© 1995 American Heart Association, Inc.
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Calcitonin Gene-Related Peptide Mediates Acetylcholine-Induced Endothelium-Independent Vasodilation in Mesenteric Resistance Blood Vessels of the Rat
From the First Department of Internal Medicine (M.T., T.E.) and the Department of Pharmacology (A.W.), Miyazaki (Japan) Medical College, and the Department of Hospital Pharmacy (H.K.), Okayama (Japan) University Medical School.
Correspondence to Hiromu Kawasaki, PhD, Department of Hospital Pharmacy, Okayama University Medical School, 2-5-1 Shikata-Cho, Okayama 700, Japan.
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
-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.
Key Words: acetylcholine • endothelium-independent vasodilation • calcitonin gene-related peptide • muscarinic receptor • rat mesenteric vascular bed
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