Biomedical subjects

D J Doolette

Publications and source records attributed to D J Doolette.

22 records · Page 2Linked to original sources

PubMed1993

3-amino-2-(4-chlorophenyl)-nitropropane is a new GABAB receptor agonist, more active peripherally.

The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 +/- 1.3 microM; N-BAC = 9.2 +/- 0.3 microM) and vas deferens (IC50s for baclofen = 30 microM; N-BAC = 100 microM), competitively antagonised by phaclofen, 2-hydroxysaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 +/- 0.2) and N-BAC (4.6 +/- 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.

Animals↗

PubMed1993

R-(-)-beta-phenyl-GABA is a full agonist at GABAB receptors in brain slices but a partial agonist in the ileum.

R-(-)-beta-phenyl-GABA has been compared at GABAB receptors using cortical and ileal preparations. R-(-)-beta-phenyl-GABA (EC50 = 25 microM) was a less potent full agonist than R,S-(+/-)-baclofen (EC50 = 2.5 microM), in depressing CA1 population spikes of rat hippocampal slices, and 5 times less potent in attenuating the spontaneous discharges of rat neocortex. However, R-(-)-beta-phenyl-GABA (100-400 microM) was only a weak partial agonist in the ileum. All these actions were sensitive to CGP 35348 (3-aminopropyl-(P-diethoxymethyl)-phosphinic acid) and therefore mediated by GABAB receptors.

Animals↗

PubMed1992

Comparison of carbon monoxide and nitrogen induced effects on synaptic transmission in the rat hippocampal slice.

A comparison has been made of the effects of carbon monoxide (CO) or nitrogen (N2) exposure on synaptic transmission in the hippocampal slice. CA1 field potentials, evoked by Schaffer collateral stimulation, were unaffected by superfusion of slices with artificial cerebral spinal fluid (ACSF) equilibrated with either 15% CO or 15% N2 for 120 min. However, superfusion with hypoxic ACSF equilibrated with either 85% CO or 85% N2 caused a rapid depression of synaptic transmission. Reperfusion with control ACSF following 30 min hypoxia led to recovery of evoked responses and a slight hyperexcitability. In the hippocampal slice, synaptic transmission, as assessed by input/output curves, was not different during or following hypoxia induced by exposure to CO or N2. In the short term, CO is not toxic.

Afferent Pathways↗

PubMedDate not supplied

Kinetic aspects of drug disposition in the lungs.

1. The pharmacokinetic role of the lungs has been extensively studied using in vitro preparations, but this information has not been well integrated into many systemic pharmacokinetic models. 2. The lung is characterized by short diffusion distances, extremely high relative perfusion and heterogeneous cell types. Anionic and neutral lipophilic drugs have relatively small distribution volumes in the lungs due to their low lipid content. Cationic lipophilic drugs can accumulate in the lungs, probably due to trapping in mitochondria and lysosomes, forming very slowly eluting pools. 3. Drug metabolism in the lungs is possible, but not universal. The lung, generally, has a low activity for many of the metabolic enzymes found in the liver, although this activity is relatively more inducible. The resultant drug extraction would be 'enzyme limited', variable and flow dependent. 4. Double indicator studies of first-pass lung kinetics can characterize short-term distribution in the lungs, but not longer-term distribution or metabolism; the converse applies for studies of drug concentration gradients across the lungs. No single study or model has adequately defined the short- and long-term kinetics of drugs in the lungs. 5. Drug clearance in the lungs can contribute to an apparent total body clearance in excess of hepatic blood flow and cardiac output. The lung is a first pass filter for any drug administered on the venous side of the circulation and can act as a 'capacitor' that damps the first-pass concentration peak in the blood after intravenous bolus injection.

Humans↗