Structure‐activity relationships of vanilloid receptor agonists for arteriolar TRPV1

Abstract

BACKGROUND AND PURPOSE The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1‐mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca2+) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild‐type or TRPV1−/− mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca2+ in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK‐195 and JYL‐79) or were without effect (resiniferatoxin and JYL‐273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL‐1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…This high level of colocalization is consistent with the concept that TRPV1 activation in the dura stimulates CGRP release and subsequent vasodilatation (Dux et al, 2003). In addition to its presence in presynaptic terminals of trigeminal afferents, TRPV1 has also been detected, albeit at a much lower abundance, in arteriolar endothelium and smooth muscle (Kark et al, 2008;Cavanaugh et al, 2011;Czikora et al, 2012). Indeed, TRPV1 expressed in cochlear arterioles has been proposed to mediate the inner ear disturbances in migraine (Vass et al, 2004) It is noteworthy that migraine is comorbid with a number of CNS disease states such as epilepsy, which implies that central sites might also be involved in the triggering of migraine attacks.…”

Transient Receptor Potential Vanilloid-1 Channels Contribute to the Regulation of Acid- and Base-Induced Vasomotor Responses

“…Indeed, a definite role for TRPV1 in the mediation of vasomotor responses to exogenous and endogenous ligand agonists has been established. For example, in response to CAP, vasodilation was shown in rat skin [17] and mesenteric arteries [39], but vasoconstriction was seen in other vessels, e.g., rat skeletal muscle [17,40] or dog mesenteric and renal arteries [41]. Similar vasomotor effects were also found with endogenous TRPV1 agonists, such as the arachidonic acid metabolites anandamide and 20-hydroxyeicosatetraenoic acid [42,43].…”

Vanilloid Receptor-1 (TRPV1) Expression and Function in the Vasculature of the Rat

“…We first tested arteries present within the gracilis muscle tissue, because we have previously provided data to suggest functional TRPV1 expression in skeletal muscle arteries (Czikora et al 2012;Kark et al 2008;Figure 9. Expression of TRPV1 in mesenteric blood vessels.…”

“…The vasoconstrictive properties of TRPV1, however, were much lesswell characterized. Nonetheless, we (Czikora et al 2012;Kark et al 2008) and others (Cavanaugh et al 2011) have recently shown that functional TRPV1 is expressed in arteriolar smooth muscle cells, where its activation results in an increase in intracellular Ca 2+ concentration and vasoconstriction.…”