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Gonadotropin Stimulates Ovarian Renin-Angiotensin System in the Rabbit

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Gonadotropin Stimulates Ovarian Renin-Angiotensin System in the Rabbit Gonadotropin stimulates ovarian renin-angiotensin system in the rabbit. Y Yoshimura, … , M Jinno, Y Nakamura J Clin Invest. 1994;93(1):180-187. https://doi.org/10.1172/JCI116943. Research Article The present study was undertaken to assess the role of ovarian renin-angiotensin system (RAS) in the preovulatory cascade induced by gonadotropin exposure. In the in vitro perfused rabbit ovaries, exposure to human chorionic gonadotropin (hCG) enhanced the secretion rate of angiotensin II (Ang II) within 1 h. The secretion rate reached maximal levels at 6 h and then declined thereafter. The intrafollicular Ang II content and renin-like activity were also significantly increased at 2 and 4 h after exposure to hCG, compared with control ovaries perfused with medium alone. The level of intrafollicular Ang II after hCG exposure significantly exceeded the concentration of Ang II in an equivalent volume of plasma. The addition of 1 microM captopril to the perfusate significantly inhibited the secretion rate of Ang II stimulated by hCG; however, captopril affected neither the ovulatory efficiency nor prostaglandin production in ovaries treated with hCG. Captopril significantly inhibited the resumption of meiosis in the ovulated ova and follicular oocytes stimulated by hCG. The administration of 100 micrograms Ang II at 2-h intervals to the perfusate reversed the inhibitory effects of captopril on hCG-induced oocyte maturation. In conclusion, these data indicate that gonadotropin stimulates renin-like activity and Ang II production in the rabbit ovary. Ovarian renin-angiotensin system may play an important role in the process of oocyte maturation after exposure […] Find the latest version: https://jci.me/116943/pdf Gonadotropin Stimulates Ovarian Renin-Angiotensin System in the Rabbit Yasunori Yoshimura, * Norihiro Koyama, * Masataka Karube, * Takahisa Oda, Masao Akiba, * Akari Yoshinaga, * Shigetatsu Shiokawa,* Masao Jinno,* and Yukio Nakamura* *Department of Obstetrics and Gynecology, Kyorin University School of Medicine, Tokyo, Japan 181; and tDepartment of Obstetrics and Gynecology, Tokyo Dental College, Ichikawa General Hospital, Chiba, Japan 272 Abstract study revealed that the addition of Ang II in the perfusate at 2-h intervals induced oocyte maturation and ovulation in the in The present study was undertaken to assess the role of ovarian vitro perfused rabbit ovaries in the absence of gonadotropin, renin-angiotensin system (RAS) in the preovulatory cascade and that the concomitant addition of saralasin completely induced by gonadotropin exposure. In the in vitro perfused rab- blocked Ang 11-induced ovulation (8). These results indicate bit ovaries, exposure to human chorionic gonadotropin (hCG) that Ang II has a direct role in follicle rupture and oocyte matu- enhanced the secretion rate of angiotensin II (Ang II) within 1 ration, and they support the hypothesis that Ang II produced in h. The secretion rate reached maximal levels at 6 h and then the ovary may act locally in the process of ovulation. An intrin- declined thereafter. The intrafollicular Ang II content and sic RAS in the rabbit ovary may be an intermediary in the renin-like activity were also significantly increased at 2 and 4 h gonadotropin-induced ovulation. However, Husain et al. (3) after exposure to hCG, compared with control ovaries perfused did not find the expected autoradiographic distribution of Ang with medium alone. The level of intrafollicular Ang II after II receptors in every developing rat follicle, suggesting that not hCG exposure significantly exceeded the concentration of Ang all preovulatory follicles necessarily respond to exogenous or II in an equivalent volume of plasma. The addition of 1 ,uM endogenous Ang II. This discrepancy in the effects of Ang II on captopril to the perfusate significantly inhibited the secretion gonadotropin-induced ovulation impedes a better understand- rate of Ang II stimulated by hCG; however, captopril affected ing of the physiological role of Ang II in ovulation. neither the ovulatory efficiency nor prostaglandin production in The finding of higher follicular concentrations of prorenin, ovaries treated with hCG. Captopril significantly inhibited the renin, and angiotensinogen in humans, and the identification resumption of meiosis in the ovulated ova and follicular oocytes of angiotensinogen and renin messenger RNA in the rat ovary, stimulated by hCG. The administration of 100 ,ug Ang II at 2-h suggest the presence of a local RAS in the ovary ( 1, 2, 5, 9, 10). intervals to the perfusate reversed the inhibitory effects of cap- The evidence that the ovary secretes prorenin into the follicular topril on hCG-induced oocyte maturation. In conclusion, these fluid and plasma at the time of gonadotropin surge of the nor- data indicate that gonadotropin stimulates renin-like activity mal menstrual cycle ( I 1, 12) and after hCG administration to and Ang 11 production in the rabbit ovary. Ovarian renin-angio- ovarian-stimulated patients ( 13) further substantiates the hy- tensin system may play an important role in the process of pothesis that the ovarian RAS may play an important role in oocyte maturation after exposure to gonadotropin. (J. Clin. In- the function of ovarian follicle. We found that the rates of Ang vest. 1994. 93:180-187.) Key words: renin-like activity * angio- II secretion were enhanced by gonadotropin in perfused rabbit tensin II - ovulation * oocyte maturation * angiotensin I-convert- ovaries, and that the concomitant addition of saralasin inhib- ing enzyme ited hCG-induced ovulation in a dose-dependent manner (8). Kuo et al. also have demonstrated that Ang II has a direct effect Introduction on the rabbit ovary, stimulating both ovulation and oocyte maturation in the absence of gonadotropin ( 14). These obser- A functional local renin-angiotensin system (RAS)' is known vations point toward a potentially important role of ovarian to exist in the ovary ( 1-6). Pellicer et al. (7) demonstrated that RAS in the preovulatory cascade induced by gonadotropin ex- the intraperitoneal administration ofan angiotensin II (Ang II) posure, and prompted us to investigate changes in the intrafol- receptor antagonist, saralasin, blocked ovulation in immature licular renin activity and the ovarian secretion rate of Ang II in rats that were treated with pregnant mare's serum gonadotro- the process of ovulation. Since local Ang II may be a significant pin and human chorionic gonadotropin (hCG). Our previous autocrine or paracrine modulator of ovarian function (7, 8, 14), we also studied the effects of captopril, an angiotensin Address correspondence to Yasunori Yoshimura, M.D., Department I-converting enzyme (ACE) inhibitor, on hCG-induced ovula- of Obstetrics and Gynecology, Kyorin University School of Medicine, tion and oocyte maturation. 6-20-2 Shinkawa, Mitaka, Tokyo, Japan 181. Receivedfor publication 18 May 1993 and in revisedform 13 Au- Methods gust 1993. Animals. Sexually mature female Japanese white rabbits weighing 3.5- 1. Abbreviations used in this paper: ACE, angiotensin I-converting 4.5 kg, which were cared for according to the guideline of Kyorin Uni- enzyme; Ang II, angiotensin II; GVBD, germinal vesicle breakdown; versity School of Medicine, were isolated for a minimum of 3 wk. The hCG, human chorionic gonadotropin; RAS, renin-angiotensin sys- rabbits were caged individually and fed water and a diet of Purina tem. rabbit chow (Clea Japan Inc., Tokyo, Japan) ad libitum under condi- tions of controlled light and temperature. They were anesthetized with J. Clin. Invest. intravenous sodium pentobarbital (32 mg/kg), administered heparin © The American Society for Clinical Investigation, Inc. sulfate ( 120 U/kg) for anticoagulation, and then subjected to laparot- 0021-9738/94/01/0180/08 $2.00 omy. Ovaries were excluded from further study if they appeared imma- Volume 93, January 1994, 180-187 ture, or if 2 50% of the surface follicles were hemorrhagic. 180 Yoshimura et al. Ovarian perfusion. Although the details of the standard perfusion ovaries from eight rabbits. Ovarian perfusion was carried out for 12 h system have been modified over the years, the basic components have after hCG exposure. Both the arterial and venous samples were ob- remained constant ( 15 ). The ovarian artery and vein were cannulated tained at the start of perfusion and 1, 2, 4, 6, 8, and 12 h thereafter. in situ after ligation of the major anastomotic connections as previ- Samples were stored at -80'C until Ang II concentrations were deter- ously described ( 16, 17). The ovary was removed along with its artery, mined. In the experiment to determine the intrafollicular contents of vein, and supporting adipose tissue, and immediately placed in a perfu- Ang II in ovaries perfused with hCG alone or hCG plus captopril, sion chamber. The perfusion fluid consisted of 150 ml of medium 199 ovarian perfusion was terminated before hCG administration and 1, 2, (Gibco Laboratories, Grand Island, NY) containing 1% BSA (Fraction 4, 6, and 8 h after hCG exposure. At least six ovaries from six different V powder; Sigma Chemical Co., St. Louis, MO), which was supple- rabbits were examined at each interval. Mature follicles were excised mented with heparin sulfate, insulin, streptomycin, and penicillin G, immediately at each time point of perfusion and stored at -80'C until and adjusted to a pH of 7.4. BSA was added to the basic perfusion fluid the intrafollicular content of Ang II was determined. to increase the oncotic pressure and reduce edema formation ( 16). The final experiment was conducted to determine whether the ad- Ovaries were observed every 15 min for evidence of follicle growth and ministration of Ang II would reverse the inhibitory effect of captopril rupture throughout the 12 h of perfusion. on hCG-induced oocyte maturation. Both ovaries from six rabbits were At the time of follicle rupture, the ovulated ovum surrounded by its perfused with captopril at a concentration of 1 AM. 30 min after the cumulus mass was recovered carefully from the ovarian surface with a onset of perfusion, 50 IU of hCG was added to the perfusate of both Pasteur pipette.
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