Lafutidine Facilitates Calcitonin Gene-Related Peptide (CGRP) Nerve-Mediated Vasodilation via Vanilloid-1 Receptors in Rat Mesenteric Resistance Arteries

Abstract

Abstract. Lafutidine is a histamine H 2 -receptor antagonist with gastric antisecretory and gastroprotective activity associated with activation of capsaicin-sensitive nerves. The present study examined the effect of lafutidine on neurotransmission of capsaicin-sensitive calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRPergic nerves) in rat mesenteric resistance arteries. Rat mesenteric vascular beds were perfused with Krebs solution and vascular endothelium was removed by 30-s perfusion with sodium deoxycholate. In preparations preconstricted by continuous perfusion of methoxamine (α 1 adrenoceptor agonist), perfusion of lafutidine (0.1 -10 µM) concentration-dependently augmented vasodilation induced by the periarterial nerve stimulation (PNS, 1 Hz) without affecting vasodilation induced by exogenous CGRP (10 pmol) injection. Perfusion of famotidine (H 2 -receptor antagonist, 1 -100 µM) had no effect on either PNS-induced or CGRP-induced vasodilation. Perfusion of lafutidine concentration-dependently augmented vasodilation induced by a bolus injection of capsaicin (vanilloid-1 receptor agonist, 30 pmol). The presence of a vanilloid-1 receptor antagonist, ruthenium red (10 µM) or capsazepine (5 µM), abolished capsaicin-induced vasodilation and significantly decreased the PNS-induced vasodilation. The decreased PNS-induced vasodilation by ruthenium red or capsazepine was not affected by perfusion of lafutidine. These results suggest that lafutidine facilitates CGRP nerve-mediated vasodilation by modulating the function of presynaptic vanilloid-1 receptors located in CGRPergic nerves.

Efficacy of lafutidine, a histamine H2-receptor antagonist, for taxane-induced peripheral neuropathy in patients with gynecological malignancies

“…Chemotherapy regimen at the time of lafutidine administration included paclitaxel plus carboplatin (TC) in 13 patients, dose-dense TC in three patients, docetaxel as maintenance chemotherapy following TC regimen in three patients, and docetaxel plus carboplatin (DC) in one patient. The median number of cycles of chemotherapy at the start of lafutidine administration was four (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Three patients complained of prolonged neuropathy after having completed the chemotherapy.…”

“…They concluded that paclitaxel may affect the ability of peripheral endings of sensory neurons to decrease the release of CGRP, which could contribute to the symptoms of neuropathy. Meanwhile, it has been reported that lafutidine facilitates nerve-mediated vasodilation by releasing CGRP via vanilloid-1 receptors [10,11]. Therefore, the effect of lafutidine on taxane-induced neuropathy may be deeply associated with CGRP, vasodilation causing changes in blood-flow, and functional changes in small-diameter sensory neurons.…”

Heteroreceptors Modulating CGRP Release at Neurovascular Junction: Potential Therapeutic Implications on Some Vascular-Related Diseases

“…In this case, histamine plays a dual role on the CGRP release where prejunctional activation of H 3 receptors inhibits the neurogenic vasodilation [116, 117], whereas H 2 receptors enhance the CGRP nerve-mediated vasodilation possible by an enhancement of prejunctional activity of TRPV1 receptors [118]. In any case, these pro- and antivasodilator effects by the same molecule could reflect a fine tuning of the CGRP release by the sympathetic nerves.…”

Protective Effects of Gastric Mucus

“…Although the exact mechanisms that underlie the gastroprotective activity of the secondgeneration H 2 -receptor antagonists are not well understood, recent findings suggest that the activation of capsaicin-sensitive sensory neurons is associated with their maintenance of gastric mucosal integrity (Fukushima et al, 2006;Harada et al, 2007;Murashima et al, 2009;Sugiyama et al, 2008). The gastrointestinal tract is known to possess a rich neural network, among which afferent neurons of extrinsic origin are reported to operate as the emergency protective system.…”