Acetaldehyde Induces an Endothelium-Dependent Relaxation of Superior Mesenteric Artery: Potential Role in Postprandial Hyperemia

Abstract

Acetaldehyde (AA) is a small, ubiquitous compound present in foods, beverages, as a gas phase combustion product, and also endogenously generated from metabolism as from ethanol (EtOH). Acetate is a short chain fatty acid derived from AA oxidation, and acetate levels were significantly higher in urine collected overnight with food provided ad libitum compared with urine collected after 9 h fasting. Feeding increases gastrointestinal blood flow, and thus, we explored the direct effects of AA (and acetate) in isolated murine superior mesenteric artery (SMA). Over the concentration range of 1–100 mM, AA strongly, and reversibly relaxed agonist-induced contractions of SMA including phenylephrine (PE), thromboxane A2 analog (U46,619) and high potassium (High K+) without toxicity. The sensitivity (EC50) but not the efficacy (>90% relaxation of PE-precontraction) of AA-induced relaxations was dependent on blood vessel (SMA was 3× more sensitive than aorta) and contractile agonist (PE EC50 = 3.3 ± 0.4 mM; U46,619 EC50 = 14.9 ± 1.5 mM; and High K+ EC50 = 17.7 ± 0.5 mM) yet independent of circadian cycle and sex. The most sensitive component of the AA-induced relaxation was inhibited significantly by: (1) a mechanically impaired endothelium; (2) nitric oxide synthase (NOS) inhibitor (L-NAME); and (3) a guanylyl cyclase (GC) inhibitor (ODQ). Both acetate and EtOH stimulated much weaker relaxations in SMA than did AA, yet these relaxations were significantly inhibited by L-NAME as well. Neither EtOH nor acetate relaxed pre-contracted aorta. Although neither cyanamide, a non-specific aldehyde dehydrogenase (ALDH) enzyme inhibitor, nor Alda-1, a specific activator of ALDH2 activity, had any effect on either sensitivity or efficacy of AA-induced relaxation in SMA, cyanamide significantly blocked both EtOH- and acetate-induced relaxations in SMA implicating a role of ALDH activity in vasorelaxation. These data show that AA relaxes SMA via an endothelium- and NO-dependent mechanism indicating that AA may be one component of the complex post-prandial hyperemia reflex via vasodilatation of mesenteric vasculature.

Current Knowledge on the Vascular Effects of Menthol

“…Its best known effect is vascular relaxation, a response typically found in pulmonary (Greenberg et al, 1993), mesenteric (Ru et al, 2008), cutaneous Altura, 1982, 1987) and cerebral blood vessels (Altura and Altura, 1999), which has been attributed to the potentiation of NO-dependent and NO-independent vasodilation pathways (Rocha et al, 2012;Tawakol et al, 2019). In certain vascular beds ethanol-induced vasodilation is rather attributed to its metabolite acetaldehyde, which mediates an endothelium-dependent relaxation (Jin et al, 2019) in mesenteric vessels. Furthermore, acetate, a metabolite of aldehyde also displays a moderate vasodilator response (Altura and Altura, 1982).…”

Pharmacologic Targeting of BET Proteins Attenuates Hyperuricemic Nephropathy in Rats

“…Brd2, Brd3 and Brd4 are three major members mediating a variety of biological responses of the BET family proteins ( Morgado-Pascual et al, 2019 ). As first step toward understanding the effect of I-BET151, a highly selective BET inhibitor, on the pathogenesis of HN, we examined the expression of Brd2, Brd3 and Brd4 in the kidneys of rats with or without HN.…”

“…Studies have shown that the transcription of genes involved in inflammation and other pathological processes in renal diseases are regulated by epigenetic changes ( Nangaku et al, 2017 ; Morgado-Pascual and Marchant, 2018 ). Epigenetic modifications, in particular histone acetylation, are dynamic processes in normal and diseased states ( Reddy and Natarajan, 2015 ; Morgado-Pascual et al, 2019 ). It is well documented that histone acetylation is positively regulated by histone transferases and negatively regulated by histone deacetylases ( Guo et al, 2019 ; Tang and Zhuang, 2019 ).…”

“…It is well documented that histone acetylation is positively regulated by histone transferases and negatively regulated by histone deacetylases ( Guo et al, 2019 ; Tang and Zhuang, 2019 ). The bromodomain and extraterminal (BET) proteins are epigenetic “readers,” which recognize and bind to acetylated lysine in histones and other proteins and then regulate gene transcription ( Morgado-Pascual et al, 2019 ). Among BET family of proteins, including bromodomain-containing protein (BRD)2, BRD3, Brd4, and the testis-specific BRDT, Brd4 is best studied and has been identified to be in the chronically injured kidney ( Xiong et al, 2016 ; Suarez-Alvarez et al, 2017 ; Morgado-Pascual et al, 2019 ).…”

“…The bromodomain and extraterminal (BET) proteins are epigenetic “readers,” which recognize and bind to acetylated lysine in histones and other proteins and then regulate gene transcription ( Morgado-Pascual et al, 2019 ). Among BET family of proteins, including bromodomain-containing protein (BRD)2, BRD3, Brd4, and the testis-specific BRDT, Brd4 is best studied and has been identified to be in the chronically injured kidney ( Xiong et al, 2016 ; Suarez-Alvarez et al, 2017 ; Morgado-Pascual et al, 2019 ). It has been reported that small-molecule inhibitors targeting BET such as I-BET and JQ1can inhibit many pathological processes by competitively binding to acetyl-lysine recognition motifs and disassociating BET proteins from chromatin.…”