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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 x kg(-1) x 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. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors in the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with N(G)-nitro-L-arginine-methyl ester (L-NAME). 2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received L-NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail-cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [125I]-Sar8, Ile1)AngII. Data was analysed using the computer program LIGAND. 3. Mean systolic blood pressure was significantly elevated in rats treated with L-NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated L-NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the L-NAME group compared with control. However, uterine AngII receptor affinity was unchanged. 4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.

Platelet angiotensin II (AngII) receptor number has been suggested as a screening test for pregnancy-induced hypertension. However, markedly different false-positive rates have been reported, perhaps the result of differing methods used. We sought therefore to compare the two methods. Platelet AngII receptor number was determined by saturation analysis with computerized curve fitting and specific binding at a single radioligand concentration. The two methods were compared by correlation and by plotting their differences v their means, to determine their limits of agreement. There were significant correlations between the value obtained by saturation analysis and each of the three single ligand concentrations studied (1 nmol/L, P < .001; 500 pmol/L, P < .001; and 250 pmol/L, P < .01). However, for none of the three did the regression line approach the line of equality. Assessment of agreement by comparing differences and means for each subject showed increasing scatter with increasing receptor number and 95% confidence intervals too large to be clinically relevant. We conclude that the receptor number estimated from specific binding at one ligand concentration differs significantly from that obtained by saturation analysis. The limits of agreement of the two methods are wide and we urge caution in the use of single ligand concentration methods for estimating binding site densities.

1. In the non-pregnant state uterine and glomerular angiotensin II (AII) receptors have been shown to regulate in a similar fashion. This study sought to determine whether such parallel regulation occurred during pregnancy. We also investigated the role of plasma AII in these changes. 2. These studies were performed in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The SHR has increased receptor number, increased sensitivity to infused AII and decreased plasma volume compared to the WKY. These features are also seen in pregnancy induced hypertension (PIH). 3. Age matched female WKY and SHR were exposed to an appropriate breeder and sacrificed on day 14 of gestation. Plasma AII was measured by radio-immunoassay. Uterine and glomerular receptor binding was determined by saturation analysis using 125I(Sar1,Ileu8)AII. Data were analysed using the program LIGAND. 4. Uterine and glomerular AII receptors showed different patterns of regulation during pregnancy. The uterine AII receptor affinity decreased significantly in both strains at 14 days of gestation and receptor number also decreased significantly in WKY. In contrast, glomerular AII receptor affinity did not change significantly in either strain. Receptor numbers in the glomeruli increased significantly compared to their respective non-pregnant controls. 5. We conclude that the uterine and glomerular AII receptors do not regulate in a parallel fashion in pregnancy. Plasma AII concentration does not appear to be involved in the regulation of either uterine and glomerular receptor expression in pregnancy.

Experimental studies demonstrate impaired regulation of the mesangial angiotensin II (AII) receptor in diabetes. This could contribute to the disturbance of glomerular blood flow and the development of diabetic nephropathy. The aim of this study was to determine whether a similar receptor abnormality occurs in patients with type I insulin-dependent diabetes mellitus (IDDM) and if so whether this is more prevalent in patients with micro- or macro-albuminuria. The platelet AII receptor was chosen because of its availability from the circulation and its comparable regulatory properties to tissue-based receptors. The interaction between plasma AII and its platelet receptor was examined in 45 patients with IDDM and 36 age- and sex-matched control subjects. Seven patients had clinical nephropathy and two had persistent micro-albuminuria. The duration of diabetes varied from 1 month to 42 years. There was a significant inverse correlation between plasma AII and the logarithm of receptor number in the control group (r = -0.555, P < 0.001). This relationship was not observed in the diabetic patients irrespective of the duration of disease or the presence of nephropathy. Receptor expression in patients without nephropathy showed no correlation with either duration of disease or the degree of glycaemic control. However, a significant relationship between AII receptor number and duration of diabetes was noted in the group with nephropathy (r = 0.723, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Quantification of platelet angiotensin II (AII) receptors has been suggested as a screening test for pregnancy-induced hypertension (PIH). Saturation analysis is too technically demanding to screen the requisite numbers and although a simplified method has been proposed, it has not been validated against saturation. This study sought to compare the two methods. 2. Platelet AII receptor number was determined by saturation analysis and from the specific binding at each of three radioligand concentrations. The two methods were compared by correlation and by plotting their differences against their means to determine limits of agreement. 3. Significant correlations were observed at all three radioligand concentrations; however, none of the regression lines approached the line of equality. There was increasing scatter as receptor number increased and 95% confidence intervals were too large to be clinically useful. 4. From this study it is concluded that the simplified method for estimating platelet AII receptor number is inaccurate and caution is urged in its use as a screening test for PIH.

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18-21 mmol/L (uncontrolled diabetes) and 4-8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 +/- 62 and 388 +/- 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 +/- 2.7, 38 +/- 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P = 0.04 and uncontrolled P = 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.

Objective: The relation between plasma angiotensin II concentrations and the platelet angiotensin II receptor was examined in four different groups of subjects. Platelet receptors were used as representative of physiologically significant sites such as in vascular smooth muscle., Subjects: A control group consisting of non-pregnant females was studied together with three pregnant groups: normal pregnant women in both early and then late gestation and women with diagnosed pregnancy-induced hypertension (PIH)., Methods: Blood was collected from each subject for estimation of plasma angiotensin II concentration and isolation of platelets, which were then used in non-competitive binding studies. Both receptor capacity and affinity for the ligand were calculated for each subject., Results: In the control group, a significant negative correlation between angiotensin II and receptor capacity was established. This was in marked contrast to the first trimester group which showed no such correlation and where there was a significant reduction or nil receptor capacity but only a slight elevation in mean plasma angiotensin II concentration. This phenomenon of reduced or absent binding persisted into the third trimester when plasma angiotensin II was significantly elevated compared with all other groups. PIH subjects had the lowest plasma angiotensin levels and 90% had clearly measurable binding to the platelet receptor, which was not however as high as that in the control group. Two normotensive subjects who demonstrated significant potentiation of receptor binding in the third trimester subsequently developed PIH., Conclusions: The inverse relation between plasma angiotensin II and its platelet receptor, found in non-pregnant subjects, is significantly altered in normal pregnancy. Reduced receptor capacity and lack of relation with circulating ligand observed in early gestation reflects an alteration at the receptor level which is independent of plasma angiotensin II concentration. This alteration appears to persist throughout pregnancy except in subjects predisposed to PIH when receptor binding is closer to non-pregnant values. Changes in receptor binding found in people who ultimately developed PIH but who were still clinically normal at the time suggest that binding to the platelet receptor could be used as a screening test for all primiparae to identify those predisposed to PIH later on in pregnancy.

The expression of the glomerular receptor for angiotensin II (Ang II-R) was examined longitudinally following the induction of anti-glomerular basement membrane (GBM) nephritis in the rat. The specific aim of the project was to determine whether immunologically-induced glomerular injury led to significant abnormalities of the relationship between glomerular Ang II-R and its circulating ligand, Ang II. Scatchard analysis was used to measure Ang II-R on purified glomeruli at selected time intervals over two months following a single dose of sheep anti-rat GBM antibody. Corresponding values for plasma Ang II were determined. Receptor density fell to approximately 50% by 16 hours following the injection of antibody (control 96.4 +/- 9.3 x 10(6); nephritic 52.6 +/- 5.6 x 10(6) receptors/glomerulus; P less than 0.001) and there was a corresponding threefold increase in plasma Ang II (control 21.0 +/- 2.5; nephritic 66.6 +/- 20.6 pg/ml; P less than 0.01). However, this reduction in receptor binding could not be explained by the rise in plasma Ang II concentration, as effective blockade of the RAS by enalapril did not alter receptor expression (56.1 +/- 4.6 x 10(6) receptors/glomerulus). Subsequently, a rise in receptor density and a corresponding fall in plasma Ang II were observed: three days after antibody administration, receptor concentration had increased significantly above control values (150.5 +/- 11.9 x 10(6] while plasma Ang II was undetectable (that is, less than 5 pg/ml). Ang II-R remained elevated for the next two weeks but returned to normal four to eight weeks after the administration of nephrotoxic antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II receptors from rat adrenal cortex and myometrium were studied with the use of tritiated angiotensin under conditions where the sensitivity of the target organs for angiotensin II is modified. Sodium status was found to modulate the number of angiotensin receptors both in adrenal gland and uterus. In both target tissues low Na+ diet increases the number of receptors, while a high Na+ diet results in an increase in uterine receptors without modifying adrenal cortical receptors. However, a more markedly positive sodium balance, such as that observed in deoxycorticosterone acetate (DOCA) hypertension and in one-kidney Goldblatt hypertension, resulted in a reduction of the adrenocortical angiotensin II binding capacity. The endogenous angiotensin II level may also regulate the number of receptor sites as demonstrated by an increased number of receptors after suppression of circulating angiotensin II. It is proposed that the number of angiotensin II receptors is determined by the combined influences of sodium status and angiotensin II concentration. Some changes in the sensitivity of the target organ can be secondary to variations in the number of angiotensin receptors. However, others cannot be so explained and stem, therefore, from events occurring beyond the hormone-receptor interaction.

Plasma renin activity (PRA) and adrenal angiotensin II receptors have been studied simultaneously in the rabbit at various stages of development. In the fetus both parameters show very low values but increase rapidly during the last 4 days of gestation. PRA reaches a maximal level in the early post-natal period but the concentration of adrenal angiotensin II receptors continues to increase further up to the adult state. In adult females, pregnancy results in an initial rise in PRA and adrenocortical angiotensin II receptors. However, PRA remains at a high level throughout the gestation period whereas the number of adrenocortical angiotensin II receptors decreases progressively as pregnancy progresses. The role of circulating angiotensin in the regulation of the concentration and affinity of its receptor sites is discussed.

1. Angiotensin II receptors from rat adrenal gland and myometrium were studied during variation of sodium intake. 2. In both target-tissues low Na+ diet increased the number of receptors whereas a high Na+ diet did not modify the adrenocortical receptors but increased the number of uterine receptors. 3. Deoxycorticosterone and one kidney Goldblatt hypertension were associated with a decrease in the number of adrenal receptors. 4. Alterations of angiotensin II receptors alone cannot explain satisfactorily the variations of sensitivity of target-cells to angiotensin II during sodium balance changes.