The bradykinin-degrading aminopeptidase P is increased in women taking the oral contraceptive pill

Abstract

Introduction. The renin-angiotensin and kininogen-kinin hormonal systems are critically involved in regulating blood pressure and are candidates in contributing to oral contraceptive pill (OCP)-induced hypertension.Angiotensin-converting enzyme (ACE) and aminopeptidase P (AP-P) are key enzymes in these systems and are both involved in the degradation of the vasodilator bradykinin.

Methods. Circulating ACE and AP-P levels were measured by activity assay using selective fluorogenic peptide substrates in plasma samples from the Leeds Family Study. In addition, the effect of progesterone on the expression of AP-P and ACE was examined in cells.

Results. Women on the OCP had higher age-adjusted plasma AP-P (mean [95% confidence interval]) (0.27 [0.23-0.32] nmol/min/ml (n = 53)) compared with women not on the OCP (0.17 [0.16-0.19] nmol/min/ml (n = 133), p < 0.001) or males (0.19 [0.17-0.20] nmol/min/ml (n = 209), p<0.001).There were no differences in the age-adjusted plasma ACE levels among the three groups. In HepG2 cells, progesterone treatment increased the AP-P protein and mRNA expression, whereas no effect of progesterone treatment was observed for ACE.

Conclusion. Increased AP-P may result in increased breakdown of bradykinin.These data suggest that progesterone-induced increases in AP-P may contribute to the development of OCP-induced hypertension in susceptible Women.

Keywords

aminopeptidase blood pressure oral contraceptive pill

Get full access to this article

View all access options for this article.

References

Miyagawa K. , Rosch J. , Stanczyk F. , Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997;3:324-7.

Meade TW Risks and mechanisms of cardiovascular events in users of oral contraceptives . Am J Obstet Gynecol 1988;158:1646-52.

Oparil S. , Miller AP Gender and blood pressure. J Clin Hypertens 2005;7:300-09.

Stachenfeld NS , Taylor HS Progesterone increases plasma volume independent of estradiol. J Appl Physiol 2005 ; 98:1991-7.

Turner AJ , Hooper NM The angiotensin-converting enzyme gene family: genomics and pharmacology . Trends Pharmacol Sci 2002;23:177-83.

Ersahin C. , Simmons WH Inhibition of both aminopeptidase P and angiotensin-converting enzyme prevents bradykinin degradation in the rat coronary circulation. J Cardiovasc Pharmacol 1997;30:96-101.

Kim K. -S, Kumar S. , Simmons WH , Brown NJ Inhibition of aminopeptidase P potentiates wheal response to bradykinin in angiotensin-converting enzyme inhibitor-treated humans. J Pharmacol Exp Ther 2000;292:295-8.

Cyr M. , Lepage Y. , Blais C., Jr. et al. Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma. Am J Physiol Heart Circ Physiol 2001;281:H275-83.

Freeman MS , Mansfield MW , Barrett JH , Grant PJ Genetic contribution to circulating levels of haemostatic factors in healthy families with effects of known genetic polymorphisms on heritability . Arterioscler Thromb Vasc Biol 2002;22:506-10.

10.

Freeman MS , Mansfield MW , Barrett JH , Grant PJ Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 2002 ;19:994-9.

11.

Freeman MS , Mansfield MW , Barrett JH , Grant PJ Insulin resistance: an atherothrombotic syndrome. The Leeds family study. Thromb Haemost 2003;89:161-8.

12.

Lefebvre, J. , Murphey, LJ , Hartert, TV , JiaoShan R. , SimmonsWH, Brown NJ Dipeptidyl peptidase IV activity in patients with ACE-inhibitor-associated angioedema. Hypertension 2002;39: 460-4.

13.

Rice GI , Thomas DA , Grant PJ , Turner AJ , Hooper NM Evaluation of angiotensin converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004;383:45-51.

14.

Ribstein J. , Halimi JM , du Cailar G. , Mimran A. Renal characteristics and effect of angiotensin suppression in oral contraceptive users. Hypertension 1999;33:90-5.

15.

Proudler AJ , Ahmed AI , Crook D. , Fogelman I. , Rymer JM , Stevenson JC Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet 1995 ;346:89-90.

16.

Stevenson JC , Oladipo A. , Manassiev N. , Whitehead MI , Guilford S. , Proudler AJ Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers . Br J Haematol 2004;124: 802-08.

17.

Schunkert H. , Danser AH , Hense HW , Derkx FH , Kurzinger S. , Riegger GA Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women . Circulation 1997;95:39-45.

18.

Fryer RM , Segreti J. , Banfor PN et al. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema . Br J Pharmacol 2008;153:947-55.

19.

Drouet C. , Desormeaux A. , Robillard J. et al. Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. J Allergy Clin Immunol 2008;121:429-33.

20.

McGlinchey PG , McCluskey DR Hereditary angioedema precipitated by estrogen replacement therapy in a menopausal woman. Am J Med Sci 2000;320:212-3.

21.

Bork K. , Fischer B. , Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-8.

22.

Andre F. , Veysseyre-Balter C. , Rousset H. , Descos L. , Andre C. Exogenous oestrogen as an alternative to food allergy in the aetiology of angioneurotic oedema. Toxicology 2003;185: 155-60.

23.

Amar L. , Lidove O. , Kahn JE et al. Hereditary angiooedema: effective treatment with the progestogen-only pill in a young woman. Br J Dermatol 2004;151:713-4.