Is there a peripheral site of action contributing to the voiding effects of α2-adrenoceptor agonists and antagonists?

PURPOSE: Since it has not been established whether there is an effect on voiding exerted by direct stimulation or blockade of α2-adrenoceptors in the bladder and urethra, MK-467, a peripherally acting α2-adrenoceptor antagonist not penetrating into the CNS, was used to test whether part of the voiding effects of systemically given α2-adrenoceptor agonists is peripheral. METHODS: Urodynamic recordings from 27 conscious male adult C57/Bl J-strain mice were performed. After vehicle (saline) administration, two groups of animals were treated first with the selective α2-adrenoceptor agonist dexmedetomidine (Dex) and then with the selective α2-adrenoceptor antagonists atipamezole (Ati) or MK-467. Two other groups were first treated with Ati or MK-467 and then with Dex. RESULTS: Treatment with vehicle or α2-adrenoceptor antagonists alone did not affect micturition parameters. All animals treated first with Dex-developed overflow incontinence. Treatment with Ati after Dex reversed almost totally the effects of Dex on all voiding parameters, but treatment with MK-467 after Dex showed no detectable improvement. Treatment with Dex after Ati had no effect on any voiding parameter except maximal pressure. When mice were treated with Dex after MK-467, overflow incontinence was produced in seven of eight animals studied. CONCLUSIONS: The absence of functionally relevant peripheral effects on voiding mediated via α2-adrenoceptors is supported by the finding that neither Ati nor MK-467 alone had any effect on micturition parameters and by the inability of MK-467 to inhibit the effects of Dex, suggesting that the relevant Dex effects were exerted within the CNS.

Comparison of simultaneous measurement of mouse locomotor activity by radiotelemetry and photobeam methods.

INTRODUCTION: Locomotor activity recordings are widely used in different physiological and pharmacological studies. There are two mainly used methods - radiotelemetry and photobeam recording systems. To our knowledge, these methods have not previously been directly and simultaneously compared. METHODS: The current study consisted of a comparison of locomotor activity data gained simultaneously from radiotelemetry and photobeam recordings, firstly from a robotic device and secondly from an animal experiment performed with mice. RESULTS: Data gained from the animal study showed relatively high variation, but overall agreement between the methods was good. DISCUSSION: The two methods were cross-validated in the current study. The data gained from both methods were in good general agreement. However, in an animal experiment, e.g. when sedative drugs or other behavior-modifying interventions are used, one should interpret the results with caution as alterations in animal behavior (e.g. in grooming) may possibly not be picked up similarly by the two methods.

Potentiation of Glibenclamide Hypoglycaemia in Mice by MK-467, a Peripherally Acting Alpha2-Adrenoceptor Antagonist.

Pharmacological antagonism and genetic depletion of pancreatic α2A-adrenoceptors increase insulin secretion in mice and enhance the insulinotropic action of glibenclamide, a representative of the sulphonylurea class of insulin secretagogues used in the therapy of type 2 diabetes. Antagonism of α2-adrenoceptors in the central nervous system (CNS) causes tachycardia and hypertension, making generalized α2-adrenoceptor blockade unfavourable for clinical use despite its potential to decrease blood glucose levels. The purpose of this study was to test the acute effects of the peripherally acting α2-adrenoceptor antagonist MK-467 alone and in combination with glibenclamide in non-diabetic C57BL/6N mice. Cardiovascular safety was assessed in freely moving mice with radiotelemetry. Dose-dependent decreases in blood glucose and increases in plasma insulin concentrations were seen with the combination of MK-467 and glibenclamide; the combinations were much more potent than glibenclamide or MK-467 alone. Furthermore, MK-467 had no effect on mean arterial pressure or heart rate in freely moving mice and did not prevent the centrally mediated hypotensive effect of the α2-adrenoceptor agonist medetomidine. Thus, peripheral blockade of α2-adrenoceptors does not evoke the same cardiovascular adverse effects as antagonism of CNS α2-adrenoceptors. The current results indicate that the combined use of small doses of a peripherally acting α2-adrenoceptor antagonist with a sulphonylurea drug could provide a novel option for the treatment of type 2 diabetes, especially in patients with increased tonic α2-adrenoceptor-mediated inhibition of insulin secretion.