Antagonism by idazoxan at low dose but not high dose, of the natriuretic action of moxonidine

Abstract

1 Recent studies concerning the imidazoline receptor have utilized idazoxan as a specific imidazoline receptor antagonist. The aim of the present study was to describe the in vivo effects of various doses of idazoxan on renal function, in the presence and absence of moxonidine, an I, imidazoline receptor agonist. 2 In anaesthetized, unilaterally nephrectomized (7 to 10 days) Sprague Dawley rats, an intrarenal infusion of moxonidine (3 nmol kg-' min-') increased urine flow rate, sodium excretion and osmolar clearance without altering free water clearance. Pretreatment with intravenous idazoxan at 0.1 and 0.3 mg kg-' produced a dose-related decrease in the renal actions of moxonidine. However, a higher dose of idazoxan (1 mg kg-') was not as effective as the 0.3 mg kg-' dose in blocking the effects of moxonidine.3 In a separate series of experiments, the direct renal actions of idazoxan alone were investigated. Idazoxan at 0.3 mg kg-' failed to alter urine flow rate and sodium excretion. However, idazoxan at 1 mg kg-' produced a significant increase in urine flow rate and sodium excretion in association with an increase in osmolar clearance. 4 These results do not prove but are consistent with low doses of idazoxan antagonizing the sites stimulated by moxonidine (renal imidazoline receptors). However, at higher doses, idazoxan may function as a partial agonist and/or interact with other receptors to increase urine flow rate, independent of imidazoline receptor blockade. These studies underscore the importance of the dose of idazoxan administered when this antagonist is used as a tool to investigate imidazoline receptors.

Pharmacologic Characterization of Imidazoline Receptor Proteins Identified by Immunologic Techniques and Other Methodsa

“…Although the agonistic/antagonistic properties of these compounds at IRs are not known, idazoxan has been used as a specific antagonist to assess the function of I 1 ‐imidazoline receptors in vivo . 31,32 The upregulation of I 2 sites and IR proteins measured after idazoxan treatment is coherent with its possible antagonist activity at IRs. It is of interest that in contrast to idazoxan and LSL 60101, chronic treatment with cirazoline did not increase levels of ∼29‐kD protein.…”

The mechanism of action of α 2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

“…Preferential imidazole binding is characteristic to low doses of idazoxan (Bricca et al 1993), while doses larger then 0.3 mg/kg were shown to lack imidazoline effects (Allan et al 1996). Propranolol binds to 5-HT 1 receptors usually at high doses (Ginefri- Gayet and Gayet 1992;Jackson and Nutt 1992;Martin et al 1992), and sometimes even these are inefficient (Gartside and Cowen, 1990).…”

Biological significance of agmatine, an endogenous ligand at imidazoline binding sites

“…Radioligand binding studies succeeded in demonstrating both α 2 ‐adrenoceptors as well as imidazoline binding sites, where different distributions could be shown within the kidney ( Coupry et al ., 1990 ; Evans & Haynes, 1995 ; Ernsberger et al ., 1995 ). Moxonidine studies suggested a functional participation of imidazoline binding sites in natriuresis ( Allan et al ., 1993 ; 1996 ), but it is not yet clear whether moxonidine influences sodium excretion and urinary flow via a central and/or peripheral mechanism (reviewed by Smyth & Penner, 1999 ). In this context the question arises as to the renal function of agmatine, especially considering its demonstration in both brain and kidney ( Raasch et al ., 1995a ; Lortie et al ., 1996 ).…”