By: Wang G, Milner TA, Speth RC, Gore AC, Wu D, Iadecola C, and Pierce JP
Division of Neurobiology, Weill Cornell Medical College, 411 East 69th St., New York, NY 10021, USA.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2008
The rostral ventrolateral medulla (RVLM) controls sympathetic nerve activity to maintain blood pressure. Many studies suggest that the bulbospinal neurons located in the RVLM have a central role in the development of hypertension. These cells, which express tyrosine hydroxylase (TH), are tonically active to control the sympathetic tone of the vasculature. They also express angiotensin II (ANG II) receptors AT1. When ANG II binds to the C1 neurons at AT1, there is an increase in sympathetic nerve activity and blood pressure. These receptors induce many changes in different pathways to produce an increase in sympathetic nerve activity. There is an increase in Ca2+ current after ANG II binds to AT1. NADPH oxidase is also activated, leading to an increase in reactive oxygen species (ROS). Upon ANG II binding to AT1, the NADPH oxidase subunit p47 is phosphorylated to produce ROS. While these effects are well documented in male rats, the sex differences in the actions of the AT1 receptor in RVLM C1 neurons have not been investigated.
Four and twelve-month-old female and male rats were used in determining the expression of AT1 and p47. It is important to note that the researchers investigated the influence of age on blood pressure since the risk of hypertension in females increases later in life after menopause. Additionally, a group of 4 and 12-week-old female rats received ovariectomies (OVX) to reduce the effects of cycling estrogen levels. Half of these rats received estrogen replacement through implantation (OVX+E) while the rest received a vehicle (OVX+V). C1 neurons underwent retrograde labeling for TH and AT1 receptors and subunit p47 were immunolabeled in all groups of rats. Therefore, the researchers studied only the RVLM neurons that were both TH-retrograde labeled and immunolabeled for one of the proteins of interest. Patch-clamp recordings of RVLM neurons measured the effects of ANG II on the voltage-gated Ca2+ channel currents. Additionally, isolated neurons from males and females were used to measure the ROS production via the use of dihydroethidium, a fluorescent molecule, as an indicator.
4 and 12-month-old female rats had more AT1 expressed on their TH-labeled dendrites in the RVLM. There was no difference between the ages, suggesting that age is not a factor in the expression of AT1. Additionally, OVX+E had a higher expression of AT1 compared to OVX+V. Therefore, estrogen is suggested to enhance AT1 labeling in female OVX animals. Lastly, females had fewer p47 labeled on the C1 dendrites compared to males. Again, there was no difference between the age groups.
Estrogen seems to have an effect on the labeling of AT1. However, it cannot be said that estrogen enhances AT1 expression in female rats. Estrogen may be only enhancing the labeling of AT1, rather than increasing the amount of receptor on the dendrites of the C1 neurons. Therefore, more research should be done to investigate the role of estrogen on AT1 expression.
ANG-II treated females had similar ROS production compared to males when acted on by ANG-II. In both sexes, the production was attenuated by the AT1 receptor inhibitor losartan, the NADPH oxidase inhibitor gp91ds-tat, and the ROS scavenger MnTBAP. Therefore, the researchers argue that ANG-II mediates ROS production in females by NADPH oxidase activity. These are similar to the results in males previously measured. Because the ROS production was similar amongst the sexes, Wang et. al suggest that the NADPH-subunit and AT1 expression counterbalance each other. The increased expression of AT1 in females increases the signaling received by the C1 neurons in the RVLM. Therefore, the NADPH is expressed less to compensate for the increased activity signaled by the receptors.
ANG-II has previously been shown to increase L-type Ca2+ currents after binding to the AT1 receptor. This type of current is associated with the voltage-gated Ca2+ channels, suggesting that the increased current coincides with an increase in AT1 activity. The L-type current was increased in female C1 RVLM neurons with the addition of Ang II. The increase was larger in females compared to males. The researchers suggest that the CA2+ current differences between the sexes was due to the difference in the density of the L-type channels. Past research has shown that there are greater L-type Ca2+ currents in females and is increased further with the activator Bay K 8644. Therefore, the density, and not the dynamics, of the receptors is different between the sexes.
The current study filled a gap in the literature. The impact that Ang-II has on the RVLM of females has not been previously studied. There are measurable sex-differences in the expressions of NADPH-subunit p47 and the AT1 receptor. Due to the ambiguity in the results with the OVX females, more research should be done to better understand the impact the female sex hormones have on the system. Nevertheless, the impact that ANG-II has on blood pressure control in the RVLM is strong and may be an important component in the development of hypertension.
-LivInLaVida
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