By N.B. Ojeda, D. Grigore, E.B. Robertson, and B.T. Alexander
Upon the onset of menopause, women typically have higher rates of hypertension compared to men, and the risk continues to rise as women age. To better understand the sex-differences of female rats and hypertension, studies began to look at the effects of estrogen loss. Past research suggested that estrogen provides a protective role against heart disease like hypertension. In animal models, normotensive female rats became hypertensive after undergoing ovariectomies. Furthermore, rat offspring that undergo intrauterine growth-restriction (IUGR) are born hypertensive. However, at the onset of puberty, only female rats stabilize their blood pressure, further suggesting the importance of sex hormones in the stabilization of hypertension. There have also been studies that have suggested estrogen modulates the renin-angiotensin system (RAS) as a mechanism to maintain hypertension in IUGR rats. Thus, these results indicate that a loss of estrogen contributes to the development and maintenance of hypertension in female rats.
The purpose of this study was to determine whether or not estrogen has protective properties against hypertension in IUGR rats and to examine if estrogen acts through the RAS to complete its protective measurements. Ovariectomies (OVX) and sham surgeries were performed in 10-week old female IUGR and standard "control" animals. These procedures created four general groups of animals: control-intact (no OVX performed); IUGR-intact; control-OVX, and; IUGR-OVX. The ACE-inhibitor enalapril was then given to a subset of these animals: control-intact+enalapril; IUGR-intact+enalapril; control-OVX+enalapril, and; IUGR-OVX+enalapril.
Another subgroup of OVX animals received estradiol (E2) supplements post-OVX: control-OVX+E2, and; IUGR-OVX+E2. OVX animals' E2 levels returned to normal ranges after the E2 supplements. The remaining animals who did not receive an additional drug were used as controls for each group. E2 levels were collected an measured while under anesthesia at ages 4, 6, 8, 10, 12, and 16 weeks of age. These measurements were used to determine the onset of adolescence while measuring the levels and stabilization of E2 in control and IUGR animals.
The kidneys of the rats in each general group were removed and used to measure the amounts of ACE and ACE2 mRNA present in them. Lastly, plasma renin activity (PRA) and plasma renin substrate were collected from intact and OVX animals post-decapitation. The study analyzed the relationship between E2 and the RAS using these two measurements. Mean arterial pressure (MAP) was measured and averaged at the first three days of the week for each rat.
MAP did not differ between the IUGR and control adult females. However, OVX induced hypertension in IUGR animals and had no significant effect on the control adults. However, their normalized values were comparable. E2 replacement at 14 weeks of age reduced the blood pressure in both groups by 16 weeks of age. Starting at 14 weeks of age, animals received enalapril to inhibit ACE. This drug did not cause significant differences in MAP between intact-control+enalapril and OVX-IUGR+enalapril animals. Enalapril also removed the difference in MAP between the untreated OVX-control and OVX-IUGR animals initially measured. E2 levels remained similar between the IUGR and control animals throughout the entire study. At 8 weeks of age, the E2 levels increased. Ovariectomies reduced the E2 levels tremendously, and the E2 supplements returned the levels to normal. PRA and PRS levels remained the same between the groups, and ovariectomies did not affect them either. The only group that saw reductions in renal ACE2 mRNA were the OVX-IUGR animals. The OVX-controls did not see this reduction.
The study's results suggest that estrogen provides protective measures against the development and maintenance of hypertension in post-adolescent IUGR rats. The only factor that led to increased MAP from baseline were the ovariectomies done to the IUGR animals. Taking into consideration that both groups usually have a similar MAP, this result suggests that E2 plays a role in normalizing blood pressure. E2 also brought MAP back to normal levels in these animals to further argue for the protective factors of E2. The study's results also argue that the RAS is a possible route of action for E2 to take to control blood pressure. Furthermore, there were ACE2 mRNA results that suggest E2 acts through ACE2 to maintain blood pressure. IUGR-OVX animals were the only group that showed reductions in their ACE2 mRNA expression, suggesting that there are effects to the system while in utero. However, despite the success of their study, based on their results and study design, this data is only applicable to IUGR rats that lose estrogen post-adolescence through ovariectomies.
- O. Flessland
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