Published online before print February 26, 2007, doi: 10.1161/01.HYP.0000259961.27920.35
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2007;49:e22.)
© 2007 American Heart Association, Inc.
Letters to the Editor |
Response to Modeling Preeclampsia: The True Model for the Uniquely Human Disease Preeclampsia Is the Human Female Not the Pregnant Rat
University of Mississippi Medical Center, Jackson, Miss
We recently reported in Hypertension1 that the elevation in arterial pressure in pregnant rats with placental ischemia was associated with significant increases in serum interleukin (IL)-6. Moreover, we found that chronic elevation in serum levels of IL-6, comparable to levels observed in our placental ischemic pregnant rat model, resulted in significant increases in arterial pressure and decreases in renal hemodynamics in pregnant rats. These results led us to conclude that IL-6 may play a role in mediating the hypertension and reduction in renal hemodynamics observed with placental ischemia in pregnant rats.1
Nama et al2 expressed concerns and indicated that "there is no adequate laboratory model of preeclampsia" and that no animal model "develops a condition during pregnancy that remotely resembles preeclampsia." They also suggested that, "any significant progress in the field of preeclampsia research can only realistically come from studies of the human model."
Although we agree that rats may not spontaneously develop preeclampsia, we believe that our rat model provides an excellent opportunity to study the relationship between placental ischemia and hypertension. Although placental ischemia has been proposed to lead to widespread endothelial dysfunction, vasoconstriction, and hypertension in the maternal circulation during preeclampsia, the mechanisms that link placental ischemia and cardiovascular and renal dysfunction have yet to be fully elucidated. We reported previously that reducing uteroplacental perfusion pressure results in significant and consistent elevations in arterial pressure associated with proteinuria; reductions in renal plasma flow and glomerular filtration rate, an endothelial dysfunction; and intrauterine growth restriction.3–10
Collectively, these data suggest that the reduced uteroplacental perfusion pressure model has many of the features of preeclampsia in women. The reduced uteroplacental perfusion pressure model, along with appropriate pharmacological tools, provides an opportunity to quantify the relative importance of complex pathophysiological factors in mediating cardiovascular and renal dysfunction in response to placental ischemia during pregnancy.
Although our data clearly demonstrate that IL-6 may play an important role in mediating the elevation in AP in response to reductions in uterine perfusion in the pregnant rat, we indicated in our article that the importance of IL-6 and other cytokines in mediating the cardiovascular and renal alterations during preeclampsia in humans remains unclear.11 Thus, in the Perspectives section of our Discussion, we noted that it is unknown whether drugs that inhibit the actions of inflammatory cytokines would be of benefit to women at high risk of developing preeclampsia. We also indicated that the importance of cytokines in the pathogenesis of preeclampsia will not be determined until well-controlled clinical studies using specific inhibitors of cytokines are performed in women with preeclampsia.
We did not suggest, as the author insinuates in the Letter to the Editor, that inhibitors of cytokines should be used as a treatment for women with preeclampsia. Therefore, Nama et al2 should not be "alarmed" but more open minded about the importance of the interplay between basic and clinical research. We strongly disagree with the authors’ contention that, "any significant progress in the field of [preeclampsia] research can only realistically come from studies of the human model." This mindset may be one reason why progress in the development of new prevention and treatment strategies for preeclampsia over the last several decades has been limited. Although the study of preeclampsia in humans is of critical importance, studies in humans have obvious limitations that prevent investigation of many pathophysiological mechanisms and that often limit the ability to establish cause-and-effect relationships in pregnant women with preeclampsia. Experimental studies in pregnant animals allow investigators to directly test whether certain factors found in preeclamptic women can indeed lead to hypertension and other disorders of preeclampsia. Therefore, we respectfully disagree with the statement of Nama et al that, "any significant progress in the field of [preeclampsia] research can only realistically come from studies of the human model."2 We believe that both basic and clinical research are important and that the discovery of new approaches for the prevention and treatment of cardiovascular diseases such as preeclampsia will likely result from the interplay between basic and clinical research.
 |
Acknowledgments |
|---|
Disclosures
None.
|
References |
|---|
 Top References |
|---|
1. Gadonski G, Lamarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of IL 6. Hypertension. 2006; 48: 711–716.
2. Nama V, Antonios TF, Manyonda IT. Modeling pre-eclampsia: the true model for the uniquely human disease preeclampsia is the human female not the pregnant rat. Hypertension. 2007; 49: e21.
3. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of hypertension during preeclampsia: Linking placental ischemia with endothelial dysfunction. Hypertension. 2001; 38: 718–722.
4. Alexander BT, Kassab SE, Miller MT, Abram SR, Reckelhoff JF, Bennett WA, Granger JP. Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide. Hypertension. 2001; 37: 1191–1195.
5. Crews JK, Herrington JN, Granger JP, Khalil RA. Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rats. Hypertension. 2000; 35: 367–372.
6. Alexander BT, Rinewalt AN, Cockrell KL, Bennett WA, Granger JP. Endothelin-A receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension. 2001; 37: 485–489.
7. Alexander BT, Cockrell KL, Sedeek M, Granger JP. Role of the renin-angiotensin system in meditating the hypertension produced by chronic reductions in uterine perfusion pressure in the pregnant rat. Hypertension. 2001; 38: 742–745.
8. Llinas MT, Alexander BT, Capparelli M, Carroll MA, Granger JP. Cytochrome P-450 inhibition attenuates hypertension induced by reductions in uterine perfusion pressure in pregnant rats. Hypertension. 2004; 430: 623–628.
9. Alexander BT, Llinas MT, Kruckeberg WC, Granger JP. L-arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure. Hypertension. 2004; 43: 832–836.
10. Lamarca BB, Bennett WA, Alexander BT, Cockrell K, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat. Role of tumor necrosis factor-
. Hypertension. 2006; 46: 1022–1025.[CrossRef]
11. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprog Immunol. 1997; 37: 240–249.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||