Endothelial dysfunction and a consequent decrease in nitric oxide production have been implicated in the pathogenesis of pre-eclampsia. A prominent feature of the pre-eclamptic syndrome is a loss of the pregnancy-induced refractoriness to infused pressor agents, such as angiotensin. In this study, we sought to determine whether a decrease in nitric oxide production might be linked via changes in angiotensin II receptors and angiotensin II metabolism to changes in pressor sensitivity to infused angiotensin II. Pregnant and non-pregnant spontaneously hypertensive rats (SHRs) were randomly allocated to receive 5 mg·kg -1 ·day -1 N G -nitro- L -arginine methyl ester ( L -NAME) in the drinking water or drinking water alone from days 7 to 14 of gestation. Steady-state metabolic clearance studies of angiotensin II were then performed, or tissues were harvested for angiotensin II receptor studies. Treatment with L -NAME caused an increase in systolic pressure ( P < 0.001) in both pregnant and non-pregnant rats, while urinary protein excretion increased only in the pregnant SHRs ( P < 0.001). Plasma angiotensin II levels were significantly increased in the L -NAME-treated SHRs compared with controls (non-pregnant, P < 0.0005; pregnant, P < 0.01). The metabolic clearance rate of angiotensin II was decreased by L -NAME treatment in non-pregnant SHRs ( P < 0.05), but was increased by L -NAME treatment in the pregnant rats ( P < 0.01). In the aorta, the angiotensin II receptor number increased after treatment with L -NAME in both non-pregnant ( P < 0.0005) and pregnant ( P < 0.05) SHRs, and the dissociation constant increased in the non-pregnant SHRs ( P < 0.005). Thus treatment of SHRs with L -NAME increased blood pressure, as well as the circulating angiotensin II concentration and vascular angiotensin II receptor expression. However, treatment with L -NAME did not affect pressor sensitivity to infused angiotensin II. We conclude, therefore, that although a decrease in nitric oxide production is associated with changes in angiotensin II concentrations and receptor numbers, it does not induce changes in pressor sensitivity to infused angiotensin II in the SHR.

1. Twenty-eight healthy non-pregnant women and 28 women in the first or second trimester of pregnancy were studied. They were given an incremental intravenous infusion of either noradrenaline or angiotensin II. Pressor and heart rate responses were documented. 2. Dose-pressor response curves were constructed for the two agents in pregnant and non-pregnant women ( n =14 in each group). The regression parameters of slope and intercept were calculated, and were used to derive the variables of dose required to elicit a 10 mmHg rise in systolic or diastolic blood pressure. 3. The pressor response to angiotensin II was diminished in pregnancy, with approximately twice the dose being required to raise the systolic or diastolic arterial blood pressure as in non-pregnant subjects. 4. The systolic pressor response to noradrenaline was slightly diminished in pregnancy, but the diastolic pressor response was unchanged. There were no significant differences between the doses of noradrenaline required to elicit a 10 mmHg rise in systolic or diastolic arterial blood pressure in pregnant or non-pregnant subjects. 5. There was a diminution in the bradycardia evoked in response to both hormones in pregnancy. 6. We conclude that the well-documented pressor insensitivity to angiotensin II during pregnancy is a specific phenomenon, not a manifestation of a generalized reduction in vascular reactivity.

1. Platelets were prepared from peripheral venous blood on iso-osmotic density gradients of Percoll, resulting in a good recovery of cells (50–80%) which were relatively free of contaminating blood cells (erythrocyte <0.1%, leucocyte <0.1%). 2. At 22°C, specific binding of 125 labelled angiotensin II (300 pmol/l) was time and temperature dependent, saturable, reversible and linear with cell concentration. 3. Scatchard analysis of saturation curves revealed a single class of binding sites with K d 1.5 ± 0.4 × 10 −10 mol/l and total binding capacity 6.3 ± 1.2 receptorslplatelet. Similar values (K d 2.4 ± 0.7 × 10 −10 mol/l and binding capacity 6.5 ± 1.0 receptors/cell) were obtained by displacement analysis. From kinetic studies the forward and reverse rate constants were 3.1 × 10 8 mol min −1 1 −1 and 3.6 × 10 −2 /min giving a K d of 1.2 × 10 −10 mol/l. 4. The relative binding potencies for angiotensin I1 and analogues were: [Sar 1 , Thr 8 ]ANC II > ANG II > ANG III > [Sar 1 , Ala 8 ]ANG II > ANG I. 5. Incubation with an extracellular marker ( 51 Cr-labelled EDTA) demonstrated that binding of angiotensin II to platelets was not due to free fluid endocytosis.

1. The effect of continuous infusion of captopril (80 μg/h) for up to 5 days on blood pressure, adrenal angiotensin II receptors and vascular reactivity to exogenous angiotensin II, arginine vasopressin and noradrenaline was studied in the rat. 2. In treated rats, blood pressure decreased transiently to a minimum after 2 days (−18 mmHg). Vascular reactivity to angiotensin II, but not to arginine vasopressin, was also increased significantly after 2 days, but vascular reactivity to noradrenaline decreased. After 5 days, vascular reactivity to angiotensin II had returned to normal and was similar to that of sham-treated controls. Adrenal angiotensin II receptor concentrations decreased significantly after 1 and 2 days, but at 5 days were again similar to controls. There was no change in receptor affinity. 3. Converting enzyme inhibition with captopril causes transient specific changes in adrenal angiotensin II receptors and vascular reactivity. The receptor and vascular effects may facilitate and oppose, respectively, the early changes in blood pressure with captopril, but a long-term contribution from either is unlikely.