Characterization of angiotensin I-converting enzyme (ACE)-containing follicles in the rat ovary during the estrous cycle and effects of ACE inhibitor on ovulation.
Ovarian angiotensin I (Ang I)-converting enzyme (ACE), estimated by the specific binding of the ACE inhibitor [125I]iodo-MK-351A, is localized on multiple ovarian structures, including follicular granulosa cells, corpora lutea, terminal epithelium, and ovarian blood vessels, but total ovarian ACE does not display a cyclic pattern of variation during the rat estrous cycle. We have previously shown that ACE is localized on the granulosa cell layer of a subpopulation of rat ovarian follicles. Our present study shows that ovarian granulosa cells contain high affinity [binding site affinity (Kd), approximately 90 pM] and low capacity [binding site density (Bmax), approximately 12 fmol/2.5 X 10(5) cells] [125I]iodo-MK-351A-binding sites and convert [125I]iodo-Ang I to [125I]iodo-Ang II (greater than 85% of this conversion was inhibited by the ACE inhibitor captopril). Throughout the rat estrous cycle, 94-100% of developing follicles and 89-96% of atretic follicles contained high levels of ACE; however, ACE was either not observed or its levels were very low in preovulatory follicles. These findings indicate the presence of high levels of biologically active ACE on the surface of granulosa cells and suggest a potential role for follicular ACE in early stages of follicular maturation and atresia. Although ACE is known to process a variety of peptides found within the ovary, and these peptides may have opposing effects on follicular maturation, we attempted to define the cumulative effect of ACE inhibition on follicular maturation. Short and long term (6- and 14-day) infusions of captopril (6-day, 30.5 +/- 3.5 ova; 14-day, 28.5 +/- 7.5 ova) in immature rats, in which ovulation was induced by sequential treatments with PMSG and hCG, did not significantly affect ovulation compared with that in vehicle-infused control rats (6-day, 22.4 +/- 2.4 ova; 14-day, 20.8 +/- 3.1 ova), suggesting that ACE inhibition does not modify the follicular selection process in a way that affects ovulation. This may explain the lack of any reports of adverse effects of clinically used ACE inhibitors on ovulation.
Daud
A I
AI
Department of Heart and Hypertension Research, Research Institute of the Cleveland Clinic Foundation, Ohio 44195-5071.
Bumpus
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Husain
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D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002216:Captopril / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D006063:Chorionic Gonadotropin / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D004971:Estrus / Q000502:physiology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006107:Granulosa Cells / Q000201:enzymology; D007457:Iodine Radioisotopes; D006080:Ovarian Follicle / Q000201:enzymology*; D010053:Ovary / Q000201:enzymology*; D010060:Ovulation / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000806:Angiotensin-Converting Enzyme Inhibitors; D006063:Chorionic Gonadotropin; D004151:Dipeptides; D007457:Iodine Radioisotopes; C042037:L-proline, N2-((1S)-1-carboxy-3-phenylpropyl)-N6-((4-hydroxyphenyl)iminomethyl)-L-lysyl-; D000804:Angiotensin II; D005640:Follicle Stimulating Hormone; D000803:Angiotensin I; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D002216:Captopril; D007703:Peptidyl-Dipeptidase A