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. 2019 Mar 20;14(3):e0214336.
doi: 10.1371/journal.pone.0214336. eCollection 2019.

Effects of ethanol and ethanol metabolites on intrinsic function of mesenteric resistance arteries

Jonathan M Eby  1   2 , Matthias Majetschak  3   4
Affiliations

Effects of ethanol and ethanol metabolites on intrinsic function of mesenteric resistance arteries

Jonathan M Eby et al. PLoS One. .

Abstract

Evidence suggests that ethanol-induced hypertension is associated with increased cardiovascular responsiveness to vasopressors in vivo and enhanced reactivity of isolated arteries to vasopressors ex vivo. The underlying mechanisms are not well understood and the contribution of ethanol metabolites to vascular effects induced by ethanol consumption are unclear. Mesenteric resistance arteries were harvested from Sprague-Dawley rats. Pressure myography was utilized to test effects of ethanol, acetaldehyde and phosphatidylethanol on myogenic tone and on vasoconstriction induced by phenylephrine, arginine vasopressin (aVP), endothelin-1 and KCl. Ethanol, acetaldehyde and phosphatidylethanol concentrations were monitored during the experiments. Ethanol concentrations in the vessel bath decreased with a half-life of 25min; acetaldehyde and phosphatidylethanol concentrations remained constant. Pretreatment with ethanol dose-dependently increased the potency of phenylephrine to induce vasoconstriction 4-fold (p<0.01). These effects were comparable when arteries were pre-treated with a single dose of ethanol for 30min and when ethanol concentrations were kept constant during 30min and 60min of pretreatment. While ethanol also dose-dependently increased the potency of aVP to induce vasoconstriction 1.7-fold (p<0.05), it did not affect vasoconstriction induced by endothelin-1 or KCl. Acetaldehyde pre-treatment (30 min) dose-dependently increased the potency of phenylephrine to induce vasoconstriction 2.7-fold (p<0.01) but did not affect other vasoconstrictor responses. Phosphatidylethanol did not affect any vasoconstrictor responses. Ethanol and its metabolites did not affect myogenic tone. These data suggest that ethanol and acetaldehyde selectively sensitize intrinsic constrictor responses upon activation of vascular α1-adrenergic and/or vasopressin receptors at clinically relevant concentrations. Our findings support the concept that enhanced vasoreactivity to vasoactive hormones contributes to the development of hypertension induced by ethanol consumption. Ex vivo exposure of resistance arteries to ethanol and acetaldehyde resembles effects of chronic ethanol consumption on intrinsic vascular function, and thus could serve as test platform to evaluate interventions aimed to mitigate vascular effects associated with ethanol consumption.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Effects of ethanol (EtOH) on phenylephrine-induced constriction of mesenteric resistance arteries.
Data are mean ± SEM. A. EtOH concentrations in the vessel bath during pressure myography experiments. Arteries were pressurized to 80 mmHg, pretreated for 30 min with a single dose of 100 mM EtOH and exposed to increasing doses of phenylephrine (PE). Squares: EtOH concentrations (mM) in the vessel bath, n = 3–5. Circles: Vasoconstriction in % of the outer diameter (o.d.) in response to increasing doses of PE (n = 5). B. PE-induced constriction in % of the o.d. in arteries pretreated with single doses of EtOH for 30 min, as in A. Vehicle—n = 5; 17.4 mM EtOH–n = 3; 50 mM EtOH–n = 5; 100 mM EtOH–n = 5. C. EC50 concentrations for the vasoconstrictor effects of PE (mM) from dose-response curves in B. *: p<0.05 vs. vehicle. D. Ethanol concentrations (open circles: 100 mM EtOH; grey circles: 17.4 mM EtOH) were measured in 5 min intervals and maintained constant by adding ethanol to the vessel bath to account for evaporative losses. N = 3. E. PE-induced constriction in % of the o.d. in arteries pretreated with constant concentrations of EtOH for 30 min. Vehicle–n = 5; 17.4 mM EtOH–n = 3; 100 mM EtOH–n = 4. F. EC50 concentrations for the vasoconstrictor effects of PE (mM) from dose-response curves in E. *: p<0.05 vs. vehicle. G. PE-induced constriction in % of the o.d. in arteries pretreated with constant concentrations of EtOH for 60 min. Vehicle–n = 3; 17.4 mM EtOH–n = 3; 100 mM EtOH–n = 3. H. EC50 concentrations for the vasoconstrictor effects of PE (mM) from dose-response curves in G. *: p<0.05 vs. vehicle.
Fig 2
Fig 2. Effects of acetaldehyde (AcH) and phosphatidylethanol (PEth) on phenylephrine-induced constriction of mesenteric resistance arteries.
Pressure myography experiments with arteries pressurized to 80 mmHg. Data are mean ± SEM. A. AcH concentrations (μM) in the vessel bath during the time frame of the experimental procedure (30 min pretreatment followed by stimulation with increasing doses of PE), n = 6 for each concentration. B. PE-induced constriction in % of the o.d. in arteries pretreated with AcH for 30 min. Vehicle—n = 4; 0.1 μM AcH–n = 3; 1 μM AcH–n = 4; 5 μM AcH–n = 4, 10 μM AcH–n = 3. C. EC50 concentrations for the vasoconstrictor effects of PE (nM) from dose-response curves in B. *: p<0.05 vs. vehicle. D. PEth concentrations (μM) in the vessel bath during the time frame of the experimental procedure (30 min pretreatment followed by stimulation with increasing doses of PE), n = 6–9. E. PE-induced constriction in % of the o.d. in arteries pretreated with PEth for 30 min. Vehicle—n = 4; 0.25 μM PEth–n = 4; 1 μM PEth–n = 4; 2.1 μM PEth–n = 5. F. EC50 concentrations for the vasoconstrictor effects of PE (nM) from dose-response curves in D.
Fig 3
Fig 3. Effects of ethanol (EtOH), acetaldehyde (AcH) and phosphatidylethanol (PEth) on other vasoconstrictor effects and myogenic tone in mesenteric resistance arteries.
Pressure myography experiments with arteries pressurized to 80 mmHg. Data are mean ± SEM. A. aVP-induced constriction in % of the outer diameter (o.d.) in arteries pretreated with single doses of EtOH for 30 min, as in Fig 1. Vehicle—n = 5; 17.4 mM EtOH–n = 5; 50 mM EtOH–n = 4; 100 mM EtOH–n = 5. B. EC50 concentrations for the vasoconstrictor effects of aVP (nM) from dose-response curves in A. *: p<0.05 vs. vehicle. C. aVP-induced constriction in % of the o.d. in arteries pretreated with AcH (10 μM, n = 6) or PEth (2.1 μM, n = 4) for 30 min. Vehicle–n = 6. D. Endothelin-1-induced constriction in % of the o.d. in arteries pretreated with EtOH (100 mM, n = 5), AcH (10 μM, n = 3) or PEth (2.1 μM, n = 3) for 30 min. Vehicle–n = 7. E. KCl-induced constriction in % of the o.d. in arteries pretreated with EtOH (100 mM, n = 3), AcH (10 μM, n = 3) or PEth (2.1 μM, n = 3) for 30 min. F. Effects of EtOH (100 mM, n = 3), AcH (10 μM, n = 3) and PEth (2.1 μM, n = 3) on myogenic tone. Vehicle–n = 3. Arteries were pretreated for 30 min. Data are expressed as % change of o.d. when arteries were exposed to various pressures (100% = o.d. at 80 mmHg).
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