Preeclampsia is a disorder of pregnancy that can result in fetal and maternal morbidity. Signs associated with preeclampsia include reduced organ perfusion, hypertension, proteinuria, and intrauterine growth retardation. Animal models that replicate many of the features of human preeclampsia are desirable for investigation into the functional consequences of, and mechanisms contributing to the pathophysiology of preeclampsia. Recent studies suggest that decreased nitric oxide (NO) production occurs in preeclampsia, and it appears that abnormal endothelial cell NO production may be a key contributing factor in the pathophysiology of preeclampsia.
In Aim 1, we will develop a model of preeclampsia in athe conscious pregnancy rabbit using chronic NO synthesis inhibition. The effect of chronic administration of the NO synthase inhibitor NG-nitro-L- arginine methyl ester (L-NAME) on hemodynamic and renal function will be studied over time in nonpregnant and pregnant rabbits. It is hypothesized that pregnancy rabbits treated with L-NAME will exhibit hypertension, increased uterine vascular resistance, plasma volume contraction, increased capillary permeability, proteinuria, decreased creatinine clearance and reductions in fetal weight. There is scant information available on the impact of preeclampsia on reflex control of cardiovascular function. Abnormal reflex function compromises the ability of the preeclamptic gravida to compensate for acute perturbations in blood volume or blood pressure.
In Aim II, the rabbit model will be used to investigate the effect of experimental preeclampsia on the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR). Baroreflex function will be evaluated by mechanically altering preload and afterload with chronic perivascular occluders, and measuring the reflex changes in RSNA and HR. The contribution of cardiac receptors to the baroreflex control of RSNA will be evaluated by generating baroreflex curves before nd after acute cardiac denervation with intrapericardial procaine. It is hypothesized that preeclampsia results in a more severe attenuation of baroreflex function than is present during normal pregnancy, and that the inhibitory influence of cardiac receptors on baroreflex function in pregnancy is greater during preeclampsia. Effects of acute NO synthesis block on baroreflex function in pregnancy will be compared to results obtained with chronic no synthesis block. Successful completion of these projects will advance our understanding of the impact of preeclampsia on cardiovascular reflex control, and will provide an animal model that can be utilized in future studies to investigate mechanisms contributing to altered neural control of the circulation, body fluid regulation and hemodynamic responses to exercise associated with preeclampsia.
| O'Hagan, K P; Skogg, K A; Stevenson, J B (2001) AT1 receptor block does not affect arterial baroreflex during pregnancy in rabbits. Am J Physiol Heart Circ Physiol 280:H1996-2005 |
