Human Reproduction, Vol. 15, No. 6, 1345-1349,
June 2000
© 2000 European Society of Human Reproduction and Embryology
Angiotensin II in human seminal fluid
1 Division of Biomedical Sciences, and 2 Academic Department of Obstetrics and Gynaecology and Reproductive Physiology, St Bartholomew's and Royal London School of Medicine and Dentistry, Queen Mary & Westfield College, London E1 4NS, UK
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The renin–angiotensin system (RAS) and angiotensin II are important in sperm function and male fertility. Angiotensin II type I (AT1) receptors have been identified in developing and ejaculated human spermatozoa, and angiotensin can stimulate sperm motility, the acrosome reaction and binding to the zona pellucida. However, there is little information on the availability of the hormone to spermatozoa during the reproductive process. Seminal plasma and blood plasma obtained from normal and subfertile subjects was extracted, and angiotensin content was analysed by radioimmunoassay. Values obtained for blood angiotensin II were within the normal range at 16.0 ± 3.1 pg/ml (mean ± SEM). Values for seminal plasma were usually 3–5 fold higher, at 51.6 ± 9.3 pg/ml (n = 34, P < 0.0001). High performance liquid chromatography analysis showed that ~80% of the immunoreactive angiotensin was attributable to angiotensin II itself. However, seminal plasma angiotensin II concentrations were not correlated with blood angiotensin II, sperm concentration or sperm motility. The results show that immunoreactive angiotensin from a source other than the circulation is available to spermatozoa in human ejaculates. The results are consistent with the concept that angiotensin II has an important role in male fertility.
Key words: angiotensin II/blood/human/seminal fluid
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The renin–angiotensin system (RAS) has largely been considered in relation to electrolyte homeostasis and haemodynamics in the normal condition and in cardiovascular disease (Peach, 1977
; Cambien et al., 1991; Jeunemaitre et al., 1992). However, the presence of angiotensin II receptors in a variety of tissues suggests that it has a multitude of roles that are unrelated to these primary functions (Vinson et al., 1997; Smits et al., 1998). There is now also abundant evidence that many tissues receive angiotensin II from local paracrine sources, and localized tissue RAS have been found in the reproductive tract, as well as in other organs (Deschepper et al., 1986; Soubrier and Corvol, 1990; Dostal et al., 1992; Mulrow, 1992; Phillips et al., 1993; Hagemann et al., 1994). In the male, RAS components have been identified at many sites in the reproductive tract. Thus, (pro)renin mRNA and mRNA coding for angiotensinogen have been identified in rat and mouse testes (Deschepper et al., 1986; Dzau et al., 1987a,b; Hellmann et al., 1988), and renin has been identified in the Leydig cells of the rat and human testis (Pandey et al., 1984; Naruse et al., 1985; Deschepper et al., 1986; Dzau et al., 1987b). In rats, testicular renin is reduced by hypophysectomy but stimulated by human chorionic gonadotrophin (HCG) administration (Naruse et al., 1984), demonstrating its independence of the circulating RAS. Prorenin is also present and may be secreted by the testis, both into the circulation (Okuyama et al., 1988a; Sealey and Rubattu, 1989) and into human seminal fluid (Mukhopadhyay et al., 1995b).
The importance of the RAS in the male is also strongly indicated by the existence of a testis-specific angiotensin converting enzyme (ACE) isozyme that depends on a testis specific promoter in the 12th intron of the ACE gene (Zhou et al., 1995, 1996). Testis-specific ACE is expressed only in seminiferous tubules and developing spermatozoa (Brentjens et al., 1986; Mukhopadhyay et al., 1995a), though earlier reports suggested it is also present in the Leydig cell (Pandey et al., 1984). In human spermatozoa it has been localized specifically in the plasma membrane of the acrosome, equatorial and post-acrosome regions, and midpiece (Kohn et al., 1998a). In humans, angiotensin II generation has been demonstrated directly in the testis (Okuyama et al., 1988b) and both active renin and angiotensin II concentrations in internal spermatic vein plasma were increased in patients receiving HCG (Okuyama et al., 1988a). Autoradiographic studies, ligand binding assays and immunocytochemistry have all shown that angiotensin II receptors are present in Leydig cells (Millan and Aguilera, 1988; Vinson et al., 1995a,b). In addition, immunocytochemistry reveals that the AT1 receptor is present in cells of the germinal line, including germinal epithelium, and in the tails of developing spermatozoa (Vinson et al., 1995b).
Further evidence comes from studies on mice with a disrupted gene coding for the somatic and the testis-specific ACE forms. In these, males have reduced fertility, despite having normal testes, spermatozoa and mating behaviour (Krege et al., 1995). Sperm motility was also apparently normal (Esther et al., 1996), although ACE gene disruption results in poor sperm transport within the oviduct, and poor binding to the zona pellucida (Hagaman et al., 1998b).
The AT1 receptor identified by immunocytochemistry in human spermatozoa is clearly functional: stimulation of ejaculated spermatozoa by angiotensin II enhances motility and this is inhibited by the specific ATI antagonist losartan (Vinson et al., 1995b, 1996). Furthermore, the acrosome reaction has been reported to be inhibited by captopril (Foresta et al., 1991), and there is direct evidence that angiotensin II stimulates acrosomal exocytosis (Muller et al., 1997; Gur et al., 1998), though this action has been attributed to the presence of AT1 receptors by some authors (Gur et al., 1998), but to AT2 receptors by others (Kohn et al., 1998b). In mouse spermatozoa, local perfusion of motile but non-progressive spermatozoa with angiotensin II evoked a rapid, substantial rise in intracellular [Ca2+], which was blocked by losartan (Wennemuth et al., 1999). These results are all consistent with the view that spermatozoa possess functional AT(1) receptors that control motility and exocytosis.
If angiotensin II is important to sperm function and fertility, then it is important to evaluate its availability during reproductive events, and during transit through the reproductive tract. Inter alia, it is clearly important to assay angiotensin II concentrations in the ejaculate, not hitherto reported.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Sample collection
Paired blood and seminal plasma samples were collected with appropriate consent from patients attending the Assisted Conception Unit at Newham General Hospital, London, UK. All patients were required to abstain from sexual activity for a period of 3 days prior to sample production. According to published methods (Paulson et al., 1994
), blood (3 ml) was collected in ice cold Na2 EDTA Vacutainer tubes containing 150 µl of 0.025 mol/l phenantroline, 0.125 mol/l Na2 EDTA, 2 g/l neomycin in 2% ethanol, 30 µl of 5 mmol/l bestatin and 2.5 mmol/l chymostatin and 12 µl of 0.5 mol/l 8-hydroxyquinoline (all from Sigma Chemical Co. Poole, UK). Once collected, blood was chilled immediately on ice until centrifuged at 4°C at 1000 g for 15 min to separate blood cells from plasma. Prior to storage at -20°C, 7 µl of 5% phenylmethyl sulphonyl fluoride (Sigma Chemical Co.) was added to all plasma samples.
Sperm quality was assessed according to WHO criteria (World Health Organization, 1992). After liquefaction at room temperature for 40 min, 1 ml of seminal plasma was added to centrifuge tubes into the same medium as for blood samples.
Angiotensin II assay
Angiotensin II was assayed in both blood plasma and seminal plasma using a radioimmunoassay kit (Peninsula Laboratories, Merseyside, UK).
Sample extraction
The extraction procedure followed the manufacturers' recommendations. Samples were collected as outlined above and acidified by addition of an equal volume of 1% trifluoracetic acid (TFA) high performance liquid chromatography (HPLC) grade (Merck, Poole Dorset, UK) and centrifuged at 6000 g for 20 min at 4°C. Reverse phase solid phase extraction tubes (Envi-18 containing 500 mg octadecyl, 17% from Supelco, Sigma-Aldrich Company Ltd, Poole, Dorset, UK) were equilibrated with 1 ml acetonitrile and subsequently washed with 3ml of 1% TFA buffer. Samples were loaded onto the pre-treated columns and each column was washed with 6 ml 1% TFA. Angiotensin II peptide fractions were then eluted with 3 ml of 60% acetonitrile in 0.1% TFA and collected in polypropylene tubes. Eluants were evaporated to dryness overnight and stored at –20°C until required.
HPLC
The HPLC system consisted of two pumps (Waters 501; Millipore UK Ltd., Watford, UK), a variable-wavelength ultra violet detector (Waters 486 turntable absorbance detector; Millipore UK Ltd.), an injection system with a 20 µl sample loop, a solvent programmer and a fraction collector.
Separations were carried at room temperature at a flow rate of 1 ml/min on a 300x3.9 mm reversed-phase column (µBondpack C18 Waters 10 µm pore size). An isopropanol gradient (Merck) was used whereby isopropanol buffers contained 10 mmol/l triethylammonium phosphate (TEAP; Merck), pH 3, adjusted with phosphoric acid (Merck), increased from 5 to 40% in a linear fashion over 45 min. Before using the mobile phase buffers, they were degassed under helium gas.
To verify the choice of column and mobile phase, 20 µg of each of the synthetic angiotensin peptides were loaded on the column and peaks detected using UV detection at 220 nm and 0.2 absorbance units full scale. Before each HPLC run, the column was equilibrated with buffer B (40% isopropanol, 10 mmol/l TEAP pH 3) for 10 min followed by buffer A (5% isopropanol, 10 mmol/l TEAP pH 3), also for 10 min.
As the amount of angiotensin II present in plasma was not detectable by UV a mixture of angiotensin peptides was loaded on the HPLC column at a concentration of 100 pg/20 µl, which was within the range of the angiotensin II assay kit, and fractions were collected over an appropriate time scale. Retention times of the synthetic angiotensin peptides were consistent with those published (Hermann et al., 1988), and fraction collections were started when each HPLC run was 30% completed and continued for a period of 15 min. The fraction collector was programmed to collect a sample every 0.5 min. These fractions were subsequently dried overnight and analysed via angiotensin II radioimmunoassay. This provided information on the exact fraction number at which each angiotensin peptide eluted and also indicated the specificity of the commercial angiotensin II radioimmunoassay kit.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Immunoreactive angiotensin II was found in all samples of seminal plasma and the mean concentration was significantly higher than in blood taken from the same patients at the time of semen production (Figure 1
). Indeed, while the values for blood were mostly within the normal range, those for seminal plasma were higher. That this immunoreactivity was probably mostly attributable to angiotensin II itself was shown by immunoassay of eluates after HPLC separation of extracted seminal plasma; little immunoactivity was associated with angiotensins I or III (Figure 2).
|
|
The relationship between angiotensin II concentrations in blood and in semen from individual subjects is shown in Figure 3
, which indicates that there was no correlation between these two sets of values overall, and although it remains a possibility that there are subsets of this group of subjects, no clinical parameter suggested any basis for recognizing them. In particular, there was no relationship between seminal plasma angiotensin II and sperm count (Figure 4). In a group of 16 patients, no correlation was found between seminal plasma angiotensin II concentrations and either rapid or slow or total progressive sperm motility (data not shown).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
In nearly all of the subjects studied, immunoactive angiotensin II was present in higher concentrations in seminal plasma than in blood plasma taken at the same time. The most important conclusion to be drawn is that angiotensin II is available directly to the spermatozoa from a source other than circulating plasma (Figure 1
). Furthermore, although the antibody used for angiotensin radioimmunoassay has some cross reactivity with both angiotensin I and angiotensin III, HPLC profiles (Figure 2) suggest that these are not present in seminal plasma, and that consequently most of the immunoreactive angiotensin present represents the active angiotensin II form.
Taken together, there was no correlation between blood and seminal plasma angiotensin II, and for the values shown in Figure 3, the correlation coefficient was 0.11. Inspection of the data suggests there may be subgroups within these samples, however, and notably a small subset has high blood angiotensin II. If the six samples with values >30 pg angiotensin II/ml blood were excluded, there was a significant relationship with seminal plasma angiotensin II (r = 0.72), though the latter values were invariably higher than blood values, by a factor of about two on average. There may also be two groups of high (>50 pg/ml) and low seminal plasma angiotensin II. Although neither of these discriminations was associated with any clinical criterion, the existence of a correlation between the two sets of values, at least in a subgroup of subjects, suggests that there may be some universal systemic regulatory system that affects both, even though seminal plasma values (and thus the seminal plasma responses to such regulation) were higher.
Perhaps remarkably, in view of all the evidence regarding the presence of the testicular and indeed germ cell specific isoform of ACE, and its relationship to fertility (Foresta et al., 1987; Esther et al., 1997; Hagaman et al., 1998a), the data presented here do not support the view that spermatozoa themselves contribute greatly to seminal plasma angiotensin II, since oligospermic or aspermic samples nevertheless contained seemingly similar concentrations of angiotensin II as normal samples (Figure 4). In preliminary results with a small group of 16 patients, no correlation was found between rapid, slow or total forward progressive spermatozoa and seminal angiotensin II. However, bearing in mind that these subjects, in attendance at a fertility clinic, may have a varied aetiology, this is a topic that will need further investigation. In addition, studies on vasectomized patients, or in split ejaculates, would also be valuable to ascertain the possible origins of the hormone.
The most important point, however, is that, taken with evidence of the actions of angiotensin II on sperm motility and the acrosome reaction (Foresta et al., 1991; Vinson et al., 1995b, 1996; Muller et al., 1997; Gur et al., 1998), it is clear that angiotensin II is not only important for sperm function, it is also available in significant concentrations.
One point this concept raises is that the acrosome reaction, and binding to the ovum, may occur only after the spermatozoa have spent some hours in the uterus (Yanamigachi, 1994). Thus the immediate significance of seminal angiotensin II to these events is less clear. How far seminal plasma angiotensin II can be transported in the vagina and uterus, and for what period it can be maintained at a significant concentration, are questions requiring answers that cannot at present even be guessed at. If it is a reasonable speculation, however, that, like most active hormones in tissue or plasma, the half-life of seminal plasma angiotensin II in the female tract is unlikely to be much more than a few minutes, then the immediate significance of the ejaculated hormone is more likely to be connected with sperm motility, and perhaps capacitation. This does not exclude a critical role for angiotensin II at later stages too, but suggests that other sources of the hormone may then be more important. As in the male, evidence for local RAS has been described for several sites in the female tract (Hsueh, 1988; Sealey and Rubattu, 1989; Hagemann et al., 1994; Vinson et al., 1997), and, of these, the ovary might perhaps be most pertinent to this discussion. Prorenin production, renin and angiotensin converting enzyme, and the mRNA coding for them, have all been demonstrated in the ovary (Derkx et al., 1987; Itskovitz and Sealey, 1987; Bumpus et al., 1988; Metzger et al., 1988; Howard and Husain, 1992). Increased peritoneal angiotensin II concentrations in the peri-ovulatory period suggest that follicular angiotensin II is released at ovulation into the Fallopian tube (Delbaere et al., 1996). It may be this source of angiotensin that is most relevant to the actions of angiotensin of spermatozoa at the time of ovum fertilization, and also facilitate ovum transport, in view of the presence of angiotensin II AT1 receptors in both Fallopian tube and uterine epithelial cells, as well as in spermatozoa (Vinson et al., 1995a,b, 1996; Delbaere et al., 1996; Saridogan et al., 1996a,b).
The present data also raise the question of the site of synthesis of seminal plasma angiotensin II, given that the contribution of the spermatozoa appears to be slight. While renin and angiotensinogen have both been identified in the testis and epididymis, production rates of angiotensin would seemingly need to be very high to account for the concentrations of the hormone that were detected in seminal plasma, given the great dilution of the testicular product by prostatic secretion. The same would seem to be true for the presence of prorenin in seminal plasma (Mukhopadhyay et al., 1995b). The possibility that the prostate itself might secrete angiotensin would seem to require careful study.
|
Acknowledgments |
|---|
O.A.O'Mahony is grateful to the Ernst Schering Foundation for financial support.
|
Notes |
|---|
3 To whom correspondence should be addressed.E-mail: O.A.OMahony{at}qmw.ac.uk
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Brentjens, J.R., Matsuo, S., Andres, G.A. et al. (1986) Gametes contain angiotensin converting enzyme (kininase-II). Experientia, 42, 399–402.[Web of Science][Medline]
Bumpus, F.M., Pucell, A.G., Daud, A.I. et al. (1988) Angiotensin II: an intraovarian regulatory peptide. Am. J. Med. Sci., 295, 406–408.[Web of Science][Medline]
Cambien, F., Poirier, O., Lecerf, L. et al. (1991) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature, 359, 641–644.
Delbaere, A., Bergmann, P.J.M., Gervydecoster, C. et al. (1996) Periovulatory elevation of angiotensin-II in the peritoneal-fluid during the human menstrual-cycle. J. Clin. Endocrinol. Metab., 81, 2810–2815.
Derkx, F.H., Alberda, A.T., Zeilmaker, G.H. et al. (1987) High concentrations of immunoreactive renin, prorenin and enzymatically-active renin in human ovarian follicular fluid. Br. J. Obstet. Gynaecol., 94, 4–9.[Web of Science][Medline]
Deschepper, C.F., Mellon, S.H., Cumin, F. et al. (1986) Analysis by immunocytochemistry and in situ hybridisation of renin and its mRNA in kidney, testis, adrenal, and pituitary of the rat. Proc. Natl Acad. Sci. USA, 83, 7552–7556.
Dostal, D.E., Rothblum, K.N., Chernin, M.L. et al. (1992) Intracardiac detection of angiotensinogen and renin: a localised renin–angiotensin system in neonatal heart. Am. J. Physiol., 263, C838–C850.
Dzau, V.J., Brody, T., Ellison, K.E. et al. (1987a) Tissue-specific regulation of renin expression in the mouse. Hypertension, 9, III36–III41.
Dzau, V.J., Ellison, K.E., Brody, T. et al. (1987b) A comparative study of the distributions of renin and angiotensin messenger ribonucleic acids in rat and mouse. Endocrinology, 120, 2334–2338.
Esther, C.R., Howard, T.E., Marino, E.M. et al. (1996) Mice lacking angiotensin-converting enzyme have low blood-pressure, renal pathology, and reduced male-fertility. Lab. Invest., 74, 953–965.[Web of Science][Medline]
Esther, C.R., Semeniuk, D., Marino, E.M. et al. (1997) Expression of testis angiotensin-converting enzyme is mediated by a cyclic AMP responsive element. Lab. Invest., 77, 483–488.[Web of Science][Medline]
Foresta, C., Indino, M., Manoni, F. et al. (1987) Angiotensin-converting enzyme content of human spermatozoa and its release during capacitation. Fertil. Steril., 47, 1000–1003.[Web of Science][Medline]
Foresta, C., Mioni, R., Rossato, M. et al. (1991) Evidence for the involvement of sperm angiotensin converting enzyme in fertilization. Int. J. Androl., 14, 333–339.[Web of Science][Medline]
Gur, Y., Breitbart, H., Lax, Y. et al. (1998) Angiotensin II induces acrosomal exocytosis in bovine spermatozoa. Am. J. Physiol., 38, E87–E93.
Hagaman, J.R., Moyer, J.S., Bachman, E.S. et al. (1998a) Angiotensin-converting enzyme and male fertility. Proc. Natl Acad. Sci. USA, 95, 2552–2557.
Hagaman, J.R., Moyer, J.S., Bachman, E.S. et al. (1998b) Angiotensin-converting enzyme and male fertility. Proc. Natl Acad. Sci. USA, 95, 2552–2557.
Hagemann, A., Nielsen, A.H. and Poulsen, K. (1994) The uteroplacental renin–angiotensin system – a review. Exp. Clin. Endocrinol., 102, 252–261.[Web of Science][Medline]
Hellmann, W., Suzuki, F., Ohkubo, H. et al. (1988) Angiotensinogen gene expression in extrahepatic rat tissues: application of a solution hybridization assay. Naunyn Schmiedeberg's Arch. Pharmacol., 338, 327–331.[Web of Science][Medline]
Hermann, K., Ganten, D., Unger, T. et al. (1988) Measurement and characterization of angiotensin peptides in plasma. Clin. Chem., 34, 1046–1051.
Howard, R.B. and Husain, A. (1992) Rat ovarian angiotensin II receptors, renin, and angiotensin I-converting enzyme during pregnancy and the postpartum period. Biol. Reprod., 47, 925–930.[Abstract]
Hsueh, W.A. (1988) Renin in the female reproductive system. Cardiovasc. Drugs Ther., 2, 473–477.[Web of Science][Medline]
Itskovitz, J. and Sealey, J.E. (1987) Ovarian prorenin–renin–angiotensin system. Obstet. Gynecol. Surv., 42, 545–551.[Medline]
Jeunemaitre, X., Soubrier, F., Kotelevtsev, Y.V. et al. (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell, 71, 169–180.[Web of Science][Medline]
Kohn, F.M., Dammshauser, I., Neukamm, C. et al. (1998a) Ultrastructural localization of angiotensin-converting enzyme in ejaculated human spermatozoa. Hum. Reprod., 13, 604–610.
Kohn, F.M., Muller, C., Drescher, D. et al. (1998b) Effect of angiotensin converting enzyme (ACE) and angiotensin on human sperm functions. Andrologia, 30, 207–215.[Web of Science][Medline]
Krege, J.H., John, S.W.M., Langenbach, L.L. et al. (1995) Male–female differences in fertility and blood-pressure in ACE-deficient mice. Nature, 375, 146–148.[Medline]
Metzger, R., Wagner, D., Takahashi, S. et al. (1988) Tissue renin–angiotensin systems aspects of molecular biology and pharmacology. Clin. Exp. Hypertens. A, 10, 1227–1238.[Web of Science][Medline]
Millan, M.A. and Aguilera, G. (1988) Angiotensin II receptors in testes. Endocrinology, 122, 1984–1990.
Mukhopadhyay, A.K., Cobilanschi, J., Brunswig-Spickenheier, B. and Leidenberger, F.A. (1995a) Relevance of the tissue prorenin-renin-angiotensin system to male reproductive physiology. In Mukhopadhyay, A.K. and Raizada, M.K. (eds), Tissue Renin–Angiotensin Systems. Plenum, New York & London, pp. 269–277.
Mukhopadhyay, A.K., Cobilanschi, J., Schulze, W. et al. (1995b) Human seminal fluid contains significant quantities of prorenin – its correlation with the sperm density. Mol. Cell, Endocrinol., 109, 219–224.[Web of Science][Medline]
Muller, C., Kohn, F.M. and Schill, W.B. (1997) Induction of the acrosome reaction by angiotensin II. Hum. Reprod., 12 (Abstract Bk.1), O75.
Mulrow, P.J. (1992) Adrenal renin: regulation and function. Front. Neuroendocrinol., 13, 47–60.[Web of Science][Medline]
Naruse, K., Murakoshi, M., Osmura, R.Y. et al. (1985) Immunohistochemical evidence for renin in human endocrine tissues. J. Clin. Endocrinol. Metab., 61, 172–177.
Naruse, M., Naruse, K., Shizume, K. et al. (1984) Gonadotropin-dependent renin in rat testes. Proc. Soc. Exp. Biol. Med., 177, 337–342.[Medline]
Okuyama, A., Nonomura, N., Koh, E. et al. (1988a) Induction of renin–angiotensin system in human testis in vivo. Arch. Androl., 21, 29–35.[Web of Science][Medline]
Okuyama, A., Nonomura, N., Nakamura, M. et al. (1988b) Renin–angiotensin system. Arch. Androl., 21, 169–180.[Web of Science][Medline]
Pandey, K.N., Misono, K.S. and Inagami, T. (1984) Evidence for intracellular formation of angiotensins – coexistence of renin and angiotensin-converting enzyme in Leydig-cells of rat testis. Biochem. Biophys Res. Commun., 122, 1337–1343.[Web of Science][Medline]
Paulson, S., Verhage, L., Mayer, D., et al. (1994) A nonequilibrium radioimmunoassay for angiotensin II. J. Pharmacol. Toxicol. Meth., 32, 93–97.[Web of Science][Medline]
Peach, M.T. (1977) Renin–angiotensin system: biochemistry and mechanism of action. Physiol. Rev., 57, 313–370.
Phillips, M.I., Speakman, E.A. and Kimura, B. (1993) Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul. Pept., 43, 1–20.[Web of Science][Medline]
Saridogan, E., Djahanbakhch, O., Puddefoot, J.R. et al. (1996a) Angiotensin II receptors and angiotensin II stimulation of ciliary activity in human Fallopian tube. J. Clin. Endocrinol. Metab., 81, 2719–2725.[Abstract]
Saridogan, E., Djahanbakhch, O., Puddefoot, J.R. et al. (1996b) Type 1 angiotensin II receptors in human endometrium. Mol. Hum. Reprod., 2, 659–664.
Sealey, J.E. and Rubattu, S. (1989) Prorenin and renin as separate mediators of tissue and circulating systems. Am. J. Hypertens., 2, 358–366.[Web of Science][Medline]
Smits, J.F.M., Passier, R.C.J.J. and Daemen, M.J.A.P. (1998) Should we aim at tissue renin–angiotensin systems? Pharmacy World Science, 20, 93–99.
Soubrier, F. and Corvol, P. (1990) Clinical implications of the molecular biology of the renin–angiotensin system. Eur. Heart J., 11, 3–10.
Vinson, G.P., Ho, M.M. and Puddefoot, J.R. (1995a) The distribution of angiotensin II type 1 receptors, and the tissue renin–angiotensin systems. Mol. Med. Today, 1, 35–39.[Web of Science][Medline]
Vinson, G.P., Puddefoot, J.R., Ho, M.M. et al. (1995b) Type 1 angiotensin II (AT1) receptors in sperm. J. Endocrinol., 144, 369–378.
Vinson, G.P., Mehta, J., Evans, S. et al. (1996) Angiotensin-II stimulates sperm motility. Regul. Pept., 67, 131–135.[Web of Science][Medline]
Vinson, G.P., Saridogan, E., Puddefoot, J.R. et al. (1997) Tissue renin–angiotensin systems and reproduction. Hum. Reprod., 12, 651–662.
Wennemuth, G., Babcock, D.F. and Hille, B. (1999) Distribution and function of angiotensin II receptors in mouse spermatozoa. Andrologia, 31, 323–325.[Web of Science][Medline]
World Health Organization (1992) Recent Advances in Medically Assisted Conception. WHO Tehcnical Report Series, 820.
Yanamigachi, R. (1994) Mammalian fertilisation. In Knobil, E. and Neill, J. (eds), The Physiology of Reproduction. Raven Press, New York, pp. 189–317.
Zhou, Y.D., Delafontaine, P., Martin, B.M. et al. (1995) Identification of 2 positive transcriptional elements within the 91-base pair promoter for mouse testis angiotensin-converting enzyme (testis ace). Dev. Genet., 16, 201–209.[Web of Science][Medline]
Zhou, Y.D., Overbeek, P.A. and Bernstein, K.E. (1996) Tissue-specific expression of testis angiotensin-converting enzyme is not determined by the –32 nonconsensus tata motif. Biochem. Biophys Res. Commun., 223, 48–53.[Web of Science][Medline]
Submitted on November 23, 1999; accepted on March 3, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Uemura, H. Ishiguro, Y. Ishiguro, K. Hoshino, S. Takahashi, and Y. Kubota Angiotensin II Induces Oxidative Stress in Prostate Cancer Mol. Cancer Res., February 1, 2008; 6(2): 250 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Rylett, M. J. Walker, G. J. Howell, A. D. Shirras, and R. E. Isaac Male accessory glands of Drosophila melanogaster make a secreted angiotensin I-converting enzyme (ANCE), suggesting a role for the peptide-processing enzyme in seminal fluid J. Exp. Biol., October 15, 2007; 210(20): 3601 - 3606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Uemura, H. Ishiguro, Y. Nagashima, T. Sasaki, N. Nakaigawa, H. Hasumi, S. Kato, and Y. Kubota Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells Mol. Cancer Ther., November 1, 2005; 4(11): 1699 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Diaz-Perales, V. Quesada, L. M. Sanchez, A. P. Ugalde, M. F. Suarez, A. Fueyo, and C. Lopez-Otin Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase J. Biol. Chem., April 8, 2005; 280(14): 14310 - 14317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mededovic and L. R Fraser Mechanisms of action of angiotensin II on mammalian sperm function Reproduction, February 1, 2005; 129(2): 211 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. A. O'Mahony, S. Barker, J. R. Puddefoot, and G. P. Vinson Synthesis and Secretion of Angiotensin II by the Prostate Gland in Vitro Endocrinology, January 1, 2005; 146(1): 392 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mededovic and L. R Fraser Angiotensin II stimulates cAMP production and protein tyrosine phosphorylation in mouse spermatozoa Reproduction, May 1, 2004; 127(5): 601 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Fraser and O. O. Osiguwa Human sperm responses to calcitonin, angiotensin II and fertilization-promoting peptide in prepared semen samples from normal donors and infertility patients Hum. Reprod., March 1, 2004; 19(3): 596 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Fraser, M. D. Pondel, and G. P. Vinson Calcitonin, angiotensin II and FPP significantly modulate mouse sperm function Mol. Hum. Reprod., March 1, 2001; 7(3): 245 - 253. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||