Administration Of 6-aminonicotinamide Research Articles

Effect of 6-aminonicotinamide on the pentose phosphate pathway: 31P NMR and tumor growth delay studies.

6-aminonicotinamide (6AN) has been shown to enhance radiosensitivity in vitro, although previous in vivo studies failed to show an effect. 31P NMR spectra were obtained by using a one-dimensional chemical shift imaging technique on a first generation transplant of the CD8FI spontaneous mammary carcinoma tumor model. Spectra were obtained both before and 10 h after treatment with 6AN (20 mg/kg). Changes in pH, nucleoside triphosphate/inorganic phosphate, and phosphocreatine/ inorganic phosphate measured at 10 h post-6AN were not significant. A new peak was detected 10 h post-6AN, which was assigned to 6-phosphogluconate (6PG), indicating inhibition of the pentose phosphate pathway (PPP). Based on the spectral data demonstrating inhibition of the PPP at 10 h post-6AN, tumor-bearing mice were irradiated (15 Gy x 3 fractions) on Days 1, 10 or 11, and 21 10 h after administration of 6-aminonicotinamide (20 mg/kg). Tumor-bearing mice receiving 6AN alone (20 mg/kg x 3), radiation alone (15 Gy x 3), or saline were also studied. Tumor growth delay studies indicated that 6AN alone induced a small but significant tumor growth delay (4.3 +/- 0.8 days). Radiation alone induced a tumor growth delay of 34.5 +/- 2.7 days. Treatment with 6AN followed by radiation induced a tumor growth delay of 57.0 +/- 3.8 days. This was significantly greater than the TGD values for treatment with 6AN alone or radiation (P < 0.01). No complete regressions were noted after treatment with 6AN or radiation alone. Concomitant therapy with 6AN plus radiation yielded 6/28 complete regressions (21%), which was significantly greater than radiation (P < 0.05) or 6AN alone (P < 0.01) on this mammary carcinoma.

Effect of intracarotid administration of 6-aminonicotinamide on cerebral blood flow in cats.

We evaluated the effects of an adenosine triphosphate blocker, 6-aminonicotinamide (6-ANA), on the cerebral blood flow (CBF), cerebral metabolism, and electroencephalogram of cats. Catheters were inserted into the common carotid artery of 16 adult cats anesthetized with ketamine via the lingual artery. We measured CBF in the infused area by the inhaled hydrogen gas clearance method and analyzed the electroencephalogram frequency. Cerebral metabolism was estimated by oxygen extraction (vol/%) and glucose utilization (millimoles) using data arterial (aorta) and sagittal sinus blood samplings. A solution of 6-ANA (6.0 mg/mL) (n = 8) or saline (n = 8) was infused via catheter at 2.0 mL/min for 3 minutes followed by a 60-minute observation of CBF, cerebral metabolism, vascular resistance, and the electroencephalogram components, alpha-2 ratio [= alpha-2/(alpha-1+alpha-2)]. The effect of 6-ANA on capillaries was evaluated by extravasation of Evans blue dye and electron microscopic findings. Moderate reductions in CBF, cerebral metabolism, and the alpha-2 ratio were observed during the infusion of 6-ANA versus saline infusion (P < .05 by paired t test and ANOVA). Vascular resistance was significantly increased (P < .05). No abnormalities were observed in the capillaries of the infused hemisphere. Results indicated that 6-ANA produced a downregulation of cerebral blood flow in cats.

Effects of Dietary 6-Aminonicotinamide, an Antagonist of Nicotinamide, on the Metabolism of Tryptophan to Nicotinamide in Rats

It has been reported that pellagra is caused by abnormal metabolism of tryptophan, although it is generally believed that pellagra is caused by a deficiency of niacin. The administration of 6-aminonicotinamide (6-AN) to rats induces central nervous lesions being similar those seen in pellagra. So, we investigated the effects of 6-AN on the metabolism of tryptophan to nicotinamide. The threshold of the toxicity of 6-AN was around 0.001% when it was incorporated in the diet. In enzyme activities involved in the metabolism of tryptophan to nicotinamide, the activities of tryptophan oxygenase and aminocarboxymuconate-semialdehyde decarboxylase were greatly increased, while that of kynureninase was decreased by feeding of 6-AN diets. In enzymes involved in catabolism of nicotinamide, the activity of nicotinamide methyltransferase was increased and those of N1-methyl-2-pyridone-5-carboxamide (2-Py)- and N1-methyl-4-pyridone-3-carboxamide (4-Py)-forming N1-methylnicotinamide (MNA) oxidases were decreased by feed...

Altered proteoglycan synthesis by micromelial limbs induced by 6-aminonicotinamide. Appearance of abnormal forms of cartilage-characteristic proteoglycan (PG-H).

Since administration of 6-aminonicotinamide (10 micrograms) to day-4 chick embryos in ovo was shown to induce micromelial limbs, biosynthesis of cartilage-characteristic proteoglycan-H (PG-H) as an important index of limb chondrogenesis was examined in day-7 normal and micromelial hind limbs by biochemical and immunological methods. (1) Metabolic labelling of the micromelial limbs with [6-3H]glucosamine and either [35S]sulphate or [35S]methionine, followed by analyses of labelled PG-H by glycerol density-gradient centrifugation under dissociative conditions, showed a marked reduction in the PG-H synthesis. (2) PG-H synthesized by the micromelial limbs was much lower than that synthesized by the normal limbs in the biosynthetic ratio of chondroitin sulphate to keratan sulphate and glycoprotein-type oligosaccharide, although no significant difference was observed in the immunological properties of these proteoglycans. (3) The degree of sulphation of chondroitin sulphates of PG-H was lowered in the micromelial limbs as judged by the increase of unsulphated disaccharide (delta Di-OS) released by chrondroitinase ABC digestion, although there were no significant differences between the normal and the micromelial limbs in the average molecular size (Mr = 38,000) of labelled chondroitin sulphates of PG-H. (4) Addition of beta-D-xyloside, an artificial initiator for chondroitin sulphate synthesis, to the micromelial limbs in culture recovered the incorporation of labelled glucosamine into chondroitin sulphate to that comparable with the normal control with beta-D-xyloside, although the incorporation of [35S]sulphate was lower in the micromelia than in the control with beta-D-xyloside. These results suggest that the reduction in the biosynthesis of the PG-H as well as the production of altered forms of PG-H induced by 6-aminonicotinamide during a critical period of limb morphogenesis may be an important factor for the micromelia.

Inhibition of glucose reabsorption induced by 6-aminonicotinamide in the rat kidney.

The relationship between natriuresis and glucosuria produced by administration of 6-aminonicotinamide (6-AN), was investigated in the rat. After intraperitoneal administration of 6-AN (75 mg/kg), urine was collected at intervals of 2 hours using a metabolic cage for assays. Sodium and glucose were excreted maximally into the urine at 2 to 4 and at 4 to 6 hours, respectively, after the administration of 6-AN, with a time delay being recognized between sodium and glucose in the peaks of their urinary excretions. This dissociation of the patterns on the urinary excretion between sodium and glucose led to the following conclusion that the natridiuresis induced by 6-AN was not mainly ascribed to the osmotic diuresis for glucose, but to the direct effect on the sodium transport in the kidney. Furthermore, additional experiments were carried out by loading animals with glucose after administration of 6-AN. The tolerance for glucose in the body was clearly depressed in rats in the 6-AN group, while no significant difference in the renal threshold concentration for glucose was shown in either group. The renal tubular transport maximum for glucose was also depressed in the 6-AN group. It is, accordingly, speculated that the glucosuria induced by 6-AN was not only due to the hyperglycemia, but also due to the decreased capacity of the renal tubular reabsorption for glucose.

Intracranial hypertension and brain oedema in albino rabbits. Part 3: Effect of acute simultaneous diuretic and barbiturate therapy.

Increased intracranial pressure due to brain oedema was produced in albino rabbits by combining a cryogenic lesion in the left hemisphere with the intraperitoneal administration of 6-aminonicotinamide (cytotoxic agent). The following parameters were assessed: intracranial pressure (ICP), systolic arterial pressure (SAP), central venous pressure (CVP), EEG, brain water and electrolyte content, gross pathology, and blood brain barrier integrity. Acute therapy to reduce ICP was performed by administering a bolus of mannitol (1 gm/kg) and 30 minutes later, also in bolus, frusemide (5 mg/kg). Immediately following the administration of mannitol an infusion of pentobarbitone was commenced; this was continued for one hour so that a total of 10 mg/kg was administered. There was a 50% reduction of ICP at one hour from initiation of treatment. The brains of the animals were extracted immediately upon cessation of therapy (pentobarbitone) and they revealed a significant reduction of water content for the right, uninjured, hemisphere only, when compared to controls; a slight but not significant reduction of the brain sodium and potassium was noted in both hemispheres. There was no change noted in the gross pathology and extent of blood brain barrier breakdown. In all animals epinephrine infusion had to be administered for between 20 and 30 minutes to maintain a SAP over 80 torr. There seems to be no advantage in the simultaneous administration of barbiturates and diuretics for the control of ICP due to brain oedema.

The effect of 6-aminonicotinamide on the levels of brain amino acids and glucose, and their labeling with 14C after injection of [U-14C] glucose.

The brains of rats paralysed at 4 hr after the administration of 6-aminonicotinamide were found to contain decreased levels of glutamate and gamma-aminobutyrate. The glucose content of the brain of the treated rats was several fold higher than in controls. The incorporation of 14C into brain amino acids at 30 min after the injection of [U-14C]glucose was decreased by 16%: this was attributed to mainly decreased labeling of glutamate and associated amino acids. The results are discussed in the light of previous findings that the administration of 6-aminonicotinamide resulted in the blockade of the direct oxidation of glucose by the pentose phosphate pathway.

Metabolic alterations in the axotomized superior cervical ganglion of the rat. II. The pentose phosphate pathway

The activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were increased in the superior cervical ganglion of the rat between 2 and 7 days after sectioning the major postganglionic nerve trunks of the ganglion. Both enzymes returned to normal levels at 10 days after axotomy. Microscopic and quantitative histochemical analyses demonstrated that these changes in the 2 oxidative enzymes of the pentose phosphate pathway occurred in chromatolytic cells in the cranial pole of axotomized ganglia. Transketolase was slightly reduced at 2, 7 and 10 days after axotomy in this region which contains the majority of the chromatolytic cells. No significant changes were observed in the activities of NADP +-dependent isocitrate dehydrogenase, malic enzyme, transketolase or ribose-5-phosphate isomerase in homogenates of axotomized ganglia as compared to those of the contralateral normal (sham-operated) ganglia. Administration of 6-aminonicotinamide (6-AN) to rats resulted in a marked accumulation of 6-phosphogluconate in both normal and axotomized ganglia, confirming that the oxidative portion of the pentose phosphate pathway is active in these tissues in vivo. From the rate at which 6-phosphogluconate accumulated in ganglia of 6-AN-treated rats it was estimated that at least 16% of the glucose metabolism of the ganglion occurs via this pathway under resting conditions. Oxidation of [1- 14C]glucose and [6- 14C]glucose to 14CO 2 in normal and axotomized ganglia was observed in vitro 2 days after nerve section. Metabolism of [1- 14C]glucose to 14CO 2 as well as the ratio of [1- 14C]glucose: [6- 14C]glucose converted to 14CO 2 were greater in axotomized than in contralateral normal ganglia. Thus, the increases in the oxidative enzymes of the pentose phosphate pathway in the axotomized ganglion appear to be associated with increased metabolism via this pathway. Activation of the pentose phosphate pathway in the axotomized ganglion was temporally correlated with early increases in lipid and RNA in the ganglion and other types of axotomized nerve cells. It is concluded that an important relationship may exist between metabolism via the oxidative enzymes of the pentose phosphate pathway and biosynthetic events during the early period of nerve regeneration.