Department of Pharmacy and Graduate Institution of Pharmaceutical Technology, Tajen University, Taiwan, the Republic of China
Journal of Biomedical Science, 2009
The purpose of this study was to better understand the actions of estrogen in the rostral ventrolateral medulla (RVLM). Specifically, the different estrogen receptors and their role in inducing its cardiovascular protective responses were investigated. Based on previous research, the study hypothesized that estrogen acts on the ERβ receptor to activate nitric oxide (NO) to inhibit sympathetic outflow from the RVLM.
So as to prevent an unexpected effect from circulating estrogen, the study used male rats. The animals received bilateral microinjections into the RVLM. They were not measuring the effects of estrogen on the activation of the RVLM, but rather how estrogen alone attenuates resting blood pressure. Therefore, the animals received microinjections of either: estradiol (E2β); a selective estrogen receptor alpha (ERα) agonist (PPT); an estrogen receptor beta (ERβ) agonist (DPN); a general ER antagonist (ICI 182780); an ERα antagonist (MPP); an ERβ antagonist (R,R-THC); a general NO synthase (NOS) inhibitor (SMT); an nNOS inhibitor (7-NI); an endothelial NOS (eNOS) inhibitor (L-NIO); or a transcription inhibitor (AMD). The transcription inhibitor was used to see if the activated ERs would mediate its actions through nontranscriptional methods, as studies have previously suggested.
The microinjections of E2β (0.5, 1, or 5 pmol) and not E2α produced a dose-dependent decrease in MAP and vasomotor outflow, with the higher doses producing a suppression that lasted longer (3-4 hours after the injection). E2α produced no changes from baseline measurements. When all three types of antagonists were given alone, no change was measured. However, when the ICI 182780 was given, the E2β-induced responses were reversed. Similarly, when the general ER antagonist was given before an E2β microinjection, the hypotension and decrease in vasomotor tone were prevented. Thus, the researchers suggested that E2β act on ERβ in the RVLM in order to produce its suppressive responses.
To further understand the selectivity of the estrogen in the RVLM, ERα and ERβ agonists were bilaterally injected. Only the ERβ agonist, DPN, produced the similar dose-related decreases in MAP and vasomotor output compared to the injections of E2β. ERα agonist DPN showed no change in the measurements. Again, these results suggested that estrogen acts on ERβ in the RVLM to produce its attenuation effects of the cardiovascular system.
The role of NO was further investigated. When the NOS inhibitors were coinjected bilaterally with E2β into the RVLM, there were no measured responses in MAP or vasomotor output. Interestingly, the general NOS inhibitor L-NAME prevented the E2β responses. Additionally, the iNOS inhibitor and not the nNOS or eNOS inhibitors prevented the responses as well. Therefore, the researchers suggested that the NO produced by iNOS is needed for E2β to produce its attenuation effects in the RVLM. The results are interesting because previous studies have shown that the NO produced by the eNOS is also important for the effects of E2β. However, these were studied within the PVN and suggests that the effects of estrogen in the brain are nucleus-specific.
Additionally, when coinjected with AMD and E2β, there was no change in the expected E2β depressive responses, suggesting that their hypothesis was correct: the effects of E2β on ERβ are mediated by nontranscriptional methods.
In summary, the study suggests that the E2β acts specifically in the ERβ in the RVLM to produce the inhibitory responses of the cardiovascular system. NO from the iNOS is suggested to contribute to the effects after the activation of the ERβ in the RVLM.
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