Brain angiotensin and the female reproductive cycle

The results consistently show from experiment to experiment that there is a surge of brain Ang II prior to the well known preovulatory LH surge. It should be pointed out that these experiments have been carried out by two different laboratories and with the help of different experimenters and some of the experiments have been repeated. Therefore, the consistency of the results is reassuring. It does appear that Ann II increases in the brain, specifically in the hypothalamus, probably in cells of the paraventricular nucleus about 1 hour before the LH levels in plasma rise to a peak. Since LH release from the anterior pituitary gland is stimulated by the release of LHRH from the arcuate nucleus into the median eminence, the results would suggest that Ann II stimulates the release of LHRH. The peak in the OVX of Ann II treated rats is sharp and short-lasting with a second, later peak. The LH surge follows the first peak and a second rise in LH follows the second Ann II peak. These data suggest that brain Ann II synthesized and stored in the brain plays a critical role in the female reproductive cycle by initiating the LH surge. The regulation of Ang II may be by estrogen and progesterone, but as the increase in angiotensinogen mRNA was nut marked, the surge of Ang II appears to result more from the sudden release of stored Ann II than its synthesis. Thus, the question is what releases Ang II. Earlier studies showed that catecholamines release Ann II from neurons and not from glia involving α2 receptor blockade to increase norepinephrine by inhibiting reuptake (7). An interaction between catecholamines, Ang II and LH had also been suggested earlier (18, 19). Therefore, a series of events triggered by steroids in proestrus may begin with increases in norepinephrine activating neuronal α2 receptors and precipitating release of brain Ang II. This is represented diagrammatically in Figure 15. The Ann II surge stimulates the cells containing GnRH (gonadotropin releasing hormone) in the arcuate nucleus. The effect of Ang II on multiple GnRH cells amplifies the effect and GnRH is released into the portal vessels of the pituitary to stimulate the large LH release, from gonadotrope cells in the anterior pituitary, into the plasma that products the LH surge. The effect of the LH surge is ovulation which cads the estrogen build up. However, the estrogen decrease occurs more slowly than the brief appearance of brain Ann II peaks suggesting that estrogen is not a sufficient cause of the peak even though it is necessary. Since control rats did not show a Ang II peak when progesterone was absent, we conclude that P is also necessary for the effect. There are two major implications from these findings. First, they show that brain Ang II levels which are generally low (fmol range) can rise physiologically to the pmole or even nmole range. This is proof that brain Ang II exists and acts independently of blood borne Ang II since plasma Ang II during the peak time period was unchanged. If brain Ang II was an artifact of measurement no such consistent elevation would occur. Thus, the results provide definitive proof of a physiologically active brain Ang II and point to a neuroendocrine role in reproduction. Secondly, the results open a new path for controlling the LH surge and suggest that Ang II receptor antagonism delivered to the hypothalamus could have a contraceptive action.