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Chronic Elevation of Endothelin-1 Alone May Not Be Sufficient to Impair Endothelium-Dependent Relaxation.

ABSTRACT: Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide considered to be causally implicated in hypertension and the development of cardiovascular disease. Increased ET-1 is commonly associated with reduced NO bioavailability and impaired vascular function; however, whether chronic elevation of ET-1 directly impairs endothelium-dependent relaxation (EDR) remains elusive. Herein, we report that (1) prolonged ET-1 exposure (ie, 48 hours) of naive mouse aortas or cultured endothelial cells did not impair EDR or reduce eNOS (endothelial NO synthase) activity, respectively (P>0.05); (2) mice with endothelial cell-specific ET-1 overexpression did not exhibit impaired EDR or reduced eNOS activity (P>0.05); (3) chronic (8 weeks) pharmacological blockade of ET-1 receptors in obese/hyperlipidemic mice did not improve aortic EDR or increase eNOS activity (P>0.05); and (4) vascular and plasma ET-1 did not inversely correlate with EDR in resistance arteries isolated from human subjects with a wide range of ET-1 levels (r=0.0037 and r=-0.1258, respectively). Furthermore, we report that prolonged ET-1 exposure downregulated vascular UCP-1 (uncoupling protein-1; P<0.05), which may contribute to the preservation of EDR in conditions characterized by hyperendothelinemia. Collectively, our findings demonstrate that chronic elevation of ET-1 alone may not be sufficient to impair EDR.

SUBMITTER: Grunewald ZI

PROVIDER: S-EPMC6854321 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Chronic Elevation of Endothelin-1 Alone May Not Be Sufficient to Impair Endothelium-Dependent Relaxation.

Grunewald Zachary I ZI Jurrissen Thomas J TJ Woodford Makenzie L ML Ramirez-Perez Francisco I FI Park Lauren K LK Pettit-Mee Ryan R Ghiarone Thaysa T Brown Scott M SM Morales-Quinones Mariana M Ball James R JR Staveley-O'Carroll Kevin F KF Aroor Annayya R AR Fadel Paul J PJ Paradis Pierre P Schiffrin Ernesto L EL Bender Shawn B SB Martinez-Lemus Luis A LA Padilla Jaume J

Hypertension (Dallas, Tex. : 1979) 20191021 6

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide considered to be causally implicated in hypertension and the development of cardiovascular disease. Increased ET-1 is commonly associated with reduced NO bioavailability and impaired vascular function; however, whether chronic elevation of ET-1 directly impairs endothelium-dependent relaxation (EDR) remains elusive. Herein, we report that (1) prolonged ET-1 exposure (ie, 48 hours) of naive mouse aortas or cultured endothelial cells did no ...[more]

PMID: 31630572

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Project description: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.

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Chronic Elevation of Endothelin-1 Alone May Not Be Sufficient to Impair Endothelium-Dependent Relaxation.

Publications

Chronic Elevation of Endothelin-1 Alone May Not Be Sufficient to Impair Endothelium-Dependent Relaxation.

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