Pharmacological analysis of the inhibition produced by moxonidine and agmatine on the vasodepressor sensory CGRPergic outflow in pithed rats

Abstract

Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T₉--T₁₂) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I₁ and I₂ receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i.v. with 25mg/kg gallamine and 2mg/kg⋅min hexamethonium) received i.v. continuous infusions of methoxamine (20μg/kg⋅min) followed by physiological saline (0.02ml/min), moxonidine (1, 3, 10 or 30μg/kg⋅min) or agmatine (1000 or 3000μg/kg⋅min). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V; 2ms) of the spinal cord (T₉-T₁₂) produced frequency-dependent vasodepressor responses which were: (i) unchanged during saline infusion; and (ii) inhibited during the above infusions of moxonidine or agmatine. Moreover, using i.v. administrations, the inhibition by 3μg/kg⋅min moxonidine or 3000μg/kg⋅min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1-1µg/kg) was: (i) unaltered after saline (1ml/kg), rauwolscine (300μg/kg; α₂-adrenoceptor antagonist) or BU224 (300μg/kg; imidazoline I₂ receptor antagonist); and (ii) reversed after AGN 192403 (3000μg/kg; imidazoline I₁ receptor antagonist). This reversion was relatively more pronounced after AGN 192403 plus rauwolscine. These blocking doses of antagonists lacked any effects on the electrically-induced vasodepressor responses. Therefore, the inhibition of the vasodepressor sensory CGRPergic outflow by moxonidine and agmatine is mainly mediated by prejunctional imidazoline I₁ receptors on perivascular sensory nerves.

Keywords: (+/-)−2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride (AGN 192403; 2-(4,5-Dihydroimidazol-2-yl)quinoline hydrochloride (BU224 hydrochloride; Agmatine; Imidazoline receptors; Moxonidine; Pithed rat; PubChem CID: 11957452); PubChem CID: 11957470); Vasodepressor sensory CGRPergic outflow; agmatine sulphate salt (PubChem CID: 2794990); gallamine triethiodide (PubChem CID: 6172); hexamethonium (PubChem CID: 3604); methoxamine (PubChem CID: 6082), moxonidine hydrochloride (PubChem CID: 11231255); rauwolscine hydrochloride (PubChem CID: 197067).