Determinants of in vitro nitroglycerin tolerance induction and reversal: influence of dose regimen, nitrate-free period, and sulfhydryl supplementation.

The influence of dose regimen on the induction and reversal of tolerance to nitroglycerin (NTG) is not well understood despite the current widespread clinical use of both sustained and intermittent modes of NTG administration. In an isolated coronary artery preparation both the NTG preexposure concentration and the duration of the NTG preexposure period were positive and independent determinants of the extent of NTG tolerance induction. During a "nitrate-free" or washout period, NTG tolerance was at least partially reversible. The apparent rate of NTG tolerance reversal during a "nitrate-free" period was not dependent on the absolute degree of NTG tolerance induced or on the dose regimen used to induce NTG tolerance. In this isolated vascular preparation, sulfhydryl (SH) supplementation with 1 mM N-acetylcysteine produced no significant augmentation of NTG-induced relaxations in either NTG tolerant or non tolerant tissues. N-acetylcysteine was ineffectual in attenuating the development of NTG tolerance in coronary artery preparations incubated in either Krebs bicarbonate buffer or in 10% human plasma. We conclude that in this model the NTG preexposure concentration, the duration of the NTG preexposure period, and the duration of the "nitrate-free" period are critical and independent determinants of the extent of NTG tolerance but that NTG tolerance is not significantly attenuated by SH supplementation.

Neurotransmitters and neuropeptides in blood pressure regulation in the spontaneously hypertensive rat.

Studies of the roles played by neurotransmitters in the development of hypertension in the spontaneously hypertensive (SHR) rat are complicated by the presence of genetic differences between SHR and normotensive control rats, which are not related to differences in blood pressure. One approach that may be used in an attempt to overcome this difficulty is to study the manner in which neurotransmitter and metabolite levels change with age, and to relate these changes to alterations in blood pressure with ageing. Noradrenaline (NA) levels in the brainstem and spinal cord of SHR and Wistar Kyoto rats fell with age, while 3,4-dihydroxyphenylethyleneglycol (DHPG) levels (a neuronal metabolite of noradrenaline) remained constant. Similar changes were seen when NA and DHPG levels were measured in the discrete brainstem A1, A2, and C2 region, and when adrenaline, NA, and DHPG levels were examined in the C1 region. Differences in age-related changes of neuropeptide Y (NPY) levels were also found in the ventromedial nucleus of the hypothalamus and the locus coeruleus, and of beta-endorphin in the anterior hypothalamic nucleus, the paragigantocellular nucleus of the brainstem, and the locus coeruleus. These changes may indicate either a progressive increase in the activity of neurons in the sympathoexcitatory C1 region or a progressive reduction in the activity of vasodepressor A1, A2, and C2 regions with ageing, or both. However, changes in catecholamines and metabolites with age were similar in both strains and therefore cannot readily explain the more rapid rise in blood pressure with ageing in SHR rats.

Dynorphin(1-8) immunoreactivity in brainstem and hypothalamic nuclei of normotensive and age-matched hypertensive rat strains.

The concentration of dynorphin (1-8) immunoreactivity [ir-dyn(1-8)] was measured in 10 hypothalamic and 11 brainstem nuclei of Sprague-Dawley (SD) and 6- and 14-week old Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The highest concentrations of ir-dyn(1-8) were found in the lateral preoptic and lateral hypothalamic areas of the hypothalamus and the solitary tract nucleus of the brainstem. Levels of the peptide were low in other brainstem nuclei compared to hypothalamic areas. There was a significant reduction in ir-dyn(1-8) concentrations at 14 weeks of age compared to 6 weeks of age in all 9 nuclei examined in SH and WKY rats. However, there were no differences between the strains at either age. These changes may be related to the increase in blood pressure that occurs in both SH and WKY rats over this age range although other factors must also be involved to produce the higher blood pressure levels of the SH rat.

6-Hydroxydopamine and excitotoxin lesions of medial prefrontal cortex fail to affect schedule-induced drinking in the rat.

Schedule-induced drinking was examined in rats following 6-hydroxydopamine and N-methyl-D-aspartate lesions of the medial prefrontal cortex. 6-Hydroxydopamine reduced the concentrations of dopamine and noradrenaline in the medial prefrontal cortex to 17 and 37% of control values respectively, while changes were not observed in the nucleus accumbens. Lesions with N-methyl-D-aspartate were confined to the medial prefrontal cortex. Schedule-induced water consumption, determined over 11 consecutive 1 h/day testing sessions, was not significantly altered by either lesion. These results suggest that the mesocortical dopaminergic projection to the medial prefrontal cortex, and reciprocal projections from medial prefrontal cortex to the nucleus accumbens and the ventral tegmental area, are not essential for the acquisition of schedule-induced drinking.

The measurement of central noradrenergic activity in spontaneously hypertensive rats: a comparison of free 3,4-dihydroxyphenylethyleneglycol levels with FLA-63 induced noradrenaline depletion.

Noradrenergic activity was measured in the brainstem, hypothalamus and thoracic spinal cord of male and female spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 6 and 28-36 weeks of age. Two techniques were used, measurement of a major noradrenaline (NA) metabolite, free 3,4-dihydroxyphenylethyleneglycol (DHPG), and measurement of the rate of decline in brain NA levels following dopamine-beta-hydroxylase (DBH) inhibition by FLA-63. There was a good correlation between the changes with age in NA turnover measured by the two techniques. NA levels and NA turnover measured by both techniques fell with age in brainstem and thoracic spinal cord in both SHR and WKY rats. In both strains these falls in turnover were associated with increases in blood pressure. However, the increase in blood pressure in the SHR was greater than in the WKY, even though NA turnover fell to a similar extent in both strains. These data show a difference in the pattern of change in NA levels and turnover in the brainstem and thoracic spinal cord compared to other brain regions and may therefore be related to the development of higher levels of blood pressure in older rats in both strains. They do not offer a simple explanation for the much higher blood pressures seen at all ages in the SHR.

High dose of antacid (Mylanta II) reduces bioavailability of ranitidine.

To investigate the effect of antacid on the bioavailability and disposition of ranitidine six healthy volunteers were studied on two occasions one week apart. In the first study the received ranitidine 150 mg with 60 ml water, and in the second study they received ranitidine 150 mg plus 30 ml of an aluminium/magnesium hydroxide mixture (Mylanta II) and 30 ml water. Giving antacid reduced both the maximum plasma ranitidine concentration and the area under the curve by one-third; elimination of the drug was not changed. Thus giving a high dose of antacid significantly diminished the bioavailability of ranitidine.

Adrenaline depletion in the hypothalamus of the rat after chronic alpha-methyldopa.

1. Individual anterior hypothalamic-preoptic nuclei were dissected from the brains of control and alpha-methyldopa treated (2 x 40 mg/kg, 5 days) rats, and the concentrations of adrenaline and other catecholamines were estimated. 2. By a combination of radioenzymatic assay and paper chromatography the concentrations of adrenaline, noradrenaline, dopamine, alpha-methylnoradrenaline and alpha-methyldopamine were determined concurrently in the same sample. 3. alpha-Methyldopa reduced the adrenaline levels of the hypothalamic nuclei by 47--68% of control concentrations. 4. A differential displacement of the parent catecholamines was observed and the depletions were ranked: adrenaline less than dopamine less than noradrenaline. 5. alpha-Methylnoradrenaline and alpha-methyldopamine were found in all hypothalamic nuclei. 6. The depletion of hypothalamic adrenaline by alpha-methyldopa could represent a pharmacological mechanism contributing to the antihypertensive action of the drug.

Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration.

The pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers. Oral administration of 10 to 15 mg/kg gave variable plasma levels (0 to 10.5 microgram/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the 'first pass' hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits in the liver. Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8 microgram/ml) during high dose (20 to 30 mg/kg/24h) slow intravenous infusion in 6 patients. These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.