Abstract
Formaldehyde (FA), the smallest aldehyde, is generated endogenously, and is widespread in the environment in foods, beverages and as a gas phase product of incomplete combustion. The main metabolite of FA, formate, was increased significantly in murine urine (∼3×) after overnight feeding. Because feeding increases mesenteric blood flow, we explored the direct effects of FA in isolated murine superior mesenteric artery (SMA). Over the concentration range of 30–1,200 μM, FA strongly and reversibly relaxed contractions of SMA induced by three different agonists: phenylephrine (PE), thromboxane A2 analog (U46,619) and high potassium (60K, 60 mM K+). Formate (to 1.5 mM) induced a modest relaxation. FA (>1,500 μM) irreversibly depressed vascular function in SMA indicating vasotoxicity. The sensitivity (EC50) but not the efficacy (% relaxation) of FA-induced relaxations was dependent on blood vessel type (SMA << aorta) and contractile agonist (PE, EC50= 52 ± 14 μM; U46,619, EC50= 514 ± 129 μM; 60K, EC50= 1,093 ± 87 μM). The most sensitive component of FA vasorelaxation was within physiological levels (30–150 μM) and was inhibited significantly by: (1) mechanically impaired endothelium; (2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); (3) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); (4) guanylyl cyclase (GC) inhibitor (ODQ); and, (5) K+ channel inhibitor (BaCl2). A similar mechanism of SMA vasorelaxation was stimulated by the TRPA1 agonist cinnamaldehyde. Positive TRPA1 immunofluorescent staining and gene-specific sequence were present in SMA but not in aorta. These data indicate FA, but not formate, robustly relaxes SMA via a sensitive TRPA1- and endothelium-dependent mechanism that is absent in aorta. Thus, as FA levels increase with feeding, FA likely contributes to the physiological reflex of post-prandial hyperemia via SMA vasodilatation.
Highlights
Formaldehyde (FA) is the simplest aldehyde and the concentration of FA in the blood ranges from 0.0127 to 2.28 μg/mL (1.9 to 5.4 mg/L; or 63–179 μM) (Wang et al, 2011; Kleinnijenhuis et al, 2013)
Formate is the primary metabolite of FA, and formate in the urine is a consequence of endogenous FA metabolism, so we measured urinary formate by guanylyl cyclase (GC)-MS
We found that feeding significantly increased the urinary levels of formate indicating a major source of endogenous FA is either directly from food or related to feeding, e.g., metabolism of food constituents, intermediary metabolism, etc
Summary
Formaldehyde (FA) is the simplest aldehyde and the concentration of FA in the blood ranges from 0.0127 to 2.28 μg/mL (1.9 to 5.4 mg/L; or 63–179 μM) (Wang et al, 2011; Kleinnijenhuis et al, 2013). FA can be found in food and beverages (likely the largest quantitative source of exogenous FA) and is metabolically derived (see Conklin et al, 2011). Because FA is toxic in cultured endothelial cells (inhibition of mitosis, increased apoptosis), vascular smooth muscle cells and cardiomyocytes (Conklin et al, 1998), it is, speculated that endogenously generated FA induces endothelium dysfunction by which it accelerates diabetic complications such as atherosclerosis (Deng and Yu, 1999). FA induces a concentration-dependent relaxation in isolated blood vessels (Tani, 1981; Conklin et al, 2004; Zhang et al, 2018) yet the relevance of this effect in vascular physiology is unclear
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