Abstract-A reduction in nitric oxide (NO) synthesis has been suggested to play a role in pregnancy-induced hypertension.We have recently reported that normal pregnancy in the rat is associated with significant increases in whole-body NO production and renal protein expression of neuronal and inducible NO synthase. The purpose of this study was to determine whether whole-body and renal NO production is reduced in a rat model of pregnancy-induced hypertension produced by chronically reducing uterine perfusion pressure starting at day 14 of gestation. Chronic reductions in uterine perfusion pressure resulted in increases in arterial pressure of 20 to 25 mm Hg, decreases in renal plasma flow (Ͻ23%) and glomerular filtration rate (Ͻ40%), but no difference in urinary nitrite/nitrate excretion relative to control pregnant rats. In contrast, reductions in uterine perfusion pressure in virgin rats resulted in no significant effects on arterial pressure. Renal endothelial (Ͻ4%) and inducible (Ͻ11%) NO synthase protein expression did not decrease significantly in the chronically reduced uterine perfusion pressure rats relative to normal pregnant rats; however, significant reductions in neuronal NO synthase were observed (Ͻ30%). The results of this study indicate that the reduction in renal hemodynamics and the increase in arterial pressure observed in response to chronic decreases in uterine perfusion pressure in pregnant rats are associated with no change in whole-body NO production and a decrease in renal protein expression of neuronal NO synthase. (Hypertension. 2000;37:1191-1195.)Key Words: preeclampsia Ⅲ hypertension, pregnancy Ⅲ glomerular filtration rate Ⅲ renal blood flow Ⅲ plasma Ⅲ endothelium Ⅲ nitric oxide P reeclampsia is a multisystemic disorder of pregnancy estimated to affect 5% to 10% of all pregnancies in the United States. 1,2 Although preeclampsia is one of the leading causes of maternal death and the main contributor of prenatal morbidity, the mechanisms responsible for this disorder are unclear. 1-3 Preeclampsia develops during pregnancy and ceases after delivery, implicating the placenta as a primary cause. 1,4 Manifestations generally associated with preeclampsia include an increased responsiveness to vasoconstrictors, increases in arterial pressure, decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF), proteinuria, and vascular endothelial damage. 1,2,5 The initiating event in preeclampsia is suggested to involve reduced placental perfusion, which leads to maternal endothelial cell dysfunction. 1,3,4 The factors involved in mediating the hypertension during preeclampsia are unknown and may involve a delicate balance of vasoconstrictors and vasodilators of which nitric oxide (NO) may play an important role. 1,4,6 Evidence indicates that NO plays an important role in mediating physiological changes during normal pregnancy. 6,7 Increases in regional blood flow, RPF, and GFR during pregnancy are attenuated by systemic NO synthesis inhibition. 8,9 Urinary excretion of cGMP, a second ...

Abstract-Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141Ϯ3 mm Hg, compared with 125Ϯ2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3Ϯ2.5 versus 10Ϯ1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5Ϯ0.9 versus 8.7Ϯ0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F 2␣ excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127Ϯ4 versus 127Ϯ4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F 2␣ in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)-mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperlipidemia, and the resultant ROS are responsible for the increased TP-mediated vasoconstriction in OZRs, resulting in impaired functional vasodilation. Eleven-week-old male lean Zucker rats (LZRs) and OZRs were fed normal rat chow or chow containing rosiglitazone (5 mg.kg(-1).day(-1)) for 2 wk. In another set of experiment, LZRs and OZRs were treated with 2 mM tempol (drinking water) for 7-10 days. After the treatments, spinotrapezius muscles were prepared, and arcade arteriolar diameters were measured following muscle stimulation and arachidonic acid (AA) application (10 muM) in the absence and presence of the TP antagonist SQ-29548 (1 muM). OZRs exhibited higher insulin, glucose, triglyceride, and superoxide levels and increased NADPH oxidase activity compared with LZRs. Functional and AA-induced vasodilations were impaired in OZRs. Rosiglitazone treatment improved insulin, glucose, triglyceride, and superoxide levels as well as NADHP oxidase activity in OZRs. Both rosiglitazone and tempol treatment improved vasodilatory responses in OZRs with no effect in LZRs. SQ-29548 treatment improved vasodilatory responses in nontreated OZRs with no effect in LZRs or treated OZRs. These results suggest that insulin resistance and the resultant increased ROS impair functional dilation in OZRs by increasing TP-mediated vasoconstriction.

We have developed Quantitative Circulatory Physiology (QCP), a mathematical model of integrative human physiology containing over 4,000 variables of biological interactions. This model provides a teaching environment that mimics clinical problems encountered in the practice of medicine. The model structure is based on documented physiological responses within peer-reviewed literature and serves as a dynamic compendium of physiological knowledge. The model is solved using a desktop, Windows-based program, allowing students to calculate time-dependent solutions and interactively alter over 750 parameters that modify physiological function. The model can be used to understand proposed mechanisms of physiological function and the interactions among physiological variables that may not be otherwise intuitively evident. In addition to open-ended or unstructured simulations, we have developed 30 physiological simulations, including heart failure, anemia, diabetes, and hemorrhage. Additional stimulations include 29 patients in which students are challenged to diagnose the pathophysiology based on their understanding of integrative physiology. In summary, QCP allows students to examine, integrate, and understand a host of physiological factors without causing harm to patients. This model is available as a free download for Windows computers at http://physiology.umc.edu/themodelingworkshop.