Calcitonin Gene-Related Peptide Mediated Neurogenic Vasorelaxation in the Isolated Canine Lingual Artery

Abstract

ABSTRACT-The nature of neurogenic relaxation was investigated in ring preparations of canine lingual artery. In all experiments, the preparations were previously treated with guanethidine (5 x 10-6 M) to block neurogenic constrictor responses. In the presence of norepinephrine (10-5 M) to induce tone, electrical stimulation (10 V, 4 to 16 Hz, for 45 sec) produced relaxation of the rings in an endothelium-independent fashion. The relaxant response in endothelium-denuded rings was not changed by propranolol (10-5 M), and atropine (10-5 M) did not affect the relaxation elicited by electrical stimulation in endothelium-intact rings. 1VG-monomethyl-L-arginine (10-4 M) or 1VG-nitro-L-arginine methyl ester (10-4 M), a nitric oxide (NO) synthase inhibitor, had no effect on the electrical stimulation-induced relaxation of endotheliumdenuded rings. Human calcitonin gene-related peptide (CGRP)-(8 -37) (2 x 10-8 M), a CGRP I-receptor antagonist, inhibited neurogenic relaxation of endothelium-denuded rings; substance P (10-6 M) failed to mimic the observed effect of electrical stimulation. The demonstrated effect of electrical stimulation was inhibited by glibenclamide (10-5 M), but not tetraethylammonium (2 x 10-4 M); glibenclamide abolished the relaxation in response to exogenous CGRP or the ATP-sensitive K+ channel opener cromakalim (10-6 M) in endothelium-denuded rings. Moreover, tetrodotoxin (3.13 x 10-6 M) inhibited the relaxation of endothelium-denuded rings induced by electrical stimulation. The relaxation was selectively inhibited when endogenous CGRP had been depleted from perivascular nerves by capsaicin (10-6 M). These results suggest that CGRP, but not NO, released from non-adrenergic non-cholinergic nerves by electrical stimulation produces relaxation of canine lingual artery that is mediated by activation of CGRP1 receptors.Keywords: Lingual artery, Calcitonin gene-related peptide, Glibenclamide, Adenosine 5 triphosphate-sensitive potassium channel, Non-adrenergic non-cholinergic nerve *To whom correspondence should be addressed .The inhibitory mechanical responses of the rabbit lingual artery consisted of two components; one is atropinesensitive but the other is a non-cholinergic component(1). This type of mixed dilator response is not unusual; it has been noted in a number of different tissues including the cat salivary gland (2), nasal mucosa (3), tongue (4) and the dog hind limb (5). The identity of the noncholinergic inhibitory transmitter in these tissues is not known. Calcitonin gene-related peptide (CGRP), a 37-amino acid peptide, is synthesized via the alternative processing of the primary RNA-transcript of the calcitonin gene (6, 7). CGRP has been shown to be widely distributed in the central and peripheral nervous system (8), and it also exists in nerve fibers throughout the cardiovascular system (9). CGRP is one of the most potent vasodilators known (10). The first goal of this study is to determine whether CGRP is involved in the neurogenic relaxation in canine lingual artery. Recently, Nelson et ...

Pathway‐specific effects of calcitonin gene‐related peptide on irideal arterioles of the rat

“…In the present study, increases in intracellular cyclic AMP, using forskolin, also caused hyperpolarizations of about 10 mV. Since hyperpolarization has been shown to be causal to CGRP‐induced vasodilatation in some vessels (Nelson et al 1990; Kitazono et al 1993; Kobayashi et al 1995), we tested the effects of CGRP after preconstriction with 30 him KCl, in which solution CGRP did not produce any hyperpolarization. Under these conditions, CGRP still produced a vasodilatation, suggesting that in iris arterioles, the vasodilatation does not result from the hyperpolarization.…”

“…This is secondary to receptor‐activated increases in cyclic AMP and protein kinase A (Quayle, Bonev, Brayden & Nelson, 1994; Miyoshi & Nakaya, 1995). The role of this hyperpolarization in the vasodilatory action of CGRP, however, varies between vascular beds, being causal to part or all of the dilatation in rabbit mesenteric arteries, rat basilar and dog lingual artery (Nelson et al 1990; Kitazono, Heistad & Faraci, 1993; Kobayashi et al 1995) and of no consequence to the dilatation in other vessels, such as the small mesenteric and renal arteries of the rat (Gao et al 1994; Lei, Mulvany & Nyborg, 1994; Gao, Nishimura, Suzuki & Nakai, 1995) and the rabbit ophthalmic artery (Zschauer et al 1992).…”

Calcitonin gene-related peptide activates different signaling pathways in mesenteric lymphatics of guinea pigs

“…However, the role of this hyperpolarization in the vasodilatory effect of CGRP varies between vascular beds. It has been shown to be causal in the dilation observed in mesenteric arteries of the rabbit, the lingual artery of the dog, and the basilar artery of the rat (32,33,38). In contrast to this, it has been shown to be of little if any consequence in the ophthalmic artery of the rabbit (62), the small mesenteric and renal arteries of the rat (20), and in rat irideal arterioles (26).…”

“…In the majority of blood vessels, application of CGRP has been reported to cause dilation through an endothelium-independent process. These vessels include cat cerebral (16,48), rat mesenteric (1,20,25,35), rat stomach mucosal (27), rabbit jejunal (34), dog basilar (40), dog lingual (33), and human uterine arteries (5). A primary signal transduction pathway involved in this form of CGRP activation is adenylate cyclase, which increases cAMP and cAMP-dependent protein kinase (PKA)-activating K ϩ channels including ATP-sensitive K ϩ (K ATP ϩ ) channels (37,38,41).…”

Receptors mediating CGRP‐induced relaxation in the rat isolated thoracic aorta and porcine isolated coronary artery differentiated by hα CGRP8–37

“…rat aorta) up to around nine (e.g. canine lingual artery; Kobayashi et al ., 1995), covering a range of species and tissue and making CGRP receptor classification more difficult. Part of this range may reflect differences in CRLR (calcitonin receptor like receptor) and the accessory protein RAMP, the combination of these two being required for a functional CGRP receptor (McLatchie et al ., 1998).…”