Activation of estrogen receptor β-dependent nitric oxide signaling mediates the hypotensive effects of estrogen in the rostral ventrolateral medulla of anesthetized rats

BACKGROUND: Apart from their well-known peripheral cardiovascular effects, emerging evidence indicates that estrogen acts as a modulator in the brain to regulate cardiovascular functions. The underlying mechanisms of estrogen in central cardiovascular regulation, however, are poorly understood. The present study investigated the cardiovascular effects of 17β-estradiol (E2β) in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, and delineated the engagement of nitric oxide (NO) in E2β-induced cardiovascular responses. METHODS: In male Sprague-Dawley rats maintained under propofol anesthesia, the changes of blood pressure, heart rate and sympathetic vasomotor tone after microinjection bilaterally into the RVLM of a synthetic estrogen, E2β were examined for at least 120 min. The involvement of ERα and/or ERβ subtypes was determined by microinjection of selective ERα or ERβ agonist into bilateral RVLM. Different NO synthase (NOS) inhibitors were used to evaluate the involvement of differential of NOS isoforms in the cardiovascular effects of E2β. RESULTS: Bilateral microinjection of E2β (0.5, 1, or 5 pmol) into the RVLM dose-dependently decreased systemic arterial pressure (SAP) and the power density of the vasomotor components of SAP signals, our experimental index for sympathetic neurogenic vasomotor tone. These cardiovascular depressive effects of E2β (1 pmol) were abolished by co-injection of ER antagonist ICI 182780 (0.25 or 0.5 pmol), but not a transcription inhibitor actinomycin D (10 nmol). Like E2β, microinjection bilaterally into the RVLM of a selective ERβ agonist 2,3-bis(4-hydroxyphenyl) propionitrile (DPN, 1, 2, or 5 pmol) induced significant decreases in these hemodynamic parameters in a dose-dependent manner. In contrast, the selective ERα agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (5 pmol) did not influence the same cardiovascular parameters. Co-administration bilaterally into the RVLM of NOS inhibitor N(G)-nitro-L-arginine methyl ester (5 nmol) or selective inducible NOS (iNOS) inhibitor S-methylisothiourea (25 pmol), but not selective neuronal NOS inhibitor 7-nitroindazole (0.5 pmol) or endothelial NOS inhibitor N5-(1-Iminoethyl)-L-ornithine (2.5 pmol), significantly attenuated the cardiovascular depressive effects elicited by DPN (2 pmol). CONCLUSION: Our results indicate that E2β in the RVLM elicited short-term cardiovascular depressive effects via an ERβ-dependent nontranscriptional mechanism. These vasodepressor effects of E2β are likely to be mediated by the iNOS-derived NO in the RVLM.