Estrogen in the Paraventricular Nucleus Attenuates L-Glutamate-Induced Increases in Mean ARterial Pressure Through Estrogen Receptor B and NO

By S. Gingerich and T. L. Krukoff

The Center for Neuroscience and Department of Cell Biology, University of Alberta

Journal of Hypertension, 2006

Previous research suggests that estrogen attenuates the blood pressure changes in rats. Due to its role in the regulation of the autonomic nervous system, it is suggested that estrogen acts on the paraventricular nucleus (PVN) of the hypothalamus to produce its protective effects. Specifically, E2 is thought to act on nitric oxide (NO). NO has been shown inhibit sympathetic outflow in the PVN, leading to a decrease in blood pressure change. Neural NO synthase (nNOS) is expressed in the neurons of the PVN, along with estrogen receptors alpha and beta (ERα and ERβ). The researchers previously showed that the when estrogen acts on the ERβ of the PVN, the expression of nNOS and endothelial NOS (eNOS) changes, although the relationship between these components is unknown. GABA has also been shown reduce blood pressure by mediating the cardiovascular effects of E2 through NO.

E2 or E2 vehicle microinjections were performed in male rats into their PVN while blood pressure and heart rate were simultaneously studied. Males were used in order to prevent any undesired effects from cycling estrogen. Additionally, microinjections of glutamate were performed after 30 minutes of the initial estrogen injection to determine the protective effects of the hormone in that brain region. In order to study the roles of NO after being exposed to estrogen, animals also received coinjections of E2 and either L-NAME (an NOS inhibitor), L-NIO (an eNOS inhibitor), 7-NiNa (an nNOS inhibitor, or bicuculine (GABAa antagonist) before receiving the glutamate microinjection.

Microinjections of glutamate (50nmol, 100nL) after a saline injection caused significant increases in both BP and HR. E2 injections alone caused no change in either response. However, a microinjection of glutamate after estrogen attenuated the BP and HR responses by up to 59%. When E2 was coinjected with a general E2 antagonist, followed by a glutamate microinjection after 30 minutes, the protective actions of E2 were blocked. The specific ERα agonist PPT produced no effects on the HR or AP. Similarly, the ERα antagonist did not produce protective effects. However, the ERβ specific agonist produced the same attenuating effects that happened with the E2 microinjections. The ERβ antagonist prevented the decrease in BP. These results suggest that ERβ and not ERα are where E2 acts to provide its protective cardiovascular effects in the PVN.

The NOS inhibitors were coinjected with E2, followed by the glutamate microinjection after 30 minutes. Both L-NAME, 7-NiNa, and L-NIO prevented the protective effects of E2 previously measured. These results suggest that both the nNOS and the eNOS are needed in order for estrogen produce its effects. It is suggested that estrogen acts on the NO produced by these two enzymes in order to attenuate the changes in blood pressure. Although, it could be that estrogen needs to act on the active enzyme and not the NO itself.

Finally, the role of the GABAa receptor was investigated. A bicuculine and estrogen coinjection was followed by a glutamate microinjection after 30 minutes. The effects of E2 were blocked once again. Again, the study suggests that this is due to blocking the estrogen effects. However, it could be many things. GABAa is needed to inhibit the PVN and prevent its activation and therefore its homeostatic effects on the cardiovascular system. Therefore, by blocking the GABAa, the researchers could have been blocking many inputs rather than just the effects of E2.

In summary, the study suggests that estrogen acts on the ERβ in the PVN to activate the two described NOS. This in turn creates NO while employing GABA so as to mediate the protective effects of estrogen. The neurons are inhibited, which reduces their firing rate and the sympathetic outflow. With a reduction in output from the PVN, the blood pressure changes are attenuated. While their results are promising, more research should be done to better understand the pathway that the study has outlined.

-LivInLaVida