Capsaicin Inhibits Multiple Voltage-Gated Ion Channels in Rabbit Ventricular Cardiomyocytes in TRPV1-Independent Manner
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Capsaicin is a naturally occurring alkaloid derived from chili pepper which is responsible for its hot, pungent taste. It exerts multiple pharmacological actions, including pain-relieving, anti-cancer, anti-inflammatory, anti-obesity, and antioxidant effects. Previous studies have shown that capsaicin significantly affects the contractility and automaticity of the heart and alters cardiovascular functions. In this study, the effects of capsaicin were investigated on voltage-gated ion currents in rabbit ventricular myocytes. Capsaicin inhibited rapidly activated (IKr) and slowly activated (IKs) K+ currents and transient outward (Ito) K+ current with IC50 values of 3.4 µM,14.7 µM, and 9.6 µM, respectively. In addition, capsaicin, at higher concentrations, suppressed voltage-gated Na+ and Ca2+ currents and inward rectifier IK1 current with IC50 values of 42.7 µM, 34.9 µM, and 38.8 µM, respectively. Capsaicin inhibitions of INa, IL-Ca, IKr, IKs, Ito, and IK1 were not reversed in the presence of capsazepine (3 µM), a TRPV1 antagonist. The inhibitory effects of capsaicin on these currents developed gradually, reaching steady-state levels within 3 to 6 min, and the recoveries were usually incomplete during washout. In concentration-inhibition curves, apparent Hill coefficients higher than unity suggested multiple interaction sites of capsaicin on these channels. Collectively, these findings indicate that capsaicin affects cardiac electrophysiology by acting on a diverse range of ion channels and suggest that caution should be exercised when capsaicin is administered to carriers of cardiac channelopathies or to individuals with arrhythmia-prone conditions, such as ischemic heart diseases.Keywords:
Capsaicin
Capsazepine
4-Aminopyridine
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Capsazepine
Resiniferatoxin
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TRPV1 channels are expressed in nociceptive neurons and are involved in sensing noxious thermal and chemical stimuli. Because of their roles in the pain pathway, these channels have emerged as important therapeutic targets for the development of new analgesics. Capsaicin, the pungent ingredient in hot chili peppers, is a known agonist of TRPV1. Transgenic C. elegans nematodes expressing rat TRPV1 in sensory neurons exhibit a reversal response upon exposure to capsaicin. Pre‐incubation of the worms with capsazepine, a selective TRPV1 antagonist, potently blocks their response to capsaicin. Thus, we are using capsaicin‐induced reversal behavior as an assay to test the effectiveness of novel TRPV1 ligands. Data on the effectiveness of N‐cyanoguanidine analogs of capsaicin, capsazepine, SB 366791 and AMG 9810 will be presented.
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Pelargonic acid vanillylamide is like capsaicin a natural capsaicinoid from chili peppers and commonly used in food additives to create a hot sensation, even in self‐defense pepper sprays and as an alternative to capsaicin in medical products for topical treatment of pain. Although the chemical structures of both compounds are similar, preclinical data suggest that capsaicin is the more potent compound. We therefore performed voltage‐clamp recordings using cells transfected with the human vanilloid receptor TRPV1 in order to assess the responses of pelargonic acid vanillylamide and capsaicin at the receptor level. We provide evidence that at the molecular target TRPV1, the concentration‐response curves, kinetics of current activation, as well as inhibition by the competitive antagonist capsazepine were not significantly different between the two capsaicinoids. We suggest that the different effects of the two capsaicinoids observed in previous studies may rather be due to different physicochemical or pharmacokinetic properties than to different pharmacological profiles at the receptor level. Copyright © 2012 John Wiley & Sons, Ltd.
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The site of action of resiniferatoxin (RTX) and capsaicin and the pharmacological consequences of the resultant tachykinin release were examined in the guinea pig trachea. RTX and capsaicin were both potent and efficacious contractors of isolated tracheal smooth muscle. RTX was about 20-fold more potent than capsaicin, with -log (M) EC50 values of 8.88 +/- 0.09 (n = 14) and 7.55 +/- 0.07 (n = 14), respectively. The putative capsaicin receptor antagonist capsazepine (10 microM) effectively inhibited responses to both RTX and capsaicin in a competitive fashion. The -log (M) pKB values for capsazepine against resiniferatoxin and capsaicin were 6.28 +/- 0.25 and 6.04 +/- 0.13, respectively. Contractile responses to RTX and capsaicin were unaffected by the NK-1 antagonist CP 96345 (0.3 microM), partially inhibited by the NK-2 antagonist SR 48968 (0.3 microM) but nearly abolished by a combination of the antagonists. Capsaicin and RTX desensitized tissues to subsequent additions of either capsaicin (1 microM) or RTX (0.1 microM). Capsaicin showed maximal desensitization at 1 microM, and RTX at 0.1 microM. This study shows that RTX is a potent activator of capsaicin-sensitive tachykinin-containing nerves in the airways. The site of action of RTX and capsaicin appears to be a receptor sensitive to capsazepine. Moreover, RTX and capsaicin both release tachykinins that act on both NK-1 and NK-2 receptor subtypes.
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T-type calcium (Cav 3) and transient receptor potential vanilloid-1 (TRPV1) channels play central roles in the control of excitability in the peripheral nervous system and are regarded as potential therapeutic pain targets. Modulators that either activate or inhibit TRPV1-mediated currents display analgesic properties in various pain models despite opposing effects on their connate target, TRPV1. We explored the effects of TRPV1-active compounds on Cav 3-mediated currents.Whole-cell patch clamp recordings were used to examine the effects of TRPV1-active compounds on rat dorsal root ganglion low voltage-activated calcium currents and recombinant Cav 3 isoforms in expression systems.The classical TRPV1 agonist capsaicin as well as TRPV1 antagonists A-889425, BCTC, and capsazepine directly inhibited Cav 3 channels. These compounds altered the voltage-dependence of activation and inactivation of Cav 3 channels and delayed their recovery from inactivation, leading to a concomitant decrease in T-type current availability. The TRPV1 antagonist capsazepine potently inhibited Cav 3.1 and 3.2 channels (KD < 120 nM), as demonstrated by its slow off rate. In contrast, neither the TRPV1 agonists, Palvanil and resiniferatoxin, nor the TRPV1 antagonist AMG9810 modulated Cav 3-mediated currents.Analgesic TRPV1-active compounds inhibit Cav 3 currents in native and heterologous systems. Hence, their analgesic effects may not be exclusively attributed to their actions on TRPV1, which has important implications in the current understanding of nociceptive pathways. Importantly, our results highlight the need for attention in the experimental design used to address the analgesic properties of Cav 3 channel inhibitors.
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