Progesterone and estradiol suppress human mononuclear cell cytotoxicity.

Fetal trophoblast is generally resistant to lysis by cytotoxic cells. We hypothesized that progesterone and estrogens secreted by the trophoblast act at the choriodecidual interface where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. Using peripheral blood mononuclear cells as effector cells in a cytotoxicity assay, we evaluated the effects of progesterone, estrone, estradiol and estriol, either alone or in combination, on cellular cytotoxicity. Both progesterone and estradiol suppressed cytotoxicity in a dose-dependent manner. Estrone, estriol, pregnenolone and cholesterol had no effect. A synergistic suppression of cytotoxicity was observed when estrone, estradiol, estriol and progesterone were combined. We speculate that trophoblast production of progesterone and estradiol may be an important local immunosuppressive mechanism contributing to fetal survival.

Comparison of the vasoactive effects of leukotrienes with thromboxane mimic in the perfused human placenta.

Vasoactive effects of leukotrienes and thromboxane mimic were tested in the perfused human placental cotyledon. Tissue viability was demonstrated by oxygen consumption and by carbon dioxide and lactate production. Vasoconstrictive effects of leukotrienes B4, C4, and D4 were compared with those of a known potent vasoconstrictor, thromboxane mimic (U 46619). The leukotrienes and thromboxane mimic were administered as bolus injections into a chorionic plate artery in doses ranging from 10(-6) to 25 micrograms. In each placenta only one leukotriene was compared with thromboxane mimic. Vasoconstrictive effects were determined by maximum increases in resistance occurring after each injection. Thromboxane mimic caused significantly greater increases in resistance than any of the leukotrienes (p less than 0.001). Thromboxane mimic and leukotriene D4 had significantly lower threshold doses than leukotriene B4 or C4 (p less than 0.001). We concluded: (1) Thromboxane mimic is a potent vasoconstrictor in the human placental vasculature; (2) leukotrienes also cause vasoconstriction but are much less potent than thromboxane; (3) thromboxane mimic and leukotriene D4 have vasoconstrictor effects at significantly lower (p less than 0.001) concentrations than leukotriene B4 or C4.

Low-dose aspirin inhibits thromboxane, but not prostacyclin, production by human placental arteries.

Preeclampsia is associated with increased thromboxane and decreased prostacyclin production by the placenta. Low-dose aspirin can selectively inhibit thromboxane production in the adult circulation, but its effects on placental vascular production of thromboxane and prostacyclin are incompletely understood. We therefore studied the effects of low-dose aspirin on the production rates of prostacyclin and thromboxane, with and without vasoconstricting doses of angiotensin II, in human placental arteries. Chorionic plate arteries were incubated and samples were assayed for thromboxane and prostacyclin by radioimmunoassay of their stable metabolites. Production rates for prostacyclin were similar in the control, aspirin, angiotensin II, and angiotensin II plus aspirin groups. Mean (+/- SEM; n = 8) thromboxane production rates in the aspirin (1.4 +/- 0.5 pg/mg/hr) and angiotensin II plus aspirin (2.9 +/- 0.6 pg/mg/hr) groups were significantly lower (p less than 0.05) than values in the control (8.6 +/- 2.7 pg/mg/hr) and angiotensin II (6.7 +/- 1.3 pg/mg/hr) groups. We conclude that low-dose aspirin significantly decreases production of thromboxane in placental arteries both with and without vasoconstricting doses of angiotensin II.

Dopamine and intraocular pressure in critically ill patients.

BACKGROUND: A recently released dopamine-1 receptor agonist, fenoldopam, increases intraocular pressure (IOP) in both healthy volunteers and patients with chronic ocular hypertension. Dopamine, a potent agonist at both dopamine-1 and -2 receptors, is frequently infused in critically ill patients for its inotropic, renal vasodilatory, and natriuretic effects. The authors hypothesized that low doses of dopamine would significantly increase IOP. METHODS: Patients in the intensive care unit who were currently receiving dopamine infusions of less than 5 microg x kg(-1) x min(-1) were studied After local ocular anesthesia was obtained, baseline IOP was measured in each eye with a hand-held tonometer. IOP was then determined after dopamine was discontinued. RESULTS: Twenty-three patients received a mean dopamine infusion of 2.6 +/- 0.2 microg x kg(-1) x min(-1). Twelve of the 23 patients were receiving mechanical ventilation during the study. Mean IOPs in nonventilated patients (n = 11) off dopamine were 13.1 +/- 0.9 mmHg (left eye) and 12.6 +/- 0.9 mmHg (right eye). Mean IOPs for the same patients receiving dopamine were significantly higher at 16.1 +/- 0.9 mmHg (left eye) and 15.9 +/- 1.1 mmHg (right eye). Mean IOPs in intubated patients (n = 12) off dopamine were 12.3 +/- 0.7 mmHg (left eye) and 12.5 +/- 1.2 mmHg (right eye). Mean IOPs for the same patients while receiving dopamine were significantly higher in intubated patients at 17.8 +/- 1.3 mmHg (left eye) and 17.3 +/- 1.3 mmHg (right eye). The average mean elevation in IOP in patients while receiving dopamine was significantly higher in intubated patients as compared with nonintubated patients (5.2 +/- 0.9 mmHg vs. 3.1 +/- 0.6 mmHg). CONCLUSIONS: Commonly used doses of dopamine are associated with increased IOP in critically ill patients. Although normal patients should be able to tolerate this elevation safely for several weeks, there may be a potential risk in patients with preexisting glaucomatous nerve damage or ocular hypertension, especially if they are sedated and mechanically ventilated.

Increased progesterone concentrations are necessary to suppress interleukin-2-activated human mononuclear cell cytotoxicity.

Fetal trophoblast is generally resistant to lysis by cytotoxic cells. Trophoblast progesterone and estrogens may act at the choriodecidual interface, where they are present in high concentrations to provide a local, paracrine immunosuppressive effect on cellular cytotoxicity. However, interleukin activation of these cytotoxic lymphocytes enhances their ability to lyse trophoblast. Recent evidence suggests that immunoactivation occurs in certain aberrant pregnancy conditions, including preeclampsia. Preeclamptic placentas produce more progesterone in vitro than do normal placentas. To study the potential association between progesterone production and immunoactivation, we evaluated the immunomodulatory effect of progesterone on cellular cytotoxicity. Comparisons were made with the use of both normal and interleukin-2-stimulated peripheral blood mononuclear cells as effector cells in a cytotoxicity assay. Progesterone suppressed cytotoxicity in a dose-dependent manner. Interleukin-2 augmented cellular cytotoxicity, and higher concentrations of progesterone were required to attenuate this response. An additive suppression of cytotoxicity was also observed when estrone, estradiol, estriol, and progesterone were combined. We speculate that the higher placental production of progesterone seen in preeclampsia may be a trophoblast compensatory response to immunoactivated maternal effector cells.

Response of placental vasculature to high glucose levels in the isolated human placental cotyledon.

We report the effect of high glucose infusion on vascular resistance in isolated human placental cotyledons perfused with Krebs-Ringer-bicarbonate solution containing 80 mg/dl (4.4 mmol/L), 160 mg/dl (8.8 mmol/L), or 320 mg/dl (17.6 mmol/L) D-glucose (n = 6). Placental vascular resistance remained constant during 25-minute perfusion periods with 80 mg/dl followed by 160 mg/dl glucose solution. Subsequent perfusion with 320 mg/dl glucose produced a significant increase in placental vascular resistance. Placentas were also studied in which the placental cotyledon was sequentially perfused for 25-minute periods with solutions containing glucose at 80 mg/dl followed immediately by 320 mg/dl (n = 5). Placental vascular resistance remained constant throughout perfusion with 80 mg/dl glucose solution but increased significantly after beginning perfusion with 320 mg/dl glucose. We conclude that the increase in placental vascular resistance appears to be a function of the high glucose level rather than the duration of glucose perfusion.

Placental thromboxane and prostacyclin production in an ovine diabetic model.

We hypothesized that streptozocin-induced ovine diabetes would cause alterations in the placental production of thromboxane and prostacyclin. With a tissue incubation technique, we examined the placental production of thromboxane and prostacyclin in cotyledons from seven normal near-term ewes (127 +/- 3 days' gestation) and six streptozocin-induced diabetic ewes (125 +/- 3 days' gestation). Diabetic status was verified with serial fasting blood glucose assessments. Placental tissue was incubated in Dulbecco's modified Eagle's medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide. Samples were collected at 0, 1, 2, 4, 8, 20, 32, and 48 hours. Radioimmunoassay of the stable metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were used to determine thromboxane and prostacyclin production, respectively. Placental thromboxane production was reduced in diabetic animals when compared with control animals (5.63 +/- 2.81 vs 7.32 +/- 1.37 pg/mg per hour, respectively; p less than 0.05). Prostacyclin production was also significantly reduced in the diabetic placentas compared with control placentas (11.44 +/- 4.06 vs 16.29 +/- 4.59 pg/mg per hour, respectively; p less than 0.05). We conclude that the ovine placenta produces thromboxane and prostacyclin. The ovine thromboxane production rate is comparable to that of the human placenta but the prostacyclin production rate is approximately two to three times higher. The observed decrease in the placental production of thromboxane and prostacyclin may reflect an adverse effect of hyperglycemia directly on eicosanoid production or indirectly through decreased placental cellular proliferation.