17 Beta-estradiol suppresses AMPA-induced increases in regional cerebral O2 consumption.

We tested the hypothesis that 17 beta-estradiol would reduce the cerebral O2 consumption response resulting from glutamate receptor stimulation by alpha amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA). Fourteen ovariectomized rats were separated into 17 beta-estradiol (0.5 mg 21 day release pellet) and control (placebo pellet) groups to determine cerebral blood flow (14C-iodoantipyrine) and O2 consumption (microspectrophotometry). After topical cortical stimulation with 10(-3) M and 10(-4) M AMPA, cerebral blood flow increased significantly in both groups in a concentration-dependent manner. Cerebral O2 extraction was not significantly different in any region of the 17 beta-estradiol treated group. In the placebo treated group, the O2 extraction in the saline treated cortex and in the 10(-3) M AMPA treated cortex was significantly higher when compared to the 10(-4) M AMPA treated cortex. Cerebral O2 consumption in the control group increased by 20%, from 5.2 +/- 0.6 to 6.1 +/- 0.7, with 10(-4) M AMPA and significantly increased by 64% to 8.5 +/- 0.8 ml O2 min-1 100 g-1 with 10(-3) M AMPA. The 17 beta-estradiol group demonstrated no statistically significant difference in O2 consumption between the saline treated and AMPA treated cortex. Thus, 17 beta-estradiol reduced the effects of AMPA in increasing cerebral O2 consumption.

Ethanol reduces cardiac myocyte function through activation of the nitric oxide-cyclic GMP pathway.

We tested the hypothesis that low-dose ethanol would reduce cardiac myocyte function through increased production in the nitric oxide/cyclic GMP signal transduction pathway, rather than reduced degradation. Ventricular myocytes were isolated from the hearts of 9 rabbits. Myocyte function was studied using a video-edge detector and cyclic GMP levels were measured by radioimmunoassay. Cells were administered 5 and 10 mmol/l ethanol alone or after 10(-6) mol/l N(G)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), 10(-6) mol/l 1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one (ODQ, soluble guanylyl cyclase inhibitor) or 10(-5) mol/l zaprinast (cyclic GMP phosphodiesterase inhibitor). Ethanol (10 mmol/l) significantly decreased percent shortening from 10.0 +/- 0.9 to 6.0 +/- 0.2%. Similar decrements occurred in the maximum rate of shortening and relaxation. After L-NAME or ODQ, the decrements in percent shortening, maximum rate of shortening and relaxation caused by ethanol were not significant. After zaprinast, ethanol significantly decreased the maximum rate of shortening and relaxation and percent shortening to 4.3 +/- 0.5. Ethanol (10 mmol/l) significantly increased cyclic GMP from 403 +/- 121 to 529 +/- 128 fmol/10(5) myocytes. Both L-NAME and ODQ lowered cyclic GMP, and ethanol did not affect cyclic GMP after either. Zaprinast raised cyclic GMP, as did its combination with 10 mmol/l ethanol (653 +/- 120). Thus, ethanol both reduced myocyte function and increased cyclic GMP. Blocking nitric oxide production or guanylyl cyclase activity prevent these effects of ethanol, while blocking cyclic GMP degradation did not. This suggests that ethanol acts as a nitric oxide stimulator in ventricular myocytes leading to reduced function and increased cyclic GMP.