[Treatment of hypertension in pregnancy. How long is ambulatory treatment enough?]. / Hochdruckbehandlung in der Schwangerschaft. Wie lange geht es ambulant?

Hypertension in pregnancy is diagnosed when pressures in excess of 140/90 mmHg are repeatedly measured. A differentiation is made between pregnancy-independent hypertension, i.e. pre-existing hypertension and gestational hypertension occurring for the first time after the 20th week of the pregnancy. If hypertension is accompanied by proteinuria, the diagnosis of pre-eclampsia is made. Feared complications are eclampsia and the HELLP syndrome. For blood pressure measurement, a number of peculiarities must be noted: thus, for example, in severe pre-eclampsia the circadian rhythm may reverse, with pressure increases in particular in the evening and at night. Ambulatory management may be permissible only in the case of pre-pregnancy and gestational hypertension, provided the blood pressure can be kept below 160/100. Restricting physical activity, and regular monitoring of weight, blood pressure and laboratory investigations usually suffice. If pre-eclampsia or the HELLP syndrome is suspected, the patient should be hospitalized without delay. A hypertensive crisis must prompt immediate measures to lower the blood pressure--but not too quickly, in order to avoid severe consequences for the fetus caused by inadequate uteroplacental perfusion.

HELLP syndrome in the 18th week of gestation in association with elevated angiotensin AT(1)-receptor autoantibodies.

We present a 24-year-old woman with a twin pregnancy who was with a typical HELLP syndrome at the 18th week of pregnancy. One fetus was dead, while the other was severely growth retarded. Our patient had agonistic autoantibodies directed at the angiotensin AT(1)-receptor. Termination of the pregnancy proved necessary. This report is the first to our knowledge associating HELLP syndrome with angiotensin AT(1)-receptor antibodies. Since the antibodies may have a pathogenic significance, their removal could permit the prolongation of pregnancy in preeclamptic and HELLP syndrome patients.

AT(1) receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor.

BACKGROUND: We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT(1)-AA) directed at the AT(1) receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT(1)-AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT(1)-AA cause vascular smooth muscle cells (VSMC) to express TF. METHODS AND RESULTS: IgG from preeclamptic patients containing AT(1)-AA was purified with anti-human IgG columns. AT(1)-AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT(1) receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT(1)-AA specificity by coimmunoprecipitating the AT(1) receptor with AT(1)-AA but not with nonspecific IgG. Angiotensin (Ang) II and AT(1)-AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT(1)-AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect. CONCLUSIONS: We conclude that AT(1)-AA and Ang II both stimulate the AT(1) receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT(1)-AA on human cells that could contribute to the pathogenesis of preeclampsia.

Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor.

Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.

Endothelial-cell permeability and protein kinase C in pre-eclampsia.

BACKGROUND: Oedema and vascular leakage play a part in the pathogenesis of pre-eclampsia. We tested the hypothesis that serum from pre-eclamptic patients increases endothelial-cell permeability and examined possible signal-transduction pathways. METHODS: We studied eight patients with pre-eclampsia, eight normotensive pregnant women, eight non-pregnant women, five pregnant patients with pre-existing hypertension, and four hypertensive non-pregnant women. Cultured human umbilical-vein endothelial-cell monolayers were used and permeability was measured by albumin flux. The part played by protein kinase C (PKC) signalling was examined by down-regulation with phorbol ester and with the inhibitors Goe 6976 and staurosporine. PKC isoforms were assessed by western blot and confocal microscopy. Antisense oligodesoxynucleotides (ODN) were used to test for specific PKC isoforms. FINDINGS: Serum from pre-eclamptic women increased endothelial permeability significantly (by 100%, p<0.01). The change in permeability decreased rapidly after delivery. Serum from normotensive pregnant women and non-pregnant women had no effect. Permeability was not influenced by serum from patients with essential hypertension or pregnant patients with pre-existing hypertension. Serum from pre-eclamptic patients induced a translocation of PKC isoforms alpha and epsilon within the cells. Goe 6976 and staurosporine (10(-8) mol/L) inhibited the increase in permeability induced by serum from pre-eclamptic patients. Down-regulation of PKC alpha and, to a lesser extent, PKC epsilon by antisense ODN also inhibited the pre-eclampsia-induced permeability increase. INTERPRETATION: Serum from pre-eclamptic patients contains a factor or factors that increase endothelial-cell permeability. The effect of pre-eclamptic serum may be mediated by PKC alpha and epsilon.

Alpha 1-adrenergic receptor antibodies in patients with primary hypertension.

Autoimmune mechanisms have been proposed to play a role in the pathogenesis of primary (essential) hypertension. Autoantibodies against the alpha 1-adrenergic receptor have been described in patients with malignant and secondary hypertension. To investigate the incidence of autoantibodies against the alpha 1-adrenoceptor in patients with primary hypertension, we examined the immunoglobulin fractions of sera from 54 patients with primary hypertension and 26 normotensive control subjects for the presence of autoantibodies against the alpha 1-adrenoceptor. Sera from 24 patients (44%) and 3 subjects (12%) were positive. An epitope analysis of 16 autoantibody-positive immunoglobulin fractions revealed that in two thirds of the cases, the antibodies were directed against the first extracellular loop of the alpha 1-adrenoceptor and in one third, against the second. The autoantibodies had a positive chronotropic effect on isolated neonatal rat cardiomyocytes, an effect that was blocked by alpha 1-adrenergic antagonists. Since the functional characteristics of the autoantibodies showed no desensitization phenomena, they may play a role in elevating peripheral vascular resistance and promoting cardiac hypertrophy in patients with primary hypertension.

Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients.

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia. 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]i in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]i was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca2+]i in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]i concentrations were correlated with the ICAM-1 expression in preeclamptic patients (r = .80, P < .001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca2+]i and enhances adhesion molecule expression.

[Clinical aspects and differential therapy of mild hypertension in pregnancy]. / Untersuchungen zur Klinik und Differentialtherapie der milden Hypertonie in der Schwangerschaft.

Pregnant patients with increases in blood pressure are often treated with medication, in our view inappropriately. We examined 222 pregnant women who were referred because of two blood pressure determinations > 140/90 mm Hg. The women were primarily treated by nonpharmacological means. Only 44 required medications to maintain a blood pressure < 140/90 mm Hg. Twenty-six additional pregnant women referred for hypertension were taught to measure their blood pressures at home. Fourteen underwent 24-h ambulatory blood pressure monitoring. Home and 24-h blood pressure measurements were both significantly lower than those obtained in the office and did not significantly differ from each other. We conclude that most pregnant women without proteinuria, who show mild to moderate blood pressures > 140/90 mm Hg are best treated conservatively without drugs. Those in whom home or 24-h blood pressures exceed 140/90 mm Hg and who do not respond to nonpharmacologic methods require medication. Finally, "white coat" hypertension is common in pregnant women.

Usefulness of piretanide plus ramipril for systemic hypertension: a multicenter trial.

To test the dose responses of piretanide, ramipril, and their combination in patients with essential hypertension, a prospective, randomized, double-blind, placebo-controlled trial was conducted in 480 patients. Twelve separate groups were studied: placebo, piretanide 3 mg, piretanide 6 mg, ramipril 2.5 mg, ramipril 5 mg, ramipril 10 mg, and their combinations, as single daily morning doses. Patients were randomized after a 2-week run-in period without drugs; treatment was given for 6 weeks. A dose response compared with placebo was found for both drugs; the combination was more effective than either drug alone. Piretanide 6 mg, combined with ramipril 5 mg, provided optimal blood pressure reduction. Self-reported adverse effects of both drugs and their combinations did not exceed those reported for placebo. A surface analysis suggested that piretanide primarily reduced systolic blood pressure, whereas ramipril was more effective in reducing diastolic blood pressure. The data attest to a combined efficacy of piretanide and ramipril in decreasing arterial blood pressure.

[A pilot study on the long-term effects of combined drug therapy and psychophysiologically-oriented therapy in patients with severe essential hypertension]. / Pilotstudie zur Langzeitwirkung einer kombinierten medikamentösen und psychophysiologisch orientierten Therapie bei Patienten mit einer essentiellen Hypertonie höheren Schweregrades.

15 patients with a severe degree of essential hypertension, which had not responded satisfactorily to pharmacological management, received an additional regimen of psychophysiological treatment. This schedule consisted of relaxation training, self-recording of the blood pressure by the patients and conversations geared at improving stress management. After 1 year 9 patients showed a lowered mean blood pressure from 162/106 mmHg to 141/95 mmHg (responders). 2 patients were excluded from the study and 4 patients failed to show any lowering of their blood pressure (non-responders). In 6 responders it was possible to reduce the dose of antihypertensive drugs by 8-71%. These results were confirmed over a 4-year follow-up period. Responders and non-responders did not differ with regard to their age, stages and duration of hypertension. Patients with a very high reactivity of blood pressure under psychological stress and a low frankness with regard to their own weaknesses and problems seem to respond to the therapy with a lower probability of success.

Nitrendipine treatment in so-called therapy-resistant arterial hypertension; effect as monotherapy and in combination with propranolol on blood pressure, heart rate, other hemodynamic parameters, plasma renin activity, and catecholamines.

Twenty-three patients [mean age 49.7 +/- 5.6 years (WHO II-III)] with severe hypertension and not responding to previous drug treatment were included in the study to evaluate the effect of nitrendipine (NTP) as monotherapy and also in combination with propranolol (PRO). After a control period of 10 days, NTP was started with 20 mg twice a day and titrated to the maximal dosage of 2 X 40 mg/day. After 1 week of NTP treatment, PRO was added in increasing dosage to a maximal 2 X 100 mg/day. NTP lowered systolic and diastolic blood pressure (BP) significantly (supine BP from 182/119 +/- 19/9 to 157/98 +/- 16/9 mm Hg). After combination with PRO, systolic BP was decreased additionally (supine BP from 157/98 +/- 16/9 to 150/97 +/- 19/9 mm Hg). Plasma norepinephrine (NE) was increased by NTP (from 1.82 +/- 0.78 to 2.38 +/- 1.08 nmol/l, p less than 0.01) and remained elevated during PRO treatment (2.76 +/- 1.10 nmol/l). Plasma renin activity (PRA) showed no significant changes by NTP. Additional effect of PRO on BP correlated significantly with NE and PRA after the NTP period. Plasma epinephrine and dopamine beta-hydroxylase remained unchanged. NTP decreased systemic resistance, calculated from isotope dilution technique (p less than 0.05); after combination with PRO no additional significant changes were registered. Nitrendipine is an effective alternative in so-called therapy-resistant hypertension.

[Saralasin test in the differential diagnosis of essential and renal hypertension]. / Der Saralasintest in der Differentialdiagnostik essentieller und renaler Hypertonien.

In a multicentric prospective study should be tested clinically the effectiveness and the tolerance of an angiotensin-II-antagonist (Saralasin-IWF) developed by the Institut für Wirkstofforschung der Akademie der Wissenschaften, its position in the differential-diagnostic step programme of the arterial hypertension should be analysed and with it should be performed pathogenetic investigations for hypertension after kidney transplantation. Taking into consideration international studies our results confirm that the Saralasin test, taking into account strongly standardized methodical prerequisites, is suited to objectify a participation of the RAAS in the hypertension pathogenesis, without, however, thus making an absolutely reliable evidence concerning the etiology of hypertension. The Saralasin test may represent an important diagnostic criterion for an optimization of the therapy of "volume-resistant" hypertension under the conditions of haemodialysis and in connection with selective renin determinations it possesses a high value in the screening diagnostics of the arterial stenosis after allogenic kidney transplantation.

[Comparative study of the relative bioavailabilities of two prazosin preparations in patients with essential hypertension]. / Vergleichende Untersuchungen zur relativen Bioverfügbarkeit von zwei Prazosinpräparaten bei Patienten mit essentieller Hypertonie.

The relative bioavailability of two different Prazosine preparations (Adversuten, VEB Arzneimittelwerk Dresden, GDR and Minipress, Pfizer GmbH, Karlsruhe, FRG) has been determined in 10 patients suffering from an essential hypertension by the cross-over test following a single oral application. The plasma concentrations determined on the same conditions revealed with both the preparations an almost equal blood level course. The pharmacokinetic parameters had been determined to the one-compartment system, demonstrating not any significant differences. Compared to the Minipress, the relative bioavailability of the preparation Adversuten was calculated to 102%. The discussion enters into a possible influence on the distribution parameters by alterations of the kidney function.