David E. Clarke

Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus

Three benzimidazolone derivatives have been evaluated in the tunica muscularis mucosae preparation of the rat oesophagus for activity at the 5-HT4 receptor. BIMU 1 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-2,3-dihydro-3-ethyl-2-ox o- 1H-benzimidazole-1-carboxamide HCl) and BIMU 8 (endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl)eth yl- 2-oxo-1H-benzimidazole-1-carboxamide HCl) acted as potent but partial agonists relative to 5-HT whereas DAU 6215 (N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)2,3-dihydro-2-oxo-1H- benzimidazole-1-carboxamide HCl) behaved as a competitive antagonist with a pA2 of 6.5. The pEC50 values for BIMU 1 and BIMU 8 were 8.0 and 7.9, respectively, compared with 8.2 for 5-HT. Intrinsic activity values were 0.7 and 0.9, respectively. BIMU 1 and BIMU 8 are the most potent synthetic agonists so far tested in rat oesophagus, and DAU 6215 exhibits an equivalent affinity to ICS 205 930 at the 5-HT4 receptor.

Sympathetic nerve function and DOCA-NaCl induced hypertension

Abstract Repeated treatment with 6-hydroxydopamine (6-HD) failed to influence the onset or maintenance of DOCA-NaCl induced hypertension in rats or to produce a sustained hypotension in normotensive rats. The DOCA-NaCl induced decrease in serum potassium and increase in urinary excretion and skeletal muscle water content were also unaffected by 6-HD. Measurements of adrenergic cardiovascular reactivity demonstrated a severe deficiency of sympathetic nerve function as a result of the 6-HD treatment. These results indicate that sympathetic postganglionic nerve function is not necessary for the pathogenesis or maintenance of DOCA-NaCl induced hypertension.

A specific increase in intraneuronal monoamine oxidase activity in the rat vas deferens following adrenalectomy

Abstract Bilateral adrenalectomy, but not adrenal demedullation, resulted in a significant increase (40%) in the monoamine oxidase (MAO) activity of the rat vas deferens. This increase was completely prevented by surgical denervation and also by daily steroid replacement therapy with dexamethasone. Hypophysectomy, adrenocorticotropic hormone (ACTH) or hypophysectomy plus ACTH, failed to affect MAO activity. It is concluded that bilateral adrenalectomy induces a specific increase in the intraneuronal MAO activity of the vas deferens, as a result of adrenal steroid insufficiency. Furthermore, the effects of steroid lack are not mediated indirectly through an enhanced secretion of ACTH from the pituitary gland.

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.

Acute effects of 6-hydroxydopa and its interaction with dopa on brain amine levels

Abstract The intravenous administration of 400 mg/kg of DL-6-hydroxydopa (6-OH-DOPA) to mice markedly depleted whole brain norepinephrine (NE). Whole brain levels of dopamine (DA) were not affected whereas 5-hydroxytryptamine (5-HT) levels were slightly elevated. These findings show that even after a high dose of 6-OH-DOPA only brain NE appears to be markedly affected. This action might be mediated indirectly, through the endogenous formation of 6-hydroxydopamine. DL-DOPA (DOPA), 400 mg/kg given intraperitoneally, failed to alter the whole brain level of NE, but depleted brain 5-HT while elevating brain DA. The increase in DA and reduction in 5-HT caused by DOPA were greatly potentiated by prior treatment with 6-OH-DOPA. Although the mechanism of this interaction is unknown, the enhanced effectiveness of DOPA following 6-OH-DOPA administration provides in vivo evidence that DOPA-induced depletion of 5-HT may be mediated by endogenously formed DA.

Chronic reserpine treatment on adrenergic neuronal and receptor function in the isolated perfused mesenteric blood vessels of the dog.

Abstract Chronic low dosage reserpine treatment significantly depressed the frequency-response curve to sympathetic nerve stimulation in the isolated perfused dog mesenteric and intestinal blood vessels. This neuronal depression was reversed by norepinephrine, indicating that chronic reserpine dosage fails to produce a drastic impairment of adrenergic nerve function. The dose-response curve to injected norepinephrine was not significantly altered, thus supersensitivity to norepinephrine following chronic reserpine treatment is not a common phenomenon in all vascular tissue. The pharmacological interaction of certain adrenergic agents with sympathetic neuronal and receptor mechanism appeared unaltered by reserpine.

Acute and chronic effects of hydrochlorothiazide on vascular adrenergic mechanisms

The acute and chronic effects of hydrochlorothiazide on adrenergic neuronal and receptor function in the isolated perfused dog mesenteric arteries have been characterized. Hydrochlorothiazide, 2.7 mg/min for 90 min, perfused directly into the arteries, failed to alter adrenergic mechanisms. Chronic oral treatment of dogs with hydrochlorothiazide, 10 mg/kg/day, for 6 months enhanced the frequency-response curve to periaterial nerve syimulation without affecting the vasoconstrictor responses to norepinephrine. However, this effect was no longer observable after an additional 6 months of treatment. Hydrochlorothiazide failed to affect the pharmacological interaction of certain adrenergic agents with sympathetic neuronal and receptor mechanisms. Also, the in vitro accumulation of tritium after incubation with [3H] norepinephrine in atria, ventricle and femoral arterial slices was unaltered by hydrochlorothiazide. The present findings do not support the proposal that hydrochlorothiazide inhibits peripheral sympathetic function.

Choline uptake in myocardial cell cultures

Abstract The uptake of [ 14 C]choline by myocardial cell cultures prepared from 7-day old embryonic chick hearts has been investigated. Choline uptake was blocked at 4°C, and at 37°C it was antagonized by hemicholinium-3 in a concentration-dependent manner. Over 90% of the accumulated radioactivity was soluble in acid or insoluble in chloroform, the remainder being primarily associated with lipid cellular constituents. Thin layer chromatography revealed the intracellular presence of unchanged choline and also indicated a considerable amount of metabolites. These observations resemble those reported for the accumulation of choline by cholinergic nerve elements, the kidney cortex and erythrocytes and suggest that cultured chick heart cells exhibit a similar transport process for the intracellular accumulation of choline.

Therapeutic Possibilities with Serotonergic Drugs

The majority of serotonergic drugs act either via blocking uptake of serotonin (5-hydroxytryptamine; 5-HT) into serotonergic neurons or by an action on a growing number of serotonin receptors. Based on operational (agonist and antagonist rank order), transductional (second messenger coupling) and structural (gene and amino acid sequence) criteria, four main types of serotonin receptors have been discerned. The responses mediated via many serotonin receptors are now well understood and this, in turn, has resulted in the development and use of serotonergic drugs in the therapy of several diseases, including anxiety and migraine, and in the prevention of vomiting caused by anticancer agents. Many other therapeutic avenues are being explored.