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To the Editor:

Although numerous effects of angiotensin-converting enzyme (ACE) inhibitors were documented in various tissues, their influence on human oviduct was not investigated. It was shown that angiotensin II receptors exist in epithelial cells of fallopian tubes, and when stimulated by an agonist, they induce movement of negatively charged ions from a basal to luminal side of the epithelial cells.[1] In a functional study on isolated human oviduct, angiotensin II-stimulated movements of the epithelial cells' cilia, suggesting indirect influence on fertilization process; however, angiotensin II did not affect fallopian tubes' motility in the same study.[2] Knowing that ACE exists in oviduct tissues, especially in the ampullary region, and that another substrate, bradykinin, triggers tonic contractions of both isthmus and ampulla,[3] we decided to test whether ACE inhibitors influence motility of isolated human oviduct.

The fallopian tubes were taken from 14 female patients (39.3±9.7 years) during abdominal hysterectomy with salpingo-oophorectomy (performed in 2011 and 2012) due to uterine fibroids causing prolonged and irregular uterine bleeding for at least 3 months. The study was approved by the ethics committee of the clinical center “Kragujevac,” and the patients signed informed consent forms. Two types of fallopian tube preparations were mounted in the isolated organ baths: isthmus and ampulla. The tension of the isolated preparations was recorded by isometric transducer (Palmer Bio Science, Los Angeles, CA) and registered on a personal computer using special interface and software (Majk Electronic, Mladenovac, Serbia). Both phasic and tonic contractions of the isolated preparations were measured as the area under the tension recordings (AUC). Captopril (Sigma-Aldrich, Buchs, Switzerland) and enalapril maleate (Sigma-Aldrich, St. Louis, MO) were separately added to the organ baths in a cumulative way, gradually increasing their concentration in the baths' solution.

Enalapril (2.7×10−7–3.9×10−4 M) did not affect either phasic, spontaneous activity, or tone of both isolated isthmus and ampulla. On the other hand, captopril (6.1×10−7–2.7×10−3 M) caused concentration-dependent tonic contraction of the isolated ampulla (EC50=0.27±2.1×10−7 M; F=9.14, df1=7, df2=16, P<.01) (Figure 1), while tone of the isolated isthmus and spontaneous activity of both isthmus and ampulla were not affected by this substance.

image

Figure 1. Concentration-dependent tonic contractions of isolated fallopian tube ampulla caused by captopril. Enalapril did not show contractile effect. (■) captopril; (●) enalapril.

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It is not surprising that captopril caused tonic contraction of ampullar segment, while enalapril did not, since captopril has much higher affinity for ACE than enalapril in various tissues.[4, 5] The affinity of captopril for ACE is more than 100 times higher than that of enalapril,[6] which explains why enalapril in almost the same bath concentrations did not cause contraction of ampulla, while captopril did.

Our finding draws attention to that possibility that ACE inhibitors may interfere with fertilization in female patients who take these drugs chronically for various reasons. Of course, this is just a hypothesis that needs to be confirmed by cohort or case-control studies in real life. But, if confirmed, it would profoundly influence prescribing of ACE inhibitors to women during their reproductive age.

Acknowledgments

  1. Top of page
  2. Acknowledgments
  3. References

The work described in this letter was partially financed by grant No. 175007 given by the Serbian Ministry of Education and by a grant given by the Ministry of Science of Montenegro.

References

  1. Top of page
  2. Acknowledgments
  3. References
  • 1
    Mahmood T, Djahanbakhch O, Burleigh DE, et al. Effect of angiotensin II on ion transport across human fallopian tube epithelial cells in vitro. Reproduction. 2002;124:573579.
  • 2
    Saridogan E, Djahanbakhch O, Puddefoot JR, et al. Angiotensin II receptors and angiotensin II stimulation of ciliary activity in human fallopian tube. J Clin Endocrinol Metab. 1996;81:27192725.
  • 3
    Fernández-Pardal J, Chaud M, Viggiano M, et al. Converting enzyme activity in sow oviducts at different stages of the sex cycle. Influence of inhibitors of prostaglandin synthesis and its possible role in the inotropic effects of bradykinin. Pharmacol Res Commun. 1986;18:4960.
  • 4
    Johnston CI, Fabris B, Yamada H, et al. Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens Suppl. 1989;7:S11S16.
  • 5
    Grinshtein SV, Binevski PV, Gomazkov OA, et al. Inhibitor analysis of angiotensin I-converting and kinin-degrading activities of bovine lung and testicular angiotensin-converting enzyme. Biochemistry (Mosc). 1999;64:938944.
  • 6
    Udupa EG, Rao NM. Inhibition of angiotensin converting enzyme from sheep tissues by captopril, lisinopril and enalapril. Indian J Biochem Biophys. 1997;34:524528.