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

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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 25 mg/kg gallamine and 2 mg/kg·min hexamethonium) received i.v. continuous infusions of methoxamine (20 μg/kg·min) followed by physiological saline (0.02 ml/min), moxonidine (1, 3, 10 or 30 μg/kg·min) or agmatine (1000 or 3000 μg/kg·min). Under these conditions, electrical stimulation (0.56–5.6 Hz; 50 V; 2 ms) 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 3 μg/kg·min moxonidine or 3000 μg/kg·min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1–1 μg/kg) was: (i) unaltered after saline (1 ml/kg), rauwolscine (300 μg/kg; α2-adrenoceptor antagonist) or BU224 (300 μg/kg; imidazoline I2 receptor antagonist); and (ii) reversed after AGN 192403 (3000 μg/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.

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