Enhanced oxidative stress/DAPK3/Akt/ERK signaling accounts for estrogen exacerbation of cardiac dysfunction caused by ethanol in male rats (652.20)

Abstract

We have previously shown that acute ethanol reduces blood pressure (BP) and cardiac output in female, but not in male, rats. Because these effects of ethanol were estrogen (E2)‐dependent, we investigated whether E2 treatment of male rats uncovers a hypotensive effect for ethanol, and whether left ventricular (LV) dysfunction, due to oxidative damage, contributes to the ethanol‐E2 hemodynamic interaction. The effect of ethanol (0.5, 1 or 1.5 g/kg; i.v.) on BP, LV function, and oxidative stress markers in male rats treated with E2 (1 μg/kg i.v.) or the vehicle were investigated. While ethanol had no effect on BP in vehicle‐treated rats, it caused dose‐related falls in BP in E2‐pretreated rats. This was associated with (i) compromised myocardial function as suggested by the reductions in LV developed pressure (LVDP), end diastolic pressure (LVEDP), and rate of rise in LV pressure (LV dP/dtmax), and (ii) oxidative damage as evidenced by the increases in LV generation of reactive oxygen species, protein expression of the malondialdehyde adducts, and phosphorylated death‐associated protein kinase‐3 (DAPK3), Akt, and ERK1/2. Together, E2 propagates LV dysfunction and hypotension in response to ethanol in male rats via facilitation of the myocardial oxidative stress/lipid peroxidation/DAPK3/Akt/ERK1/2 cascade. Because E2 was administered acutely, its effects are likely to involve rapid nongenomic mechanisms. Grant Funding Source: Supported by NIAAA [2R01 AA014441‐07].