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Calcitonin Gene-Related Peptide Mediates Acetylcholine-Induced Endothelium-Independent Vasodilation in Mesenteric Resistance Blood Vessels of the Rat

1995; Lippincott Williams & Wilkins; Volume: 76; Issue: 6 Linguagem: Inglês

10.1161/01.res.76.6.935

1524-4571

Makoto Takenaga, Hiromu Kawasaki, Akihiko Wada, Tanenao Eto,

Receptor Mechanisms and Signaling

Abstract The role of calcitonin gene-related peptide (CGRP)–containing vasodilator nerves in acetylcholine chloride (ACh)–induced vasodilation was studied in the perfused mesenteric vascular bed isolated from the rat. Bolus infusions of ACh at smaller doses (0.1 and 1 nmol) produced rapid and short-lived vasodilation. However, larger doses (10 and 100 nmol) of ACh caused a rapid and subsequent long-lasting vasodilator response in which the duration of vasodilation was prolonged in a concentration-dependent manner. Pretreatment with capsaicin (1 μmol/L for 20 minutes) significantly shortened the duration of vasodilator response to ACh but did not affect the initial rapid phase of ACh-induced vasodilation. Chemical removal of the vascular endothelium by perfusion with sodium deoxycholate (1.75 to 1.80 mg/mL) for 30 seconds and subsequent treatment with N ω -nitro- l -arginine (100 μmol/L) to inhibit nitric oxide synthesis abolished the initial rapid vasodilator action of ACh at any given concentration. However, in the same preparation, increasing concentrations (from 1 to 1000 nmol) of ACh produced only the long-lasting vasodilator responses in a concentration-dependent manner. This long-lasting vasodilator response to ACh infusion was abolished by capsaicin pretreatment (1 μmol/L), human CGRP[8-37] (CGRP receptor antagonist, 1 μmol/L), and atropine (muscarinic ACh receptor antagonist, 1, 10, and 100 nmol/L) but not by hexamethonium (nicotinic ACh receptor antagonist, 1 and 10 μmol/L). In the preparations without endothelium, the bolus infusion of ACh (300 nmol for 30 seconds) evoked a long-lasting vasodilation and release of CGRP-like immunoreactivities into the perfusate. These results suggest that the ACh-induced vasorelaxation consists of two elements: an initial transient endothelium-dependent component and a secondary long-lasting endothelium-independent component. Moreover, ACh activates muscarinic receptors located on CGRP-containing neurons to release CGRP, which then acts at CGRP receptors on vascular smooth muscles to cause the endothelium-independent vasodilation.