Vanillin and Vanillin Analogs Relax Porcine Coronary and Basilar Arteries by Inhibiting L-Type Ca<sup>2+</sup>Channels

Raffai, Gábor; Khang, Gilson; Vanhoutte, Paul M.

doi:10.1124/jpet.114.217935

Cited by 20 publications

(18 citation statements)

References 55 publications

(69 reference statements)

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“…The vanilloid moiety, both as an amine ( i.e ., 4-hydroxy-3-methoxybenzylamine or vanillyl amine) and as an alcohol ( i.e., 4-hydroxy-3-methoxybenzyl alcohol or vanillyl alcohol), is a well-known construct in many candidate anti-inflammatories (Pal et al, 2009; Tomohiro et al, 2013). Vanillyl alcohol itself is a natural anti-inflammatory found in ginger and in a wide variety of other botanicals utilized as an additive in foods, pharmaceuticals, and cosmetics (Jung et al, 2008; Raffai et al, 2015). Our compounds were all synthesized from vanillyl alcohol with the lipophilic (fatty amine) side chain derived from either phenethyl, phenoxyethyl, cyclohexylmethyl, or morpholinylethyl (Laskin et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Wohlman

Composto

Heck

et al. 2016

Toxicology and Applied Pharmacology

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Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants.

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Section: Discussionmentioning

confidence: 99%

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Wohlman

Composto

Heck

et al. 2016

Toxicology and Applied Pharmacology

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“…), while their endothelium‐independent vasodilator properties result from inhibition of L‐type Ca 2+ channels in vascular smooth muscle (Raffai et al . ).…”

Section: Nitric Oxidementioning

confidence: 97%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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“…In order to examine the effect of A769662 on calcium release from intracellular stores, rings were incubated with calcium-free solution (omitting CaCl 2 from control solution) for 5 min before the addition of phenylephrine (Hisayama, Takayanagi, & Okamoto, 1990;Low, Kwan, & Daniel, 1992). In a subset of experiments, the effect of A769662 on L-type calcium channels was estimated from contractions obtained in depolarizing (6 × 10 −2 M KCl) solutions at increasing calcium concentrations, after incubation in calcium-free solution (Raffai, Khang, & Vanhoutte, 2015).…”

Section: Isometric Tension Recordingsmentioning

confidence: 99%

Acute activation of endothelial AMPK surprisingly inhibits endothelium‐dependent hyperpolarization‐like relaxations in rat mesenteric arteries

Chen

Vanhoutte

Leung

2019

British J Pharmacology

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Background and Purpose Endothelium‐dependent hyperpolarizations (EDHs) contribute to the regulation of peripheral resistance. They are initiated through opening of endothelial calcium‐activated potassium channels (KCa); the potassium ions released then diffuse to the underlying smooth muscle cells, causing hyperpolarization and thus relaxation. The present study aimed to examine whether or not AMPK modulates EDH‐like relaxations in rat mesenteric arteries. Experimental Approach Arterial rings were isolated for isometric tension recording. AMPK activity and protein level were measured by ELISA and western blotting respectively. Key Results The AMPK activator, AICAR, reduced ACh‐induced EDH‐like relaxations and increased AMPK activity in preparations with endothelium; these responses were prevented by compound C, an AMPK inhibitor. AICAR inhibited relaxations induced by SKA‐31 (opener of endothelial KCa) but did not affect potassium‐induced, hyperpolarization‐attributable relaxations or increase AMPK activity in preparations without endothelium. A769662, another AMPK activator, not only caused a similar inhibition of relaxations to ACh and SKA‐31 in preparations with endothelium but also inhibited hyperpolarization‐attributable relaxations and augmented AMPK activity in rings without endothelium. Protein levels of total AMPKα, AMPKα1, or AMPKβ1/2 were comparable between preparations with and without endothelium. Conclusions and Implications Activation of endothelial AMPK, by either AICAR or A769662, acutely inhibits EDH‐like relaxations of rat mesenteric arteries. Furthermore, A769662 inhibits signalling downstream of smooth muscle hyperpolarization. In view of the major blunting effect of AMPK activation on EDH‐like relaxations, caution should be applied when administering therapeutic agents that activate AMPK in patients with endothelial dysfunction characterized by reduced production and/or bioavailability of NO.

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Vanillin and Vanillin Analogs Relax Porcine Coronary and Basilar Arteries by Inhibiting L-Type Ca²⁺Channels

Cited by 20 publications

References 55 publications

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Endothelial dysfunction and vascular disease - a 30th anniversary update

Acute activation of endothelial AMPK surprisingly inhibits endothelium‐dependent hyperpolarization‐like relaxations in rat mesenteric arteries

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Vanillin and Vanillin Analogs Relax Porcine Coronary and Basilar Arteries by Inhibiting L-Type Ca2+Channels

Cited by 20 publications

References 55 publications

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Endothelial dysfunction and vascular disease - a 30th anniversary update

Acute activation of endothelial AMPK surprisingly inhibits endothelium‐dependent hyperpolarization‐like relaxations in rat mesenteric arteries

Contact Info

Product

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Vanillin and Vanillin Analogs Relax Porcine Coronary and Basilar Arteries by Inhibiting L-Type Ca²⁺Channels