Bosch Institute and School of Medical Sciences (Physiology), University of Sydney, Sydney, Australia American Journal of Physiology: Regulatory, Integrative, and Comparative Physiology, 2008
The rostral ventrolateral medulla (RVLM) is a brain region that is central to the maintenance and regulation of blood pressure. It drives the blood pressure changes through the use of the sympathetic nervous system. As the nerve outflow increases, so does the response in blood pressure. According to this paper, one of the most important influences on blood pressure is the action of angiotensin II (ANG II) on the RVLM. The neurons of the RVLM contain angiotensin receptors that have been shown to drive increases in blood pressure by activating NADPH oxidase to create reactive oxygen species (ROS). Thus, previous research suggests that ANG-II can lead to the development of hypertension by overproducing ROS in the RVLM neurons. To further support these claims, it would be beneficial if they author noted the effects of ANG-II receptor antagonists. If the antagonists reduced the SNA outflow and responding blood pressure, the importance of ANG-II in the alteration in blood pressure would be highlighted much more. Nevertheless, it does appear that the hormone contributes to the control of blood pressure in the RVLM.
Some strong evidence exists to support the importance of ANG II in the sex-differences of blood pressure. The researchers state that understanding the ANG II effects in males versus females would reveal one of the causes of sex differences in human hypertension. The paper notes that males respond to ANG II infusions with greater increases in blood pressure from sympathetic nerve outflow than females. ANG type 1 receptors (AT1) are expressed at a higher quantity compared to males in the RVLM. The NADPH subunit p47 is lower in females, however. Nevertheless, ROS production, which was used to measure neuron activation levels in dissociated neurons after ANG II application, was similar in both sexes. The author suggests that the higher amounts of AT1 but not p47 counterbalanced each other’s effects in females. This counterbalance would then produce similar responses in males and females. However, the use of a receptor antagonist here would provide further support for these claims. If the blocked receptor prevents increases in blood pressure, it would be harder to argue that other inputs may be contributing to the attenuated response seen in females. Circulating female hormones may be somewhat responsible for the response that is seen with ANG-II. They may be acting on another component of the ROS pathway, such as the p47 subunit expression, to alter the response seen in females. Therefore, the antagonism of the AT1 would be an avenue worth investigating. Additionally, studies should investigate the impact of the sex hormones has on the expression of the ANG-II component's genes. If estrogen impacts their expression, it could explain why the AT1 and p47 levels differed between the sexes. Nonetheless, there are measurable sex-differences within the ANG-II pathway that can be accounted for in the RVLM.
Some strong evidence exists to support the importance of ANG II in the sex-differences of blood pressure. The researchers state that understanding the ANG II effects in males versus females would reveal one of the causes of sex differences in human hypertension. The paper notes that males respond to ANG II infusions with greater increases in blood pressure from sympathetic nerve outflow than females. ANG type 1 receptors (AT1) are expressed at a higher quantity compared to males in the RVLM. The NADPH subunit p47 is lower in females, however. Nevertheless, ROS production, which was used to measure neuron activation levels in dissociated neurons after ANG II application, was similar in both sexes. The author suggests that the higher amounts of AT1 but not p47 counterbalanced each other’s effects in females. This counterbalance would then produce similar responses in males and females. However, the use of a receptor antagonist here would provide further support for these claims. If the blocked receptor prevents increases in blood pressure, it would be harder to argue that other inputs may be contributing to the attenuated response seen in females. Circulating female hormones may be somewhat responsible for the response that is seen with ANG-II. They may be acting on another component of the ROS pathway, such as the p47 subunit expression, to alter the response seen in females. Therefore, the antagonism of the AT1 would be an avenue worth investigating. Additionally, studies should investigate the impact of the sex hormones has on the expression of the ANG-II component's genes. If estrogen impacts their expression, it could explain why the AT1 and p47 levels differed between the sexes. Nonetheless, there are measurable sex-differences within the ANG-II pathway that can be accounted for in the RVLM.
Additionally, the researchers found that, when acted upon by ANG-II, the L-type Ca2+ currents in female neurons were higher than males. These results were supported by an additional study that showed the amount and the sensitivity of the Ca2+ channels differed between the two sexes. Due to the similar ROS production in males and females, it is suggested that the activation of the Ca2+ channels is independent of the previously mentioned ANG-II/ROS pathway. This hypothesis is supported by the results of another study. When the ANG-II/ROs pathway was blocked and the L-type Ca2+ current was activated with ANG-II, females had a greater blood pressure response compared to the males--thus the ANG-II/ROS pathway was not necessary to activate the neurons located there.
These results should raise some additional questions. Females typically have attenuated blood pressure responses when compared to males. Therefore, why would the female RVLM neurons have increased activation levels compared to males? Estrogen is finally introduced into the ANG-II pathway and its effects are measured. 17-estradiol produced a decrease in the L-type Ca2+ currents in the RVLM, suggesting that this is one of the mechanisms that lead to lower blood pressure changes in female rats. Thus, the paper suggests that the change in blood pressure would depend on the ratio of ANG-II and estrogen that is in circulation and acting on the RVLM. Additional studies should be done to consider the in vivo levels of both compounds in order to determine if this is indeed the case.
These results should raise some additional questions. Females typically have attenuated blood pressure responses when compared to males. Therefore, why would the female RVLM neurons have increased activation levels compared to males? Estrogen is finally introduced into the ANG-II pathway and its effects are measured. 17-estradiol produced a decrease in the L-type Ca2+ currents in the RVLM, suggesting that this is one of the mechanisms that lead to lower blood pressure changes in female rats. Thus, the paper suggests that the change in blood pressure would depend on the ratio of ANG-II and estrogen that is in circulation and acting on the RVLM. Additional studies should be done to consider the in vivo levels of both compounds in order to determine if this is indeed the case.
The research that was reviewed above suggests that there are sex-related differences in the ANG-II pathway expressed within the RVLM. While more research should be done to further support the results presented here, ANG-II and its effects on the RVLM seem to play an important role in regulating blood pressure and possibly on the development of hypertension.
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