THE ROLE OF AT(1) ANGIOTENSIN RECEPTOR ACTIVATION IN THE PATHOGENESISOF PREECLAMPSIA

OBJECTIVES: Preeclampsia is characterized by an increase in vascular t one associated with reduced uteroplacental flow. The nature of hyperte nsion arising in pregnancy suggests that the abnormal increase in bloo d pressure is dependent on some humoral factor that mediates vasospasm . There is evidence that preeclampsia results from a breakdown in the balance between vasodilators such as prostacyclin and prostaglandin E- 2 and nitric oxide and the vasoconstrictors angiotensin II, thromboxan e A(2), serotonin, and endothelin. Furthermore, vascular reactivity to angiotensin II is greatly enhanced in preeclampsia as opposed to norm al pregnancies. The increased vascular tone and the enhanced thromboxa ne production noted in preeclampsia may be mediated by the increased s ensitivity to angiotensin II because angiotensin II coupled to an AT(1 ) receptor is a potent vasoconstrictor and stimulates the accumulation of free arachidonic acid, the precursor of thromboxane and the prosta glandins. STUDY DESIGN: We used a rat model that has been shown to exp ress the relevant clinical features of human preeclampsia to investiga te the involvement of the AT(1) angiotensin receptor in this pathologi c condition. Pregnant rats were divided into three groups that were ei ther infused with saline or endotoxin on the 14th day of pregnancy. On e of the endotoxin-infused groups was further treated with the AT(1)-s elective antagonist losartan from day 11 until day 19 of pregnancy. RE SULTS: Perinatal outcome, blood pressure, and urine protein were monit ored for each group. We observed that endotoxin infusion resulted in a decrease in pup weight and number of pups and caused an increase in m ean arterial pressure as well as increased proteinuria when compared w ith saline solution-infused animals. In contrast, endotoxin-infused ra ts receiving losartan exhibited no change in number or weight of pups when compared with control, and losartan tended to diminish the rise i n mean arterial pressure. In addition, the increase in urinary protein excretion was completely blocked by losartan. CONCLUSIONS: Endotoxin infusion in pregnant rats appears to be a suitable model for the study of preeclampsia. Moreover, the angiotensin II-dependent activation of an AT(1) receptor appears to mediate a portion of the pathophysiologi c features associated with preeclampsia.