3-aminopropylphosphinic-acid and 2-hydroxysaclofen

The purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions.

Topics: Anesthesia; Animals; Baclofen; Capsaicin; GABA Agonists; GABA Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Gastric Mucosa; Male; Organophosphorus Compounds; p-Methoxy-N-methylphenethylamine; Pepsinogens; Perfusion; Rats; Rats, Wistar; Receptors, GABA-B; Vagotomy

Amacrine and ganglion cells in the amphibian retina contain GABAB, as well as GABAA, receptors. Baclofen, a GABAB agonist, hyperpolarizes the dark membrane potential of these third order neurons and makes their light responses more transient. GABAB receptors in the retina have a similar agonist profile to GABAB receptors described at other sites in the brain. Namely, preferential activation by the R-enantiomer of baclofen, and agonist sensitivity in the order 3-aminopropylphosphinic acid > baclofen >> 3-aminopropylphosphonic acid. The GABAB receptor was not activated by 4-aminobutylphosphonic acid. Several antagonists, such as phaclofen, saclofen, and 2-hydroxysaclofen, were ineffective in the amphibian retina. However, CGP35348 blocked the action of applied baclofen and produced effects on the light response that were opposite to those of baclofen. Applied agonists and antagonists support the hypothesis that GABAB receptors serve to regulate the balance of sustained and transient signals to the inner retina.

Topics: Ambystoma; Animals; Baclofen; Butylamines; Evoked Potentials; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; In Vitro Techniques; Membrane Potentials; Necturus; Organophosphorus Compounds; Propylamines; Receptors, GABA-B; Retina; Retinal Ganglion Cells; Stereoisomerism; Structure-Activity Relationship

The actions of 3-aminopropanephosphinic acid (APPA) were examined using whole-cell patch-clamp recording in rat hippocampal slice. In recordings from neurons in subfield CA1 of slices from young (2-4 weeks) and adult (greater than 2 month) rats, APPA (0.5-50 microM) produced membrane hyperpolarization and outward current under voltage-clamp. APPA also inhibited excitatory postsynaptic potentials with an IC50 of 2.3 microM, and reduced inhibitory postsynaptic potentials at concentrations from 0.1 to 1 microM. The hyperpolarizing and synaptic depressant effects of APPA were reduced by 2-OH-saclofen an antagonist at the B-type receptor for the neurotransmitter gamma-aminobutyric acid (GABA). In this preparation APPA exhibited potencies similar to those previously reported for the GABAB receptor agonist baclofen. APPA was much less effective in inhibiting synaptic transmission measured using field potential recordings. The observations made with whole-cell patch-clamp recording indicate that in hippocampus APPA acts as a potent agonist at presynaptic GABAB receptors associated with both excitatory and inhibitory synapses, and also activates postsynaptic GABAB receptors.

Topics: Action Potentials; Aging; Animals; Baclofen; GABA Antagonists; Hippocampus; Membrane Potentials; Organophosphorus Compounds; Rats; Receptors, GABA-A; Synapses; Synaptic Transmission