Biomedical subjects

R Dunstan

Publications and source records attributed to R Dunstan.

7 recordsLinked to original sources

PubMed1992

Adenosine triphosphate-magnesium chloride in radiation injury.

Although adenosine triphosphate-magnesium chloride (ATP-MgCl2) has demonstrated cytoprotective effects in a variety of adverse pathophysiologic conditions, its ability to alter radiation injury is unknown. The purpose of this study, therefore, was to assess the effects of ATP-MgCl2 on colorectal radiation injury after preoperative pelvic radiotherapy. Mixed-breed pigs (n = 36) received 4250 cGy preoperative external-beam pelvic radiotherapy (350 cGy fractions three times per week for 4 weeks). During radiotherapy, animals were randomly assigned to one of three treatment groups: (1) intravenous infusions of normal saline during radiotherapy, (2) intravenous ATP-MgCl2 (30 mumol/kg) during radiotherapy, or (3) intravenous ATP-MgCl2 (60 mumol/kg) during each radiotherapy session. After completion of radiotherapy and a 4-week rest period, animals underwent colorectal resection by either the two-layer hand-sewn (n = 18) or stapled end-to-end anastomosis technique (n = 18). Laser Doppler velocimetric readings were obtained to assess mural colonic blood flow after completion of anastomosis. A second laparotomy on postoperative day 5 or 11 was done to examine the following anastomotic parameters: (1) repeat laser Doppler velocimetry, (2) gross inflammatory scoring, (3) bursting pressure, (4) preoperative barium enema to identify leak or stenosis, (5) analysis of anastomotic hydroxyproline content, and (6) incidence of cutaneous injury in the radiation portals. ATP-MgCl2 administered intravenously at 60 mumol/kg led to (1) diminished colorectal seromuscular ischemia evidenced by laser Doppler velocimetric readings, (2) decreased skin and subcutaneous tissue injury in the treatment portals, (3) significantly decreased perianastomotic inflammatory reaction, and (4) increased early hydroxyproline content. There was no significant difference in the incidence of leakage or stenosis between the study groups, nor was the anastomotic bursting strength significantly different between the treatment groups. Therefore the administration of ATP-MgCl2 (60 mumol/kg) appears to offer significant cytoprotection from preoperative pelvic radiation therapy.

Adenosine Triphosphate↗

PubMed1979

The hyperkinetic syndrome following long-term haloperidol treatment: involvement of dopamine and noradrenaline.

Mice withdrawn for 7 days from a 35-day treatment period with haloperidol (3 mg/kg/day) displayed significantly greater spontaneous locomotor activity (hyperkinesia) than animals withdrawn from the vehicle. The hyperkinesia was antagonized by phenoxybenzamine (an alpha-adrenergic receptor antagonist) and by FLA-63 (a dopamine-beta-hydroxylase inhibitor) but not by haloperidol (a dopamine receptor antagonist). alpha-Methyl tyrosine (a tyrosine hydroxylase inhibitor) was effective in antagonizing the hyperkinesia and this blockade by alpha-methyl tyrosine could be completely reversed by the administration of a low dose of the catecholamine precursor, DOPA. The data suggest that noradrenergic systems are of importance for the manifestation of the hyperkinetic syndrome seen in mice withdrawn from long-term haloperidol treatment.

Animals↗

PubMed1979

Long-term haloperidol-treatment of mice: a change in beta-adrenergic receptor responsiveness.

Mice administered haloperidol 3 mg/kg/day in their drinking water for 21 days were tested for their locomotor responsiveness to saline or acid vehicle, dl-, l- or d-propranolol, metoprolol, butoxamine or practolol. Haloperidol-treated animals administered saline or acid-vehicle were, in five of six experiments, more active than animals withdrawn from vehicle-treatment. Haloperidol- and vehicle-treated animals responded differently to the non-selective beta-adrenoreceptor antagonists (dl-propranolol and l-propranolol) and selective beta1-adrenoreceptor antagonists (practolol and metoprolol), but not to a selective beta2-adrenoreceptor antagonist (butoxamine). With dl-propranolol (4 mg/kg) the locomotor activity of haloperidol-treated animals was significantly (0.01 less than P less than 0.02) greater than that of the vehicle-treated animals. Similar effects in the same direction were seen with l-propranolol (1 mg/kg, 0.005 less than P less than 0.01), practolol (10 and 100 mg/kg, 0.025 less than P less than 0.05 and 0.01 less than P less than 0.025 respectively) and metoprolol 8 mg/kg, 0.005 less than P less than 0.01). The d-isomer of propranolol which is about 50 times less active as a beta-adrenoreceptor antagonist than the l-isomer, although having equal membrane stabilizing effects, did not differentially affect haloperidol- or vehicle-treated groups. The results suggest that there has been a change in beta 1-adrenoreceptor responsiveness in animals withdrawn from long-term haloperidol treatment.

Adrenergic beta-Antagonists↗

PubMed1978

Further evidence for a change in central alpha-adrenergic receptor sensitivity after withdrawal from long-term haloperidol treatment.

Phenoxybenzamine, FLA-63 and alpha-MT produced less locomotor depression in mice withdrawn for 4 days from a 21 day treatment with haloperidol than that produced in vehicle-treated animals. There were no differences between the two groups when challenged with yohimbine or phentolamine. The data support the hypothesis that central alpha-adrenergic receptors had become supersensitive and suggest that the sensitivity changes are restricted to post-synaptic receptors.

Animals↗

PubMed1977

The demonstration of a change in responsiveness of mice to physostigmine and atropine after withdrawal from long-term haloperidol pretreatment.

Mice, administered haloperidol 3 mg/kg/day, in their drinking water for 21 days, were tested for their responsiveness to cholinergic and anticholinergic drugs 4 days after withdrawal from haloperidol (or vehicle). Haloperidol-treated animals administered methylhyoscine (1 mg/kg i.p.) and various doses of physostigmine (5 to 1215 microgram/kg) displayed significantly less depression of locomotor activity than vehicle-treated animals. Atropine, 5 mg/kg, whilst ineffective in producing locomotor stimulation in vehicle-treated animals, produced marked stimulation in haloperidol-treated animals. Methylatropine (5 mg/kg) did not produce significant stimulation in either group. Dopamine receptor supersensitivity was present in these animals as haloperidol-treated mice, pretreated with alpha-methyltyrosine and reserpine, displayed a significantly greater locomotor response to apomorphine than did vehicle-treated animals. The data support the hypothesis that long-term administration of haloperidol produces an apparent hyposensitivity of central muscarinic receptors.

Animals↗

PubMed1976

The demonstration of a change in adrenergic receptor sensitivity in the central nervous system of mice after withdrawal from long-term treatment with haloperidol.

Mice, administered haloperidol (3 mg/kg/d) in their drinking water for 21 days, displayed, 4 days after cessation of the haloperidol-treatment, marked locomotor stimulation to clonidine (100 or 500 mug/kg) which lasted for about 6 h. 25 mug clonidine/kg was inactive. Premedication with FLA-63 (25 mg/kg) blocked the difference in stimulation after clonidine between the haloperidol- and vehicle-treated animals, but locomotor activity was still present in both groups. Haloperidol-treated animals displayed a supersensitive response to dexamphetamine. The difference in stimulation produced by dexamphetamine in the two groups was completely blocked by phenoxybenzamine (2.5 mg/kg), phentolamine (10 mg/kg), which drugs did not, however, block the locomotor stimulation produced by dexamphetamine in vehicle-treated animals. Pimozide (3 mg/kg) blocked all locomotor stimulation produced by dexamphetamine in both vehicle- and haloperidol-treated groups, while 1 mg/kg completely blocked the dexamphetamine response in vehicle-treated animals but not in haloperidol-treated animals. FLA-63 (25 mg/kg) blocked the difference in response between the haloperidol- and vehicle-treated groups to dexamphetamine, but did not antagonise the stimulation in the vehicle-treated animals. The data suggest that long-term haloperidol treatment leads to the development of "supersensitive" adrenergic receptors in the central nervous system, which, appropriately stimulated, effect an increase in locomotor activity. Moreover, the results indicate that a large component of the supersensitive response to dexamphetamine observed after long-term haloperidol-treatment is due to adrenergic receptor supersensitivity. However, the dopamine receptor (which was shown to be supersensitive to apomorphine) is of fundamental importance because phenoxybenzamine and phentolamine, while blocking the supersensitive response to dexamphetamine, failed to block the response to dexamphetamine in vehicle-treated animals, which was, however, blocked by pimozide.

Adrenergic alpha-Antagonists↗

PubMedDate not supplied

The effect of apomorphine and clonidine on locomotor activity in mice after long term treatment with haloperidol.

1. Mice were given haloperidol (approximately 3 mg.kg-1 day-1) or vehicle for 21 days and then withdrawn from the drug. All tests were performed 4 days after withdrawal. 2. Haloperidol treated mice (premedicated with reserpine plus alpha-methyl-p-tyrosine) displayed an increased locomotor response to apomorphine and to apomorphine plus clonidine, but neither haloperidol- or vehicle-treated animals revealed any stimulant response to clonidine. 3. In mice which had not been pretreated with reserpine plus alpha-methyl-p-tyrosine, clonidine produced a significant stimulation of locomotor activity in animals withdrawn from haloperidol but not in those withdrawn from the vehicle. Phenoxybenzamine blocked the locomotor stimulat difference between these two groups, but did not completely antagonized the stimulant effect of clonidine in mice withdrawn from haloperidol. Pimozide was largely effective in blocking the clonidine-induced stimulation. Co-administration of phenoxybenzamine and pimozide was completely effective in blocking the stimulant effect of clonidine in mice withdrawn from haloperidol. 4. The evidence for a change in catecholamine receptor sensitivity was supported compared to the vehicle-treated animals. 5. The data suggest that there is a change in the functional responsiveness of both adrenergic and dopaminergic receptors after withdrawal from long term haloperidol treatment.

Animals↗