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Alcohol Binge-Induced Cardiovascular Dysfunction Involves Endocannabinoid-CB1-R Signaling

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Alcohol Binge-Induced Cardiovascular Dysfunction Involves Endocannabinoid-CB1-R Signaling

Janos Paloczi et al. JACC Basic Transl Sci.

Abstract

Excessive binge alcohol drinking may adversely affect cardiovascular function. In this study we characterize the detailed hemodynamic effects of an acute alcohol binge in mice using multiple approaches and investigate the role of the endocannabinoid-cannabinoid 1 receptor (CB1-R) signaling in these effects. Acute alcohol binge was associated with elevated levels of cardiac endocannabinoid anandamide and profound cardiovascular dysfunction lasting for several hours and redistribution of circulation. These changes were attenuated by CB1-R antagonist or in CB1-R knockout mice. Our results suggest that a single alcohol binge has profound effects on the cardiovascular system, which involve endocannabinoid-CB1-R signaling.

Keywords: 2-AG, 2-arachidonyl glycerol; AEA, anandamide; CB1-R (CB1), cannabinoid 1 receptor; CB2-R (CB2), cannabinoid 2 receptor; EF, ejection fraction; LV, left ventricle; MAP, mean arterial pressure; P-V, pressure-volume; PRSW, preload recruitable stroke work; TPR, total peripheral resistance; binge alcohol drinking; cannabinoids; contractility; dP/dtmax, maximal slope of pressure increment; endocannabinoids.

Figures

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Figure 1
Figure 1
Binge Alcohol Induces Left Ventricular Dysfunction (A) Representative records of left ventricular (LV) pressure and its derivative (dP/dt) in control and alcohol-binged (EtOH 3h) mice, 3 h after maltodextrin or alcohol administration respectively. (B) Representative pressure-volume loops of control and alcohol-binged mice. (C) Systolic indices of LV performance [maximal slope of pressure increment (dP/dtmax), end-systolic pressure, stroke work, stroke volume, cardiac output and ejection fraction] in control (ctrl) and alcohol-binged (EtOH 3h) mice. Data are expressed as mean ± SEM, n = 7 to 8; *p < 0.05 vs. control group.
Figure 2
Figure 2
Binge Alcohol Decreases Load-Independent Indices of Left Ventricular Function (A) Pressure-volume (P-V) loops of control and alcohol-binged mice after gradual preload reduction obtained by vena cava inferior occlusion. Red lines indicate the slope of end-systolic P-V relationship; blue lines display the slope of end-diastolic P-V relationship. (B) Load-independent indices of LV performance: end-systolic elastance (Ees), the dP/dtmax-end-diastolic volume (EDV) relation and preload recruitable stroke work (PRSW). Data are expressed as mean ± SEM, n = 7 to 8; *p < 0.05 vs. control group. Abbreviation as in Figure 1.
Figure 3
Figure 3
Binge Alcohol Induces Vascular Dysfunction, Blood Redistribution, and Increased Cardiac Anandamide Levels (A) Mean arterial blood pressure and total peripheral resistance measured in control and alcohol-binged (EtOH 3h) mice 3 h after maltodextrin or alcohol administration, respectively. (B) Representative images of the jowl and hindlimb microcirculation in control and alcohol-binged mice. Red color indicates more intense, whereas blue color represents lower microcirculation. Right panel shows data on hindlimb microcirculation in control and alcohol-binged mice. (C) Superior mesenteric artery and renal artery blood flow changes in control and alcohol-binged mice. Data are expressed as mean ± SEM, n = 6 to 8; *p < 0.05 vs. control group. Abbreviation as in Figure 1.
Figure 4
Figure 4
Binge Alcohol Increases Cardiac Anandamide Level Cardiac levels of anandamide (AEA) and 2-arachidonyl glycerol (2-AG) measured in control and alcohol-binged mice. Data are expressed as mean ± SEM, n = 5 to 6; *p < 0.05 vs. control group. Abbreviations as in Figure 1.
Figure 5
Figure 5
Cannabinoid 1 receptor Antagonist Attenuates the Binge Alcohol-Induced Vascular Changes (A) Mean arterial blood pressure and total peripheral resistance measured after 3 h in control or in alcohol-binged mice before (ctrl base and EtOH base, respectively) and 15 min after intravenous rimonabant (Rimo) (ctlr + Rimo and EtOH + Rimo, respectively) administration. (B) Hindlimb microcirculation in control or in alcohol-binged mice before (ctrl base and EtOH base, respectively) and 15 min after intravenous Rimo. (C) Superior mesenteric artery and renal artery blood flow changes in control and in alcohol-binged mice before the treatment (ctrl base and EtOH base, respectively) and 15 min after intravenous Rimo (ctlr + Rimo and EtOH + Rimo, respectively) administration. Data are expressed as mean ± SEM, n = 5 to 7; *p < 0.05 vs. corresponding control group; #p < 0.05 vs. EtOH base group. CB1-R = cannabinoid 1 receptor; other abbreviations as in Figure 1.
Figure 6
Figure 6
CB1-R Blockade Attenuates the Binge Alcohol-Induced Contractile Dysfunction (A) Representative records of LV blood pressure changes and dP/dt in mice 3 h after either maltodextrin or alcohol binge alcohol binge following intravenous rimonabant (Rimo) (EtOH + Rimo) administration. (B) Representative pressure-volume (P-V) loops of maltodextrin and alcohol-binged mice before (red and dark blue, respectively) and 15 min after intravenous Rimo (ctrl + Rimo and EtOH + Rimo, light green and dark green loops, respectively) injection. (C) Systolic indices of LV performance [maximal slope of pressure increment (dP/dtmax), end-systolic pressure, stroke work] in control and in alcohol-binged mice before (ctrl base and EtOH base, respectively) and 15 min after intravenous Rimo (ctlr + Rimo and EtOH + Rimo, respectively) administration. Data are expressed as mean ± SEM, n = 6 to 8; *p < 0.05 vs. corresponding control group; #p < 0.05 vs. EtOH base group. Abbreviations as in Figures 1 and 5.
Figure 7
Figure 7
CB1-R blockade attenuates the binge alcohol induced depression of load-independent indices of left ventricular contractile function (A) Representative P-V loops obtained by gradual preload reduction obtained by vena cava occlusion of vehicle (veh) (ctrl + veh and EtOH + veh) or Rimo (ctrl + Rimo and EtOH + Rimo) treated mice 3 h after either oral alcohol or maltodextrin administration, respectively. Red lines indicate the slope of end-systolic P-V relationship, whereas blue lines depict the slope of end-diastolic P-V relationship (B) Load-independent indices of LV performance (Ees, the dP/dtmax–end-diastolic volume (EDV) relation, and PRSW) in vehicle-treated control or alcohol-binged mice (ctrl base, or EtOH base, respectively); or in rimonabant (Rimo)-treated control or alcohol-binged mice (ctlr + Rimo, or EtOH + Rimo, respectively). Data are expressed as mean ± SEM, n = 5 to 6; *p < 0.05 vs. corresponding control group; #p < 0.05 vs. EtOH base group. Abbreviations as in Figures 1, 2, 5, and 6.
Figure 8
Figure 8
CB1-R Deletion Attenuates the Binge Alcohol Intoxication-Induced Cardiac Dysfunction (A) Representative P-V loops of alcohol-binged CB1+/+ and CB1-/- mice after gradual preload reduction obtained by vena cava occlusion. Red lines indicate the slope of end-systolic P-V relationship, whereas blue lines show the slope of end-diastolic P-V relationship. (B) Load-independent indices of LV performance (Ees, the dP/dtmax – EDV relation, and PRSW) in control or in alcohol-binged CB1+/+ and CB1-/- mice. Data are expressed as mean ± SEM, n = 5 to 6; *p < 0.05 vs. corresponding control group; #p < 0.05 vs. alcohol-binged CB1+/+ group. Abbreviations as in Figures 1, 2, 5, and 6.

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