Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB140

Poster Communications

Adaptations to Pregnancy: Role of the Proteinase Activated Receptor 2 (PAR2)

D. West1, C. West1

1. Medicine, Georgetown University, Washington, District of Columbia, United States.

Pregnancy requires avid sodium retention to drive a massive plasma volume expansion (~40%), which occurs in the setting of reduced or normal blood pressure. This volume expansion is critical to the development of the growing uterus and fetus as inadequate plasma volume expansion and hypertension are associated with preeclampsia, the leading cause of maternal and fetal morbidity and mortality. The mechanisms permitting the decreased maternal blood pressure and increased renal sodium retention are still largely unknown. Research in non-pregnant rats has shown that activation of proteinase activated receptor type 2 (PAR2) can produce vasodilation and stimulate sodium chloride reabsorption by two collecting duct mediate mechanisms pendrin/NDCBE and ENaC. Here, we investigate PAR2 activation and inhibition in virgin (V) and normal late pregnant (LP) Sprague Dawley rats (Envigo). Catheters (PE-50) were implanted into the bladder, left femoral artery, and left femoral vein under 1-4% isoflurane anesthesia. We measured in vivo blood pressure (BP) and natriuretic responses to 0.1mg/kg, 0.3mg/kg, and 1 mg/kg doses of PAR2 agonist peptide (SLIGRL-NH2) in anesthetized V and LP rats. We then measured net natriuretic response to thiazide (HCTZ, 7.5mg/kg) and benzamil (Bz, 1.05mg/kg) with and without PAR2 inhibitory peptide (FSLLRY-NH2) in LP rats to determine the transport mechanism. Values are presented as means ± SEM. We found that LP rats had larger decreases in BP compared to baseline than V rats at 0.1 mg/kg (V=-3.67±0.92 vs. LP=-6.93±0.53 mmHg, p<0.05 by two-way RM ANOVA, V n=7, LP n=11) and 0.3 mg/kg (V=-6.96±3.62 vs. LP=-21.49±1.86 mmHg, p<0.05 by two-way RM ANOVA, V n=7, LP n=11) doses of agonist peptide. We also found that LP rats had increased net sodium retention compared to V rats following 0.3mg/kg (V=23±4 vs. LP=106±33 umol/hr, p<0.05 by two-way RM-ANOVA, V n=7, LP n=11) and 1mg/kg (V=29±4 vs. LP=125±29 umol/hr, p<0.05 by two-way RM-ANOVA, V n=7, LP n=11) agonist peptide. We found increased HCTZ-mediated sodium transport after PAR2 inhibition (Veh=621±41 vs. Inh=728±52 umol/hr, p<0.05 by t-test, Veh n=5, Inh n=7), however there were no differences detected in Bz-mediated transport (Veh=581±67 vs. Inh=551±75, N.S., n=8/group) in LP rats. These data taken together, demonstrate that activation of PAR2 causes larger decreases in BP and increases in sodium retention in LP compared to V controls. Furthermore, that the PAR2 mediated sodium reabsorption in LP rats is through the pendrin/NDCBE-mediated transport mechanism, not ENaC. These data suggest that PAR2 may play a role in the renal and vascular adaptations to pregnancy and thus this mechanism could potentially provide new targets for treatment of preeclampsia.

Where applicable, experiments conform with Society ethical requirements