. Quinolinate (QUIN) is a neurotoxic endogenous tryptophan metabolite that has been linked to Huntington's disease, Alzheimer's disease, and many inflammatory diseases. We used the rat hippocampal slice preparation and its electrophysiology to study the interaction of QUIN with glutamate receptor agonists such as N-methyl-D-aspartate (NMDA), glutamate, aspartate, kainate, and AMPA ((R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate). The majority of slices could tolerate an exposure to 10-min hypoxia (86% recovered their neuronal function), but doses of glutamate receptor agonists which were harmless under normoxic conditions, significantly reduced this recovery rate under hypoxic conditions. QUIN, at doses that even under hypoxic conditions were innocuous (20-50 microM), potentiated the neurotoxic effects of all the glutamate receptor agonists tested in hypoxic hippocampal slices. The NMDA antagonist D,L-2-amino-5-phosphonovalerate blocked this potentiation while 7-chlorokynurenate, at a dose sufficient to block the effect of NMDA alone, was ineffective in blocking the potentiation of NMDA toxicity by QUIN. Non-toxic analogues of QUIN (6-methyl-QUIN and 2,3-pyrazine dicarboxylate) were also able to potentiate NMDA toxicity in hypoxic slices. The results of these experiments provided indirect evidence that QUIN is an endogenous potentiator of the NMDA and the kainate receptor subtypes; therefore, we postulate that QUIN has a specific modulatory binding site on all glutamate receptor subtype complexes. Regardless of its site of interaction, the importance of QUIN as a potentiator of the agonistic activation of these receptors cannot be overemphasized.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1988

Theoretical analysis of a site-specific chemiluminescence reaction and its application to quantitation of lipid hydroperoxides.

A system was designed for chemiluminescent measurement of lipid hydroperoxides by their site-specific reaction in sodium dodecylsulfate micelles. Ferrous ion-induced decomposition of lipid hydroperoxides in the sodium dodecylsulfate micelles resulted in strong chemiluminescence of the Cypridina luciferin analog, 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2-alpha]pyrazin-3-one (CLA). After addition of ferrous sulfate to the micelles containing lipid hydroperoxide and luciferin, the chemiluminescence intensity reached a maximum rapidly and then decreased. The sequence of this reaction was elucidated by theoretical analysis, which demonstrated that the maximum chemiluminescence intensity is proportional to the initial concentration of hydroperoxide. Good linear relationships were observed between the maximum counts of chemiluminescence and the amounts of hydroperoxides of linoleic acid, phosphatidylcholine, choresterol (5 alpha), cumene and tert-butyl and hydrogen peroxide. This chemiluminescence method was simple and sensitive enough to detect picomole levels of linoleic acid and phosphatidylcholine hydroperoxides.

Binding Sites↗

PubMed1978

Effect of 1-(m-trifluoromethylphenyl)-piperazine on 3H-serotonin binding to membranes from rat brain in vitro and on serotonin turnover in rat brain in vivo.

1-(m-Trifluoromethylphenyl)-piperazine inhibited the specific binding of tritiated serotonin to membranes from rat brain in vitro at lower concentrations than did quipazine or MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine). In rats 1-(m-trifluoromethylphenyl)-piperazine decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) without altering the concentration of serotonin in whole brain. The decrease in 5-HIAA was apparently due to a decrease in serotonin turnover, since 1-(m-trifluoromethylphenyl)-piperazine caused a slower decline in serotonin concentration after synthesis inhibition by alpha-propyldopacetamide and a slower accumulation of 5-HIAA after probenecid injection to block its efflux from brain. The decrease in serotonin turnover is an expected result of stimulating serotonin receptors in brain and has earlier been reported to occur with quipazine. Thus all of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.

Animals↗

PubMed1995

Relaxant influence of phosphodiesterase inhibitors in the cat gastric fundus.

The breakdown of the relaxation-inducing second messengers cAMP and cGMP is mediated by phosphodiesterases. Inhibitors of functionally present phosphodiesterases can be expected to induce relaxation by increasing the basic amount of cAMP and/or cGMP. In the cat gastric fundus, vinpocetine, which has some selectivity for phosphodiesterase type I, only induced contractions, but the inhibitors of type III [5-(4-acetimidophenyl)pyrazin-(1H)-one; SKF 94120], type IV (rolipram) and type V (zaprinast) phosphodiesterase all caused concentration-dependent relaxation, as did the non-specific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The most potent relaxant agent was rolipram (EC50 9 +/- 5 x 10(-7) M and 3 +/- 1 x 10(-7) M in longitudinal and circular smooth muscle strips, respectively). These results suggest that type III, IV and V phosphodiesterases are functionally present in the cat gastric fundus and are involved in the regulation of tone. The possible influence of the phosphodiesterase inhibitors on non-adrenergic non-cholinergic (NANC) relaxation induced by nitric oxide (NO), vasoactive intestinal polypeptide (VIP) and train and sustained electrical field stimulation was then tested. Rolipram (3 x 10(-8) M), SKF 94120 (10(-5) M) and IBMX (10(-6) M) did not potentiate any of the relaxant stimuli studied. Zaprinast (10(-5) M), the cGMP specific type V phosphodiesterase inhibitor, caused a significant increase of the relaxation induced by exogenous NO and by train electrical field stimulation. These stimuli are thought to induce relaxation via an increase of intracellular cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1995

Novel 5-HT2-like receptor mediates neurogenic relaxation of the guinea-pig proximal colon.

The aim of the current investigation was to characterize the 5-HT receptors that mediate neurogenic relaxation of the guinea-pig proximal colon. After blockade of 5-HT2A, 5-HT3 and 5-HT4 receptor-mediated contractions, 5-hydroxytryptamine (5-HT) induced relaxations yielding a biphasic concentration-response curve. Other tryptamines were also agonists with the following rank order of potency: 5-HT > 5-carboxamidotryptamine = 5-methoxytryptamine > or = alpha-methyl-5-HT (partial agonist) > tryptamine (partial agonist). 5-Hydroxytryptophan, 2-methyl-5-HT and N-methyltryptamine were virtually inactive as agonists. The curve to 5-HT was not affected by pargyline, citalopram, phentolamine, or by the 5-HT4 receptor antagonists 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205-557) and (1-butyl-4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan+ ++-5-carboxylate (SB 204070). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), 5-methoxy-3[1,2,3,6-tetrahydroxypyridin-4-yl]-1H-indole (RU 24969), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 1-(3-chlorophenyl)piperazine (mCPP), 1-(m-trifluoromethylphenyl)-piperazine (TFMPP), flesinoxan, sumatriptan and 6-chloro-2-(piperazinyl)-pyrazine (MK212) were inactive as 5-HT receptor agonists. The first phase of the curve to 5-HT was inhibited by: metergoline (pA2 = 8.8 +/- 0.3, against 5-methoxytryptamine 9.3 +/- 0.3), methysergide (non-surmountable), methiothepin (non-surmountable), spiroxatrine (non-surmountable), MK212 (non-surmountable), mesulergine (7.8 +/- 0.3), mCPP (7.1 +/- 0.1), mianserin (7.0 +/- 0.4), ritanserin (8.9 +/- 0.2), rauwolscine (7.0 +/- 0.2), yohimbine (6.2 +/- 0.2), 1-(1-naphthyl)-piperazine (7.7 +/- 0.2) and RU 24969 (6.4 +/- 0.1), but not by 1-(2-methoxyphenyl)4-[4-(2-phthalimidobtyl]-piperazine (NAN-190), spiperone, sumatriptan, 8-OH-DPAT and flesinoxan. It is suggested that the 5-HT receptor under study could be considered an unknown 5-HT2-like receptor.

Animals↗

PubMed1993

Solvent oxygen is not incorporated into N10-formyltetrahydrofolate in the reaction catalyzed by N10-formyltetrahydrofolate synthetase.

The mechanism of the reaction catalyzed by N10-formyltetrahydrofolate synthetase involves the formation of formyl phosphate as an intermediate which then formylates tetrahydrofolate at the N-10 position. Previous studies demonstrated that the non-enzymic formylation of tetrahydrofolate by formyl phosphate occurs exclusively at the more nucleophilic 5-nitrogen in the reduced pyrazine ring. The experiments described in this report were designed to determine whether N5-formyltetrahydrofolate might be the first product to be formed on the enzyme, followed by formyl transfer to the 10-nitrogen via the cyclic intermediate N5,10-methenyltetrahydrofolate. If this were the case, oxygen from solvent H2O would be incorporated into the formyl group of the N10-derivative. By conducting the reaction in a 1:1 mixture of [16O]H2O and [18O]H2O and using 13C NMR spectroscopy we show that no 18O is incorporated into the product and conclude that the reaction proceeds via a direct formylation of the N-10 position by formyl phosphate.

Catalysis↗

PubMed1991

Low superoxide scavenging activity associated with enhanced superoxide generation by monocytes from male hypertriglyceridemia with and without diabetes.

To investigate the mechanism of increased superoxide (O2-) generation by monocytes from patients with hypertriglyceridemia, superoxide scavenging activity (SSA) and O2- generation by monocytes were determined concomitantly employing an electron spin resonance/spin trapping method and 2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo [1,2-a]-pyrazin-3-one (MCLA)-dependent chemiluminescence, respectively. Peripheral monocytes were separated by the adherent methods from the following four male groups: normal control, diabetes alone (DM), diabetes with hypertriglyceridemia (DM + HTG) and hypertriglyceridemia alone (HTG). Monocytes were stimulated by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) or opsonized zymosan (OZ). O2- generation by monocytes upon stimulation was enhanced in HTG and HTG + DM but not in DM as compared to that in normal controls. The mean value of SSA in monocytes was similar among the 4 groups. When the relationship was analyzed using various parameters, a significant positive relationship was found between O2- generation and the plasma triglyceride level; a significant negative correlation was found between SSA and both the O2- generation and the plasma triglyceride level. In the in vitro system, the SSA in monocytes decreased significantly after the the stimulation by either of PMA or OZ. The results indicate that the decrease of SSA in monocytes may originate from the enhanced in vivo O2- generation and is responsible for the enhanced O2- release against the stimuli in hypertriglyceridemia. These abnormal functions of monocytes may in part accelerate the development of atherosclerosis.

Adult↗

PubMed1990

Stereochemical mechanism of action for thymidylate synthase based on the X-ray structure of the covalent inhibitory ternary complex with 5-fluoro-2'-deoxyuridylate and 5,10-methylenetetrahydrofolate.

The structure of the Escherichia coli thymidylate synthase (TS) covalent inhibitory ternary complex consisting of enzyme, 5-fluoro-2'-deoxyuridylate (FdUMP) and 5,10-methylene tetrahydrofolate (CH2-H4PteGlu) has been determined at 2.5 A resolution using difference Fourier methods. This complex is believed to be a stable structural analog of a true catalytic intermediate. Knowledge of its three-dimensional structure and that for the apo enzyme, also reported here, suggests for the first time how TS may activate dUMP and CH2-H4PteGlu leading to formation of the intermediate and offers additional support for the hypothesis that the substrate and cofactor are linked by a methylene bridge between C-5 of the substrate nucleotide and N-5 of the cofactor. By correlating these structural results with the known stereospecificity of the TS-catalyzed reaction it can be inferred that the catalytic intermediate, once formed, must undergo a conformational isomerization before eliminating across the bond linking C-5 of dUMP to C-11 of the cofactor. The elimination itself may be catalyzed by proton transfer to the cofactor's 5 nitrogen from invariant Asp169 buried deep in the TS active site. The juxtaposition of Asp169 and bound tetrahydrofolate in TS is remarkably reminiscent of binding geometry found in dihydrofolate reductase where a similarly conserved carboxyl group serves as a general acid for protonating the corresponding pyrazine ring nitrogen of dihydrofolate.

Binding Sites↗

PubMed1987

Inhibition of the Na+/Ca2+ exchange in cardiac sarcolemmal vesicles by amiloride.

The pyrazine diuretic amiloride inhibits the Na+/Ca2+ exchange activity of cardiac sarcolemmal vesicles in a concentration-dependent way. A good relationship between the uptake of amiloride by the vesicles and the inhibition of the exchanger has been found. Kinetic analyses indicate that the inhibition of Na+/Ca2+ exchange activity by amiloride is non-competitively removed by Ca2+ and competitively overcome by an outwardly directed Na+ gradient.

Amiloride↗

PubMed1993

The design of novel muscarinic partial agonists that have functional selectivity in pharmacological preparations in vitro and reduced side-effect profile in vivo.

Antagonist/agonist binding ratios (NMS/Oxo-M ratio) were used as an index of the efficacy of novel compounds acting at muscarinic receptors. These binding ratios have been used with a range of functional pharmacological assays to investigate the effects of varying the efficacy of muscarinic agonists. This strategy has been used as a means of obtaining functional receptor selectivity by exploiting differences in effective receptor reserves. The oxadiazole and pyrazine muscarinic agonists L-670,548 (NMS/Oxo-M ratio 1100) and L-680,648 (NMS/Oxo-M ratio 690) are amongst some of the most potent and efficacious agonists known. Decreasing the efficacy of compounds from these series, resulted in compounds with functional selectivity. The chloropyrazine L-689,660 (NMS/Oxo-M ratio 28) was an agonist on the rat superior cervical ganglion (M1), a partial agonist on the guinea-pig ileum (M3), but was an antagonist in the guinea-pig atria (M2). Synthesis of compounds with even lower predicted efficacy, such as the cyclopropyloxadiazole L-687,306 (NMS/Oxo-M ratio 15), maintained agonist activity in the ganglion, but showed antagonist activity in the M3 ileal, as well as the M2 atrial preparations. When tested in vivo these compounds did not produce many of the side effects associated with more efficacious agonists, particularly those associated with the cardiovascular system. However, they were active in reversing scopolamine-induced deficits in a variety of behavioural paradigms. This approach shows how functional selectivity for muscarinic receptor subtypes can be achieved in vitro, that in vivo reduces the dose-limiting side effects normally associated with muscarinic agonists.

Animals↗

PubMed1996

Pharmacologic evaluation of the discriminative stimulus of metachlorophenylpiperazine.

A pharmacologic analysis of the discriminative stimulus of metachlorophenylpiperazine (mCPP) is reported. mCPP and m-trifluoromethylphenylpiperazine generalised, whereas 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole, 6-chloro-2-(1-piperazinyl)-pyrazine, and mesulergine partially generalised to the mCPP discriminative cue. However, although mianserin, methiothepin, ritanserin, mesulergine and N-(1-methyl-5'-indolyl)-N'-(3-pyridyl)urea hydrochloride (SB 200646) all antagonised the effect of 5-hydroxytryptamine (5-HT) on IP3 formation in the rat choroid plexus, they failed to antagonise the mCPP response in the drug discrimination studies. The 5-HT3 receptor antagonist MDL 72222 neither generalised nor antagonised the mCPP cue. These data suggest that neither the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5, 5-HT6, nor 5-HT7 receptors are involved. The response does appear to be mediated by a postsynaptic 5-HT receptor, however, because fenfluramine generalised to the cue. Haloperidol generalises, and amphetamine partially antagonises the mCPP discriminative cue and low doses of apomorphine partially generalises to the mCPP cue, which suggests that a decrease in dopamine neurotransmission may also be involved.

Amphetamine↗

PubMed1980

Mutagenicity of 1,2 ring-fused acenaphthenes against S. typhimurium TA1537 and TA1538: structure-activity relationship.

A number of 1,2-ring fused acenaphthenes, together with the parent compounds acenaphthene and acenaphthylene, were evaluated for mutagenicity, using the Pour-Plate Technique with S. tpyhimurium strains TA1538 and TA1537. Although acenaphthene and acenaphthylene were non-mutagenic, all the 1,2-ring fused acenaphthene were found to be indirect frameshift mutagens in strain TA1537. The chemical nature of the 1,2-fused ring did not appear to be important for mutagenic activity against TA1537, however, its nature did affect the mutagenesis of strain TA1538. Only acenaphthenes fused with a pyrimidine or pyrazine ring were capable of mutating the hiD 3052 locus of TA1538. Substitution at the 8-position of the ring system with an amino group rendered the molecule inactive against TA1538, whilst substitution at the 10-position only reduced, but did not eliminate the mutagenic effect against TA1538. Methyl substitution at various sites on the molecule modified the mutagenic activity against TA1537, and indicated the formation of an electrophilic species (epoxide) at the 2,3-position of the acenaphthene nucleus. The incorporation of a competitive substrate for ring hydroxylation (naphthalene) reduced the mutagenic effect of acenaphthopyrimidine against TA1537 and confirmed this assumption. However, naphthalene did not reduce the mutagenic effect of the compound against TA1538, indicating the possible formation of a second metabolite by an alternative enzymic pathway. The fusion of a pyridine ring to the system to give a pentacyclic compound resulted in a molecule sufficiently planar to allow for a weak direct mutagenic effect against TA1537.

Acenaphthenes↗

PubMed1984

The organic aerosols of Titan.

A dark reddish organic solid, called tholin, is synthesized from simulated Titanian atmospheres by irradiation with high energy electrons in a plasma discharge. The visible reflection spectrum of this tholin is found to be similar to that of high altitude aerosols responsible for the albedo and reddish color of Titan. The real (n) and imaginary (k) parts of the complex refractive index of thin films of Titan tholin prepared by continuous D.C. discharge through a 0.9 N2/0.1 CH4 gas mixture at 0.2 mb is determined from x-ray to microwave frequencies. Values of n (approximately equal to 1.65) and k (approximately equal to 0.004 to 0.08) in the visible are consistent with deductions made by ground-based and spaceborne observations of Titan. Many infrared absorption features are present in k (lambda), including the 4.6 micrometers nitrile band. Molecular analysis of the volatile component of this tholin was performed by sequential and non-sequential pyrolytic gas chromatography/mass spectrometry. More than one hundred organic compounds are released; tentative identifications include saturated and unsaturated aliphatic hydrocarbons, substituted polycyclic aromatics, nitriles, amines, pyrroles, pyrazines, pyridines, pyrimidines, and the purine, adenine. In addition, acid hydrolysis produces a racemic mixture of biological and non-biological amino acids. Many of these molecules are implicated in the origin of life on Earth, suggesting Titan as a contemporary laboratory environment for prebiological organic chemistry on a planetary scale.

Aerosols↗

PubMed1987

Biological and chemical studies on overheated brewed coffee.

Vapour formed from overheated decaffeinated coffee was condensed and tested for mutagenicity using the Ames assay in Salmonella typhimurium strains TA98 and TA100. Vapour produced at 73 and 100 degrees C exhibited no mutagenicity. The basic fraction of vapour produced at 350 degrees C showed weak mutagenicity towards strains TA98 with metabolic activation. The chemical analysis of this fraction identified pyridines and pyrazines as the major constituents. None of the compounds identified in this fraction has been reported as mutagenic when tested in the Ames assay.

Caffeine↗

PubMed1996

Inorganic tin -- a new selective inducer of the murine coumarin 7-hydroxylase (CYP2A5).

The coumarin 7-hydroxylase of mice (Coh, CYP2A5) is known to be highly selectively inducible by both a set of heavy metals such as cobalt, indium and cerium and a variety of organic nitrogen-containing heteroaromatic compounds such as 3-amino-1,2,4-triazole, pyrazine and pyrazole. The investigations presented reveal that inorganic divalent tin has to be included in the list of selective inducers. Pretreatment of NMRI-mice with 50 mg SnCl2/kg body weight, daily for 2 days, increases the coumarin hydroxylation 40- and 20-fold in the kidney and liver, respectively. So far, the inducing potency of tin chloride is higher than that of the agents already known. The diagnostic inhibitor metyrapone strongly inhibits the coumarin model reaction. In the kidneys tin generates an almost pure fraction of a cytochrome P450 isozyme catalyzing the metabolism of coumarins, as inhibition experiments reveal.

Animals↗

PubMed1983

Resonance Raman spectra of flavin semiquinones stabilized by N5 methylation.

Resonance Raman spectra are reported for the semiquinone of N5-methyl derivatives of FMN (flavin mononucleotide) in H2O and 2H2O, 8-chloro FMN and FAD (flavin adenine dinucleotide) with 647.1 nm excitation, in the first pi-pi absorption band, using KI to quench fluorescence. The spectral pattern is similar to that of oxidized flavin, in its first absorption band, but with appreciable shifts, up to approx. 50 cm-1, in corresponding frequencies. There are also significant shifts with respect to the previously reported resonance Raman spectrum of flavodoxin semiquinone, reflecting the substitution of CH3 for H at N5. The N5-methyl FAD semiquinone spectrum is also reported for 514.5 nm excitation, in resonance with the second pi-pi transition. The intensity pattern is quite different, the spectrum being dominated by a band at 1611 cm-1, assigned to a mode localized primarily on the central pyrazine ring.

Carrier Proteins↗

PubMed1993

Enhancement of hyperthermia effect in vivo by amiloride and DIDS.

PURPOSE: Intracellular pH is regulated mainly by Na+/H+ antiport and Cl-/HCO3- exchange through the cell membrane. Amiloride (3,5-diamino-6-chloro-N-(diaminomethylene)pyrazine carboxamide) is a diuretic drug that blocks Na+/H+ antiport and DIDS (4,4-diisothiocyanatostilbene-2,2'-disulfonic acid) is an inhibitor of Cl-/HCO3- exchange. We investigated the potency of these drugs to lower pHi and increase the thermosensitivity of tumors in vivo. MATERIALS AND METHODS: The cytocidal effect of heat in combination with drug effect in vivo was studied using the in vivo-in vitro clonogenic assay method and the tumor growth delay method with SCK tumors, a mammary adenocarcinoma, on the hind limbs of A/J mice. The effects of amiloride and DIDS on tumor pHi and high energy phosphate levels were investigated using 31P-NMR. RESULTS: We observed that amiloride or DIDS alone increased the effect of hyperthermia at 42.5 degrees C or 43.5 degrees C to suppress tumor growth. The thermosensitization was greater when the two drugs were combined. For example, hyperthermia at 43.5 degrees C alone resulted in a tumor growth delay of about 4 days. When 10 mg/kg amiloride or 25 mg/kg DIDS was injected prior to heating, the growth delay increased to about 6 days. When both drugs were injected prior to heating, a total growth delay of 8 days was obtained. In vivo-in vitro excision assays for cell survival demonstrated that these drugs enhanced the heat-induced tumor cell death. An i.p. injection of 10 mg/kg amiloride plus 25 mg/kg DIDS did not lower the tumor pHi over a 120 min interval. Heating the tumors at 42.5 degrees C for 1 hr significantly lowered the pHi and when the tumor-bearing mice were injected i.p with amiloride and DIDS, and the tumors were heated 1 hr later, the drop in pHi was greater relative to that by heating alone. Heating alone significantly lowered the tumor energy levels as indicated by PCr/Pi and beta-ATP/Pi ratios and an i.p. injection of 25 mg/kg amiloride prior to heating further reduced the energy status in the tumors. CONCLUSION: Amiloride or its analogs and DIDS may be useful in increasing the therapeutic efficacy of hyperthermia treatments by enhancing the reduction in tumor pHi.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗