Abstract
Introduction: The pleiotropic kininogen–kallikrein–kinin system is upregulated in pregnancy and localizes in the uteroplacental unit. To identify the systemic and local participation of the bradykinin type 2 receptor (B2R), this was antagonized by Bradyzide (BDZ) during 2 periods: from days 20 to 34 and from days 20 to 60 in pregnant guinea pigs. Methods: Pregnant guinea pigs received subcutaneous infusions of saline or BDZ from gestational day 20 until sacrifice on day 34 (Short B2R Antagonism [SH-B2RA]) or on day 60 (Prolonged B2R Antagonism [PR-B2RA]). In SH-BDZA, systolic blood pressure was determined on day 34, while in PR-BDZA it was measured preconceptionally, at days 40 and 60. On gestational day 60, plasma creatinine, uricemia, proteinuria, fetal, placental and maternal kidney weight, and the extent of trophoblast invasion were evaluated. Results: The SH-B2RA increased systolic blood pressure on day 34 and reduced trophoblast myometrial invasion, spiral artery remodeling, and placental sufficiency. The PR-B2RA suppressed the normal blood pressure fall observed on days 40 and 60; vascular transformation, placental efficiency, urinary protein, serum creatinine, and uric acid did not differ between the groups. The proportion of all studied mothers with lost fetuses was greater under BDZ infusion than in controls. Conclusion: The increased systolic blood pressure and transient reduction in trophoblast invasion and fetal/placental weight in the SH-B2R blockade and the isolated impact on blood pressure in the PR-B2R blockade indicate that bradykinin independently modulates systemic hemodynamics and the uteroplacental unit through cognate vascular and local B2R receptors.
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References
Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A. The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci. 2005;99(1):6–38.
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6.
Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin- receptor blockade on the response to angiotensin-converting-enzyme inhibitor innormotensive and hypertensive subjects. N Engl J Med. 1998;339(18):1285–92.
Cockcroft JR, Chowienczyk PJ, Brett SE, Bender N, Ritter JM. Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol. 1994;38(4):317–21.
Nunes RAB, Lima LB, Tanaka NI, da Costa PA, Krieger JE, Mansur AJ. Genetic associations of bradykinin type 2 receptor, alpha-adrenoceptors and endothelial nitric oxide synthase with blood pressure and left ventricular mass in outpatients without overt heart disease. Int J Cardiol Heart Vasc. 2018;21:45–9.
Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62(8):842–56.
Charignon D, Spath P, Martin L, Drouet C. Icatibant, the bradykinin B2 receptor antagonist with target to the interconnected kinin systems. Expert Opin Pharmacother. 2012;13(15):2233–47.
Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79–99.
Regoli D, Gobeil F. Kinins and peptide receptors. Biol Chem. 2016;397(4):297–304.
Vidal MA, Astroza A, Matus CE, et al. Kinin B2 receptor-coupled signal transduction in human cultured keratinocytes. J Invest Dermatol. 2005;124(1):178–86.
Alves JM, Martins AH, Lameu C, et al. Kinin-B2 receptor activity in skeletal muscle regeneration and myoblast differentiation. Stem Cell Rev. 2018. https://doi.org/10.1007/s12015-018-9850-9.
Erices R, Corthorn J, Lisboa F, Valdés G. Bradykinin promotes migration and invasion of human immortalized trophoblasts. Reprod Biol Endocrinol. 2011;9:97.
Buchinger P, Rehbock J. The bradykinin B2-receptor in human decidua. Semin Thromb Hemost. 1999;25(6):543–9.
Valdés G, Germain AM, Corthorn J, Chacón C, Figueroa CD, Müller-Esterl W. Tissue kallikrein and bradykinin B2 receptor in human uterus in luteal phase and in early and late gestation. Endocrine. 2001;16(3):207–15.
Valdés G, Acuña S, Munizaga A, Soto GX, Figueroa CD. Utero-placental cellular and nuclear expression of bradykinin B2 receptors in normal and preeclamptic pregnancies. Pregnancy Hypertens. 2016;6(1):30–7.
Rabaglino MB, Post Uiterweer ED, Jeyabalan A, Hogge WA, Conrad KP. Bioinformatics approach reveals evidence for impaired endometrialmaturation before and during early pregnancy in women who developed preeclampsia. Hypertension. 2015;65(2):421–9.
Valdés G, Corthorn J, Oyarzún E, et al. Urinary kallikrein excretion in the human menstrual cycle, normal pregnancy and lactation. Prenatal Neonatal Med. 1998;3:474–81.
Elebute OA, Mills IH. Urinary kallikrein in normal and hypertensive pregnancies. Perspect Nephrol Hypertens. 1976;5:329–38.
Millar JG, Campbell SK, Albano JD, Higgins BR, Clark AD. Early prediction of preeclampsia by measurement of kallikrein and creatinine on a random urine sample. Br J Obstet Gynaecol. 1996;103(5):421–6.
Khedun SM, Naicker T, Moodley J, Naidoo S, Bhoola KD. Changes in urinary tissue kallikrein excretion in black African women with hypertensive disorders of pregnancy. Immunopharmacology. 1997;36(2-3):243–7.
Kaufmann P, Davidoff M. The guinea-pig placenta. Adv Anat Embryol Cell Biol. 1977;53(2):5–91.
Nanaev A, Chwalisz K, Frank HG, Kohnen G, Hegele-Hartung C, Kaufmann P. Physiological dilation of utero-placental arteries in the guinea pig depends on nitric oxide synthase activity of extravillous trophoblast. Cell Tissue Res. 1995;282(3):407–21.
Craven CM, Morgan T, Ward K. Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta. 1998;19(4):241–5.
Mess A, Zaki N, Kadyrov M, Korr H, Kaufmann P. Caviomorph placentation as a model for trophoblast invasion. Placenta. 2007;28(11-12):1234–8.
Csapo AL, Purri CT, Tarro S. Relationship between ovariectomy and maintenance of pregnancy in the guinea-pig. Prostaglandins. 1981;22(1):131–40.
Mitchell BF, Taggart MJ. Are animal models relevant to key aspects of human parturition? Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R525–45.
Seidl DC, Hughes HC, Bertolet R, Lang CM. True pregnancy toxemia (preeclampsia) in the guinea pig (Cavia porcellus). Lab Anim Sci. 1979;29(4):472–8.
Golden JG, Hughes HC, Lang CM. Experimental toxemia in the pregnant guinea pig (Cavia porcellus). Lab Anim Sci. 1980;30(2 Pt 1):174–9.
Valdés G, Erices R, Chacón C, Corthorn J. Angiogenic, hyper-permeability and vasodilator network in utero-placental units along pregnancy in the guinea-pig (Cavia porcellus). Reprod Biol Endocrinol. 2008;6:13.
Corthorn J, Rey S, Chacón C, Valdés G. Spatio-temporal expression of MMP-2, MMP-9 and tissue kallikrein in utero-placental units of the pregnant guinea-pig (Cavia porcellus). Reprod Biol Endocrinol. 2007;5:27.
Morrison JL, Botting KJ, Darby JRT, et al. Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J Physiol. 2018;596(23):55385–569.
Burgess GM, Perkins MN, Rang HP, et al. Bradyzide, a potent non-peptide B(2) bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia. Br J Pharmacol. 2000;129(1):77–86.
Valdés G, Schneider D, Corthorn J, Ortíz R, Acuña S, Padilla O. Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guineapigs. Reprod Biol Endocrinol. 2014;12:49–57.
Hart MV, Hosenpud JD, Hohimer AR, Morton MJ. Hemodynamics during pregnancy and sex steroid administration in guinea pigs. Am J Physiol. 1985;249(2 Pt 2):R179–85.
Fowden AL, Sferruzzi-Perri AN, Coan PM, Constancia M, Burton GJ. Placental efficiency and adaptation: endocrine regulation. J Physiol. 2009;587(Pt 14):3459–72.
Detry MA, Ma Y. Analysing repeated measurements using mixed models. JAMA. 2016;315(4):407–8.
El-Mas MM, Abdel-Rahman AA. Bradykinin B2 receptor-dependent enhancement of enalapril-evoked hypotension in ethanol-fed female rats. J Cardiovasc Pharmacol. 2011;57(1):72–8.
Teixeira JM, de Oliveira-Fusaro MC, Parada CA, Tambeli CH. Peripheral P2X7 receptor-induced mechanical hyperalgesia is mediated by bradykinin. Neuroscience. 2014;277:163–73.
Cervenka L, Maly J, Karasova J, et al. Angiotensin II–induced hypertension in bradykinin B2 receptor knockout mice. Hypertension. 2001;37(3):967–73.
Madeddu P, Parpaglia PP, Demontis MP, et al. Bradykinin B2-receptor blockade facilitates deoxycorticosterone-salt hypertension. Hypertension. 1993;21(6 Pt 2):980–4.
Pijnenborg R, Vercruyse L, Hanssens H, Brosens I. Endovascular trophoblast and preeclampsia: a reassessment. Pregnancy Hypertension. 2011;1(1):66–71.
Figueroa CD, Marchant A, Novoa U, et al. Differential distribution of bradykinin B(2) receptors in the rat and human cardiovascular system. Hypertension. 2001;37(1):110–20.
Schmitz S, Henke J, Tacke S, Guth B. Successful implantation of an abdominal aortic blood pressure transducer and radio-telemetry transmitter in guinea pigs - Anaesthesia, analgesic management and surgical methods, and their influence on hemodynamic parameters and body temperature. J Pharmacol Toxicol Methods. 2016;80:9–18.
Clemons DJ, Terril-Robb LA. The Laboratory Guinea pig. 1st ed. New York, NY: CRC Press; 1998.
Thompson LP, Pence L, Pinkas G, Song H, Telugu BP. Placental hypoxia during early pregnancy causes maternal hypertension and placental insufficiency in the hypoxic guinea pig model. Biol Reprod. 2016;95(6):128–38.
Cooper AC, Robinson G, Vinson GP, Cheung WT, Broughton PF. The localization and expression of the renin-angiotensin system in the human placenta throughout pregnancy. Placenta. 1999;20(5-6):467–74.
Herse F, Dechend R, Harsem NK, et al. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension. 2007;49(3):604–11.
Anton L, Merrill DC, Neves LA, et al. The uterine placental bed renin-angiotensin system in normal and preeclamptic pregnancy. Endocrinology. 2009;150(9):4316–25.
Williams PJ, Mistry HD, Innes BA, Bulmer JN, Broughton PF. Expression of AT1 R, AT2 R and AT4 R and their roles in extravillous trophoblast invasion in the human. Placenta. 2010;31(5):448–55.
Tower CL, Lui S, Charlesworth NR, Smith SD, Aplin JD, Jones RL. Differential expression of angiotensin II type 1 and type 2 receptors at the maternal–fetal interface: potential roles in early placental development. Reproduction. 2010;140(6):931–42.
Pringle KG, Tadros MA, Callister RJ, Lumbers ER. The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: roles in trophoblast invasion and angiogenesis? Placenta. 2011;32(12):956–62.
Lumbers ER, Pringle KG. Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy. Am J Physiol Regul Integr Comp Physiol. 2014;306(2):R91–R101.
Su JB. Different cross-talk sites between the renin-angiotensin and the kallikrein-kinin systems. J Renin Angiotensin Aldosterone Syst. 2014;15(4):319–28.
Regoli D, Gobeil F. Kallikrein-kinin system as the dominant mechanism to counteract hyperactive renin-angiotensin system. Can J Physiol Pharmacol. 2017;95(10):1117–24.
Than NG, Romero R, Tarca AL, et al. Integrated systems biology approach identifies novel maternal and placental pathways of preeclampsia. Front Immunol. 2018;9:1661. https://doi.org/10.3389/fimmu.2018.01661.
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Valdés, G., Acuña, S., Schneider, D. et al. Bradykinin Exerts Independent Effects on Trophoblast Invasion and Blood Pressure in Pregnant Guinea Pigs. Reprod. Sci. 27, 1648–1655 (2020). https://doi.org/10.1007/s43032-020-00195-6
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DOI: https://doi.org/10.1007/s43032-020-00195-6