The role of AT1 angiotensin receptor activation in the pathogenesis of preeclampsia

Preeclampsia is characterized by an increase in vascular tone associated with reduced uteroplacental flow. The nature of hypertension arising in pregnancy suggests that the abnormal increase in blood 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 E2 and nitric oxide and the vasoconstrictors angiotensin II, thromboxane A2, serotonin, and endothelin. Furthermore, vascular reactivity to angiotensin II is greatly enhanced in preeclampsia as opposed to normal pregnancies. The increased vascular tone and the enhanced thromboxane production noted in preeclampsia may be mediated by the increased sensitivity to angiotensin II because angiotensin II coupled to an AT1 receptor is a potent vasoconstrictor and stimulates the accumulation of free arachidonic acid, the precursor of thromboxane and the prostaglandins. We used a rat model that has been shown to express the relevant clinical features of human preeclampsia to investigate the involvement of the AT1 angiotensin receptor in this pathologic condition. Pregnant rats were divided into three groups that were either infused with saline or endotoxin on the 14th day of pregnancy. One of the endotoxin-infused groups was further treated with the AT1-selective antagonist losartan from day 11 until day 19 of pregnancy. Perinatal outcome, blood pressure, and urine protein were monitored for each group. We observed that endotoxin infusion resulted in a decrease in pup weight and number of pups and caused an increase in mean arterial pressure as well as increased proteinuria when compared with saline solution-infused animals. In contrast, endotoxin-infused rats receiving losartan exhibited no change in number or weight of pups when compared with control, and losartan tended to diminish the rise in mean arterial pressure. In addition, the increase in urinary protein excretion was completely blocked by losartan. Endotoxin infusion in pregnant rats appears to be a suitable model for the study of preeclampsia. Moreover, the angiotensin II-dependent activation of an AT1 receptor appears to mediate a portion of the pathophysiologic features associated with preeclampsia.