Characterization of vinblastine-induced supersensitivity in the rat.

A single dose of vinblastine (3 mg/kg, i.v.) in the rat produced a long lasting depletion of endogenous (-)noradrenaline (NA) in atria as well as in vasa deferentia, the depletion being greater in atria than in vasa deferentia. The maximum depletion of NA in atria occurred between 60 and 90 h after vinblastine, while in vasa deferentia the maximum depletion was 35%, 120 h after vinblastine. The 30 min in vitro uptake of (-)-(3H) NA in atria was inhibited between 78 and 83% at 30, 60 and 120 h after vinblastine. In vasa deferentia the maximum inhibition of 25% was seen 15 h after vinblastine, however the NA uptake had returned to control level between 60 and 120 h after vinblastine. The effect of vinblastine pretreatment on the sensitivity of atria to NA and (-)isoprenaline(ISOP), and of vasa deferentia to NA, (-)phenylephrine (PHE), and methoxamine (ME) was evaluated. It was found that atria became highly sensitive to the (+) chronotropic effect of NA without significant change in sensitivity to ISOP. The sensitivity of vas deferens to NA and PHE was moderately increased without significantly affecting the sensitivity to ME. The magnitude of the supersensitivity was expressed in terms of the ratio of the geometric mean ED50 of an agonist in control tissue to that obtained in the same tissue from treated animals. The sensitivity of atria to NA increased 1.5, 3.9, 7.8, and 6.7 fold, 15, 30, 60 and 120 h after vinblastine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the renin-angiotensin system in the blood pressure rebound to sodium nitroprusside in the conscious rat.

Intravenous infusions of sodium nitroprusside (SNP) at doses of 20, 40 or 80 micrograms/kg min-1 for 30 min produced dose-related decrements in blood pressure in conscious rats fitted with indwelling aortic and vena caval catheters. Immediately upon termination of SNP infusions, blood pressure rebounded to levels which were significantly above pre-SNP control values. The following evidence indicates that the rebound increase in blood pressure was due to increased activity of the renin-angiotensin system: (1) plasma renin activity was increased approximately four-fold by SNP, (2) rebound did not occur in nephrectomized rats, (3) rebound was markedly attenuated in animals treated with an angiotensin converting enzyme inhibitor, SQ14225, (D-3-mercapto-2-methylpropanoyl-L-proline) and (4) beta-adrenergic receptor blockade with propranolol reduced the rebound response. In addition, the magnitude of the rebound following SNP infusions was directly related to the dose of SNP infused. These results are consistent with the hypothesis that renin accumulates during SNP infusion more rapidly than it is metabolized. Consequently, the accumulated renin elicits a hypertensive response when SNP treatment is withdrawn.

Sensitive fluorescence assay for d,l-methadone.

d,l-Methadone forms a fluorophore when reacted with paraformaldehyde in concentrated sulfuric acid. Based on this reaction, a fluorescence assay suitable for quantitative d,l-methadone analysis from plasma and other tissues was developed. d,l-Methadone was extracted at pH 9.2 from the deproteinized filtrate of plasma or of aqueous tissue homogenate into an organic phase of 25% isobutanol in ethylene dichloride. After an aliquot of the organic phase was evaporated to dryness at 50--55 degrees with an air jet, paraformaldehyde (0.1%, in concentrated sulfuric acid) was added, and fluorescence was read at 450 nm with excitation at 275 nm. By this method, d,l-methadone can be assayed in the presence of its metabolites, morphine, diacetylmorphine (heroin), codeine, and cocaine; however, amphetamine, meperidine, and quinine interfere.

The effect of repeated administration of delta9-tetrahydrocannabinol on serotonin metabolism in the rat brain.

The level of serotonin (5-HT) was increased in the whole rat brain as well as in the hypothalamus plus midbrain region at 0.5 hr after the fifth or sixth daily dose of delta9-tetrahydrocannabinol (THC), 20.0 mg/kg, i.p., respectively. A decreased rate of 5-HT synthesis was also observed. A slight development of tolerance was indicated by the fact that elevation of 5-HT was smaller than that seen after a single dose (1).

Characterization of (+/-)-methadone uptake by rat lung.

1. By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (+/-)-methadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (+/-)-methadone against a concentration gradient. 2. This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio). 3. The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (+/-)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (+/-)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.5; (iii) When the concentration of (+/-)-methadone in the incubation medium was varied from 0.005 to 0.5 mM, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4. These results suggested that at low concentrations, (+/-)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5. At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (+/-)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of O2, lack of glucose, lack of Na+ in the incubation medium, and by exposure of the tissue to high temperature (approximately 100 degrees C). The uptake was also inhibited by relatively high concentration of iodoacetate (1.0 mM) and of naloxone (1.0 mM). 6. Kinetic analysis of data showed that the diffusion constant for (+/-)-methadone was 5.0 (h-1) and the Vmax of the active transport process was 6.5 micronmol g-1h-1.

Effect of ethanol on the oxidative metabolism of tryptamine by rat liver homogenate.

1 The effect of a wide range of ethanol concentrations (v/v) on indoleacetic acid (IAA) formation from the oxidative deamination of tryptamine was studied in vitro, in rat whole liver homogenate.2 IAA production was inhibited progressively by ethanol in concentrations between 0.01% to 0.2%, but the inhibition declined when the ethanol concentration was increased further to 6%.3 Ethanol-induced inhibition of IAA formation was only partially reversed by excess aldehyde dehydrogenase, whereas reductions in IAA formation were completely prevented by pyrazole or ethanol (6% and 10%) itself.4 Excess nicotinamide adenine dinucleotide failed to alter the inhibitory effect of ethanol and no evidence was obtained for inhibition of monoamine oxidase by ethanol or its metabolite, acetaldehyde.5 We conclude that ethanol indirectly inhibits IAA production as a result of oxidation of ethanol by alcohol dehydrogenase, during which the oxidative metabolism of tryptamine is shifted towards the reductive pathway, thus favouring the formation of tryptophol in place of IAA.