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Objective: Determine the definitive position of ketanserin and dihydralazine for treatment of severe hypertension in pregnancy., Study Design: A single centre double blind randomized controlled trial was performed at the obstetrical tertiary high care unit of the University Medical Centre in Rotterdam, the Netherlands. Women with severe hypertension in pregnancy (diastolic blood pressure (DBP)≥110mmHg), and significant proteinuria (≥300mg/24h), and gestational age≤32 weeks were eligible for the study. All patients (n=30) received two infusions (double dummy technique): one contained the active ingredient (ketanserin or dihydralazine), the other was used for placebo. Nicardipine was used as rescue medication. The main outcome measures were persistent severe hypertension (DBP>100mmHg>120min) despite maximum dosage of study medication and prolongation of pregnancy., Results: Dihydralazine was significantly more effective in lowering blood pressure than ketanserin. No significant difference in prolongation of pregnancy was seen between the two groups. After 30 inclusions, the study was stopped because of the high rate of persistent hypertension using ketanserin and the high rate of maternal side effects using dihydralazine and the apparent succesful use of the rescue drug nicardipine., Conclusions: Our results do not support the use of either dihydralazine or ketanserin for the treatment of severe hypertension in pregnancy. Future research is needed to compare nicardipine with other antihypertensive drugs currently in use for treatment of severe hypertension in pregnancy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: An animal study reported that TGF-β1 maturation was linked to the homeostasis of blood pressure and elastogenesis of essential hypertension (EH). Recent advances require further research of TGF-β1 receptor in EH., Methods: A case-control study comprised of 2,012 adult hypertension case patients and 2,210 adult control subjects was conducted, and the association with blood pressure was further tested in children. Logistic regression and calculated genetic risk score were used to evaluate the effects of one single nucleotide polymorphism (SNP) and multiple SNPs on EH, respectively., Results: The genetic risk score of 10 SNPs showed a significant association with hypertension; the odds ratio of the upper quartile vs. the lower quartile was 1.282 (P = 4.67 × 10(-3)). rs7256241 in miR-518 was significantly associated with diastolic blood pressure (DBP) change in control subjects (P = 0.002), and this association was also observed in children (P = 0.04). The systolic blood pressure (SBP) and DBP of female patients taking reserpine were higher with the C and G alleles of rs3773661 (P = 0.004) and rs7256241 (P = 0.002), respectively. In patients taking Zhen Ju Jiang Ya tablets, SBP and DBP decreased linearly with rs749794 (P = 0.004 and P = 0.048, respectively). SBP decreased linearly with rs1155705 (P = 0.007) and rs11709624 (P = 0.04), but increased with rs1036096 (P = 0.03) in male patients. In male patients taking Jiang Ya tablets, SBP increased linearly with rs11709624 (P = 0.007), DBP increased linearly with rs1155705 (P = 0.03) whereas decreased with rs7256241 (P = 0.04)., Conclusions: Our results suggest that TGFBR2 and miR-518 harbor variants that increase the risk of EH and affect blood pressure homeostasis as well as efficacy of antihypertensive agents., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although HTDR has been used in China for more than 30 years, there have been few comprehensive evaluations of this treatment., Objective: The aim of this study was to investigate the long-term efficacy and tolerability of HTDR in Chinese patients with essential hypertension., Methods: This was a 36-month, community-based, open-label surveillance study, conducted in the Huangpu District (Shanghai, China). The study was based in local primary healthcare settings. Subjects were recruited if they had essential hypertension, were aged ≥35 years at the time of enrolment, were expected to remain in the area for 3 years, and were able to provide informed consent. Patients who had secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional hydrochlorothiazide was added. Blood pressure (BP) was measured at baseline and throughout the 36-month surveillance period every 3 months. Biochemical indicators (e.g. fasting blood glucose, plasma lipid parameters, plasma sodium and potassium, plasma uric acid and serum creatinine) were also measured, and adverse events were noted. BP reductions and the rate at which patients achieved BP targets (systolic BP [SBP] <140 mmHg and diastolic BP [DBP] <90 mmHg) throughout the period were determined. Subgroup analyses by sex and age were also conducted., Results: A total of 1529 patients (550 male, 979 female; mean age 65.7 years) entered the study. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipid profiles were improved after 24 months of treatment. In addition, a significant increase in plasma potassium and a significant reduction in plasma uric acid were seen., Conclusion: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension.

Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis.

Objective: To evaluate the effect of plasma volume expansion (PVE) and nitric oxide (NO) donors, in addition to antihypertensive therapy for gestational hypertensive pregnancies complicated by intrauterine growth restriction (IUGR) with absent end-diastolic flow (AEDF) in the umbilical artery (UA)., Methods: This was a case-control study into which 32 gestational hypertensive pregnancies with IUGR and AEDF were enrolled. Sixteen of these were treated with antihypertensive drugs, NO donors and PVE (Group A), and 16, matched for maternal age, gestational age and fetal conditions, were treated with antihypertensive drugs only (Group B). All patients underwent fetal and uteroplacental assessment and maternal echocardiography to evaluate total vascular resistance (TVR) and cardiac output before and 5-14 days after initiation of treatment., Results: After 5-14 days of treatment, the maternal TVR in Group A fell from 2170 +/- 248 to 1377 +/- 110 dynes.s.cm(-5) (P < 0.01), and that in Group B fell from 2090 +/- 260 to 1824 +/- 126 dynes.s.cm(-5) (P < 0.01), with the reduction being greater in Group A than in Group B (P < 0.01). There was a significant increase in cardiac output in Group A after 5-14 days of treatment vs. baseline (6.19 +/- 0.77 vs. 4.32 +/- 0.66, P < 0.001), and, after treatment, cardiac output was significantly greater in Group A than it was in Group B (6.19 +/- 0.77 vs. 4.70 +/- 0.44, P < 0.001). Reappearance of end-diastolic flow in the UA occurred in 14/16 patients in Group A but in no patients in Group B (87.5% vs. 0%, P < 0.05). The interval between detection of UA-AEDF and delivery was 28 +/- 16 days in Group A and 11 +/- 6 days in Group B (P < 0.05)., Conclusion: Administration of NO donors and PVE in gestational hypertensive pregnancies affected by IUGR and UA-AEDF appears to improve both maternal and fetal hemodynamics, inducing prolongation of gestation., (Copyright (c) 2007 ISUOG. Published by John Wiley & Sons, Ltd.)

Background: Drug treatment is imperative for pregnant women with pregnancy-induced hypertension (PIH) and pre-eclampsia. For more than 40 years, dihydralazine has been the drug of choice for this indication. Another particularly effective and better tolerable antihypertensive is urapidil. Yet only a few studies on limited patient collectives have been published on the clinical experience with urapidil in PIH., Methods: Urapidil was interindividually compared to dihydralazine in a total of 42 patients, at six participating clinical centres. Patients were randomly assigned to the treatment groups. Urapidil was administered at an initial dose of 12.5-25mg, dihydralazine was administered at a uniform initial dose of 5mg. Patients were closely monitored for the initial 24h of therapy. Until delivery and in the postpartal phase, mother and baby underwent four additional follow-up checks at regular intervals., Results: Either drug was effective in lowering BP. Urapidil treatment proved to be better controllable. There were clear differences as to tolerability. In the urapidil group, one patient complained of headaches. In the dihydralazine group, six patients experienced adverse occurrences. Under dihydralazine treatment, some marked HR increases occurred, interpretable as reflectory tachycardia., Conclusions: Urapidil proved to be equally effective as dihydralazine in lowering BP in patients with pre-eclampsia, but showed a better controllability and tolerability. Urapidil can hence be recommended as a promising alternative for patients with PIH.

Objective: Impaired hepatic perfusion after hemorrhagic shock frequently results in hepatocellular dysfunction associated with increased mortality. This study characterizes the effect of the vasodilators dihydralazine and urapidil on hepatocellular perfusion and integrity after hemorrhagic shock and resuscitation., Design: Prospective, randomized, controlled experimental study., Setting: University experimental laboratory., Subjects: Male Sprague-Dawley rats., Interventions: To register systemic and regional hepatic hemodynamics, rats (n=6 per group) were instrumented and randomly assigned to the following groups: shock+vehicle; shock+dihydralazine (1.5 mg/kg); or shock+urapidil (3 mg/kg). After 1 hr of hemorrhagic shock, animals were resuscitated for 5 hrs and mean arterial pressure was maintained at 70+/-5 mm Hg by administration of dihydralazine or urapidil. To evaluate hepatic heme oxygenase-1 expression and liver injury (determination of levels of alanine and aspartate aminotransferase [ALT, AST] and histology), an additional series of experiments with six animals per group was performed. At the end of each experiment, animals were killed and blood and liver tissue was obtained for subsequent analyses., Measurements and Main Results: Dihydralazine increased cardiac output and portal and hepatic microvascular flow (p<.05) and reduced liver injury after shock (lower ALT and AST levels [p<.05]; improvement of histopathological changes). In contrast, urapidil had no effect on portal flow or liver injury. Hepatic heme oxygenase-1 mRNA expression was upregulated in animals subjected to hemorrhagic shock but did not differ among experimental groups., Conclusions: Dihydralazine increases nutritive portal and hepatic microvascular flow and limits liver injury after hemorrhagic shock. This protective effect appears to be the result of increased cardiac output and increased portal flow. These findings may offer a new strategy for hepatic protection after hemorrhagic shock.

Objective: To assess morbidity and development in childhood of infants born after temporising management of severe early onset pre-eclampsia., Design: Cohort study with matched controls., Setting: University centre for high risk obstetrics., Samples: Three groups of neonates matched for gender and year of birth: one born after temporising treatment of severe early onset (<32 weeks) pre-eclampsia with an average delay of delivery of two weeks (n= 193); one born at the duration of pregnancy [1 week] of the pre-eclamptic mother on admission (control group I, n = 192); and one born at the same gestational age [1 week] as the infant of the pre-eclamptic mother (control group II, n= 189)., Method: Follow up at four years of age or more using medical records and questionnaires., Main Outcome Measures: The presence of various morbidities including mental retardation, cerebral palsy, motor skill problems, visual handicap, hearing loss, speech and language problems, education level and acute or chronic respiratory problems., Results: Median follow up of seven years (range 4-12) was achieved in 159 infants in the study group (83%), 122 in control group I (64%) and 110 in control group II (58%). Missing data analysis showed no differences in neonatal characteristics and morbidity between infants with and without follow up in the study group. All major and minor handicaps were less frequent in the study group than in control group I but statistical significance was reached only for acute and chronic respiratory disorders in the study group (13.8%) compared with control group I (27%)., Conclusion: Average delay of delivery of two weeks with temporising management in severe early onset pre-eclampsia is associated with a reduced risk of respiratory disorders in childhood.

Systemic hypertension (HTN) is one of the major problems associated with chronic renal failure (CRF). HTN is a symptom and complication of CRF. The prevalence of HTN varies with the cause of CRF. The incidence of HTN increased up to 90% with progressive deterioration of the glomerular filtration rate (GFR). HTN is the major risk factor for decline in renal function and progression of CRF. It is the most important risk factor for cardiovascular diseases and morbidity and mortality in patients with CRF and end-stage renal disease (ESRD) on dialysis. The target blood pressure for hypertensive children with CRF should be under the 95th percentile for sex and age. The therapeutic approach in CRF is directed at reducing volume expansion and sodium retention, and decreasing peripheral vascular resistance. Diuretics are first-line therapy for HTN in patients with CRF with sodium and water retention. ACE inhibitors are the first-class drugs because of their renoprotective effect in preventing deterioration of kidney function. Calcium channel blockers are excellent first-line antihypertensive drugs. Recently angiotensin II receptor blockers and ACE inhibitors have been efficiently used together for the treatment of HTN and to prevent further decline in renal function.

Objectives: To establish the effects of plasma volume expansion (PVE) followed by intravenous dihydralazine (DH) administration on maternal whole blood viscosity (WBV) and hematocrit, uteroplacental and fetoplacental downstream impedance and umbilical venous (UV) volume flow in pre-eclampsia., Methods: In 13 pre-eclamptic women maternal and fetal hemodynamics were established by means of combined measurement of maternal arterial blood pressure (BP), WBV, hematocrit and uterine artery (UtA) resistance index (RI) in addition to umbilical artery (UA) pulsatility index (PI) and UV volume flow obtained from UV vessel area and UV time-averaged flow velocity. In each woman all parameters were measured four times at baseline, after PVE, after DH and 24 h after the start of treatment., Results: Maternal diastolic BP, hematocrit and WBV display a significant reduction after PVE. In the fetus UA PI decreases significantly whereas a significant increase in UV cross-sectional area was detected. After maternal DH administration, arterial systolic and diastolic BP and UA PI show a significant decrease compared with the measurements following PVE. At 24 h, only maternal systolic and diastolic BP display a significant further decrease. No significant changes were established for the UtA RI, UV time-averaged velocity and UV volume flow during the entire study period., Conclusions: During pre-eclampsia, maternal PVE followed by DH administration results in a significant reduction in maternal diastolic BP, maternal hematocrit and WBV. Maternal PVE is associated with a significant increase in UV cross-sectional area and a non-significant rise of 11% in UV volume flow. Maternal DH administration does not result in any change in UV cross-sectional area. However, UA PI decreases significantly after both PVE and DH treatment., (Copyright 2004 ISUOG.)

Left ventricular hypertrophy (LVH) develops very early in experimental renovascular hypertension after clipping of one renal artery and is accompanied by a remodeling of cardiac structure which has not yet been investigated in detail. It was the aim of the present study to analyze changes in cardiomyocyte number and volume in LVH after 2 weeks of renovascular hypertension. Sprague-Dawley rats were subjected to clipping of the left renal artery (2K1C) or sham operation (sham). One group of 2K1C rats received antihypertensive treatment with dihydralazine. The experiment was terminated after 2 weeks. Hearts were investigated using stereological methods, electron microscopy, immunohistology for the proliferation marker proliferating cell nuclear antigen, the pro- and anti-apoptotic proteins Bax and Bcl-2 as well as the TUNEL technique. After 2 weeks, systolic blood pressure and relative left ventricular weight were significantly higher in untreated 2K1C animals than in sham and dihydralazine-treated 2K1C rats. Volume fraction of interstitial tissue and capillary length density were not different, whereas wall thickness of intramyocardial arteries was significantly higher in untreated 2K1C (5.12+/-0.7 micro m) than in sham (3.92+/-0.6 micro m) and in dihydralazine-treated 2K1C (3.91+/-0.7 micro m) rats. Cardiomyocyte diameter and volume were significantly higher in untreated 2K1C than in sham animals. The number of cardiomyocytes per left ventricle was significantly lower in untreated 2K1C rats (5.5+/-1.6 vs 3.9+/-6.9 x10(7)). Using immunohistochemistry, no direct evidence of apoptosis was found, but a relative higher expression of the anti-apoptotic protein bcl-2 expression was seen in untreated 2K1C than in sham animals. This may reflect a protective mechanism as a consequence of earlier occurring apoptosis. These observations document that experimental renovascular hypertension induces a rapidly developing LVH characterized by marked cardiac remodeling and substantial loss of cadiomyocytes.

Objective: For the therapy of preeclamptic patients is Urapidil besides Dihydralazine another possible option for iv-therapy with good results in first clinical studies. Effects of both drugs on the newborns were observed. -, Methods: The maternal and fetal Urapidil plasma-concentrations and cardiovascular parameters of the newborns were observed in a randomised comparative therapy-study. -, Results: We found low fetal Urapidil plasma-concentrations as well as a less influence on cardiovascular parameters compared to dihydralazine. -, Discussion: With Urapaidil we have another therapeutic option in preeclampsia where we could not show any negative side-effects on the newborns.

Objective: To compare maternal and perinatal outcome with the use of either intravenous ketanserin or dihydralazine in treatment of women with preeclampsia., Methods: The records from January 1989 to January 1997 of all patients receiving intravenous ketanserin or dihydralazine as first line antihypertensive therapy were reviewed and standardized data forms were completed. 315 charts of patients were identified and evaluated for effects on blood pressure, laboratory parameters, maternal and perinatal outcome., Results: During the study interval 169 patients received ketanserin and 146 dihydralazine. Significantly fewer antepartum (27% versus 38%, p = 0.04) and postpartum (25% versus 39%, p = 0.01) maternal complications were noted in patients receiving ketanserin. Occurrence of HELLP syndrome was significantly lower among patients who received ketanserin (20%) than among those who received dihydralazine (40%, p = 0.0001). Side-effects were reported with significantly higher frequency in patients receiving dihydralazine (60%) as compared to those receiving ketanserin (17%, p < 0.0001). Perinatal outcome was comparable, however, umbilical cord arterial pH values (mean +/- SD) were higher with ketanserin compared to dihydralazine (7.25 +/- 0.07 vs 7.23 +/- 0.09, p = 0.038). The incidence of placental abruption was higher in patients receiving dihydralazine (5.5%) versus those receiving ketanserin (0.6%, p = 0.014)., Conclusion: Ketanserin appears to be a better option than dihydralazine for treatment of severe preeclampsia since fewer maternal complications and side-effects were observed in patients receiving ketanserin.

Objective: To evaluate the safety and outcome of women undergoing expectant management of early onset, severe pre-eclampsia., Design: Prospective case series extending over a five-year period., Setting: Tygerberg Hospital, a tertiary referral centre., Population: All women (n = 340) presenting with early onset, severe pre-eclampsia, where both the mother and the fetus were otherwise stable., Methods: Frequent clinical and biochemical monitoring of maternal status, together with careful blood pressure control, in a high care obstetric ward., Main Outcome Measures: Major maternal complications and prolongation of gestation., Results: Multigravid women constituted 67% of the group. Antenatal biochemistry was reassuring with some expected, but not severe, deteriorations. Twenty-seven percent of women experienced a major complication, but few had poor outcomes. No maternal deaths occurred. Most major complications resolved quickly, necessitating only three admissions (0.8%) to the intensive care unit. One woman required dialysis. Pregnancies were prolonged by a mean (median) number of 11 days (9) before delivery, with more time being gained at earlier gestations. The postpartum inpatient stay (89% < or =7 days, bearing in mind that 82% of women were delivered by caesarean section) was not extended., Conclusion: Careful noninvasive management of early onset, severe pre-eclampsia in a tertiary centre can diminish and limit the impact of serious maternal complications. Valuable time to prolong the pregnancy and improve neonatal outcome is thereby gained.

Aims: The goal of the present retrospective study was to examine the peripheral blood lymphocytes for expression of phenotypic and activation markers concerning the development of hypertension in pregnancy., Methods: 16 women (aged 25-43 years; mean 35.1) developing hypertension in the third trimester (week 25-34) have had blood samples taken in the first (< 14 weeks), the second (week 14-23), the third trimester (week 24-35), in late pregnancy (week 36-termination of pregnancy) and within 1 week post-partum, The control group consisted of 16 age-matched pregnant healthy women, who underwent the same regime. All blood samples were taken in the morning, stored at room temperature and stained within 6 hours and measured within 24 hours. Kruskal-Wallis analysis of variance between both groups was done with multiple comparison according to Dunn., Results: Comparing both groups, the total white cell count was significantly increased in all pregnancies and post-partum. In case of hypertension in pregnancy the cell numbers of suppressor/cytotoxic (CD 8+) and CD 56(+)-activated T cells showed a significant increase in the first trimester (< 14 weeks) [p < 0.05] and decreased thereafter to normal values. In the second trimester (week 14-23) helper/inducer lymphocytes and CD 56+/CD 3+ lymphocytes decreased in case of pre-ecclampsia and cytotoxic lymphocytes elevated [p < 0.05]. In the third trimester (week 24-35) there was no difference in both study groups and in late pregnancy (week 36-termination) there were only small differences without statistical significance. Within 1 week postnatal the value of Il-2 receptor T lymphocytes decreased in the group of pre-eclampsia in comparison to normal pregnancies [p < 0.05]., Conclusions: Regarding the major changes in activated T cells in both study groups no specific pattern of lymphocyte subsets in case of pre-eclampsia could be found in comparison to healthy pregnant women. Further investigations should focus on functional activation and/or suppression of the cellular immune system. Perhaps this could lead to a screening test for pre-eclampsia in future, which is non-invasive for the patient and economic for our social community because it might reduce medical costs.

The coincidence of HELLP syndrome and cortical blindness is an uncommon but very dramatic event, for the patient as well as the obstetrician. This report describes the first case of HELLP-syndrome-associated cortical blindness occuring suddenly in the third stage of labour. There were only modest correlates of cortical blindness in cerebral CT, MRI and angiography findings, but no signs of a posterior leucoencephalopathy syndrome. Mother and baby were discharged from hospital to outpatient care in good health on the 12th day.

Objective: An open, randomized, prospective, multicenter trial was conducted to compare the efficacy and safety of intravenous ketanserin, a selective serotonin 2 receptor blocker, with that of intravenous dihydralazine in the management of severe early-onset (<32 weeks' gestation) preeclampsia. End points of this study were blood pressure control and maternal outcome., Study Design: Patients with a diastolic blood pressure >110 mm Hg were randomly assigned to receive either ketanserin (n = 22) or dihydralazine (n = 22) as initial therapy. Plasma volume expansion preceded antihypertensive treatment, which was administered according to a fixed schedule., Results: The reductions in blood pressure with the 2 drugs were similar; however, adequate blood pressure control was reached significantly earlier with ketanserin (84 +/&#95; 63 vs 171 +/- 142 minutes, P = .017). Occurrence of maternal complications was significantly lower among patients who received ketanserin than among patients who received dihydralazine (n = 6 vs n = 18, P =.0007). A significant difference in favor of ketanserin was noted in daily fluid balance., Conclusion: Antihypertensive efficacies of ketanserin and dihydralazine were comparable, but significantly fewer maternal complications were noted among the patients receiving ketanserin. Ketanserin is an attractive alternative in the management of severe early-onset preeclampsia.

Preeclampsia is a disease which occurs in Europe in about 6-8%, in the USA in about 7-10% and in Africa in about 18% of all pregnancies. A causal treatment of preeclampsia is, with the exception of delivery, not possible up to now. Since a prematurely delivery of the newborn has to be avoided because of the risks caused by immaturity of lungs, treatment and care of pregnant women having preeclampsia or any other kind of hypertensive diseases is restricted to the following approaches: antihypertensive treatment, volume expansion, and eclampsia prophylaxis with magnesium sulfate. Object of this treatment is to avoid complications on the mother's side caused by the disease and to postpone delivery, as far as possible from the child's side, in order to reduce the consequences of premature birth. During antihypertensive treatment of patients with serious hypertension, i.e. with diastolic blood pressure of 110 x mm Hg and higher, dihydralazine is in clinical use since 40 years, although many patients suffer from side-effects of dihydralazine such as distinctive tachycardia, headaches, fluid retention and nausea. With urapidil a well controllable antihypertensive is available, which prevents the effect of catecholamines at the vascular wall by a postsynaptic alpha-1 receptor blockade. Previous studies related to the application of urapidil in the treatment of hypertension during pregnancy certify the good controllability of urapidil following intravenous application as well as minor side-effects after start of treatment.

Objective: To compare the haemodynamic efficacy of ketanserin (a selective serotonin2-receptor blocker) with dihydralazine in the management of severe early-onset hypertension in pregnancy., Design: Subgroup analysis within a randomised prospective multicentre trial to compare haemodynamic effects as measured by pulmonary artery catherization., Setting: Departments of Obstetrics and Gynaecology and Intensive Care Medicine, Free University Hospital, Amsterdam and Sophia Hospital, Zwolle., Participants: Thirty-one women with a diastolic blood pressure > 110 mmHg and a gestational age between 26 and 32 weeks., Results: The antihypertensive efficacy of both drugs was comparable. Dihydralazine significantly increased cardiac output (P < 0.01), while ketanserin induced only minor changes in cardiac output. Systemic vascular resistance decreased in both groups, but the decrease was significantly more pronounced with dihydralazine compared with ketanserin. Ketanserin induced a significant but not clinically relevant increase in heart rate (P < 001, while dihydralazine caused marked tachycardia (P < 0.005). Left ventricular stroke work index was reduced to similar values in both groups., Conclusions: The antihypertensive profile of ketanserin is characterised by an early and gradual reduction of blood pressure in combination with a moderate decrease in systemic vascular resistance and no significant change in cardiac output. Dihydralazine causes market tachycardia resulting in a considerable increase in cardiac output.

Background: The primary objective of treatment in women with severe hypertension and pre-eclampsia is to prevent complications such as encephalopathy and haemorrhage. In many countries dihydralazine is considered the drug of choice for treating hypertension in pregnancy, because it now has been used safely for about 30 years, and the introduction of a new drug in pregnancy is a difficult task with partially unknown hazards. In some other countries combined alpha- and beta-blockers are also used. Taking into account that some patients with pre-eclampsia do not respond to dihydralazine and the drug has serious side-effects like headache and reflex tachycardia, there is some need for developing alternative treatment strategies using drugs that are more adequate for pregnancy than dihydralazine., Methods: Urapidil is a post-synaptic alpha 1 adrenoceptor antagonist, which is widely used to control hypertensive crises unrelated to pregnancy. Since it is known that pre-eclampsia is associated with increased sympathetic activity, administration of an alpha 1 adrenoceptor antagonist provides a reasonable therapeutic basis. So far there is only one report describing the i.v. use of urapidil in the treatment of hypertension in pregnancy unresponsive to dihydralazine and one report which describes the oral use of urapidil. In an earlier pilot study we examined the dose range for i.v. application of urapidil necessary for adequate blood pressure control in patients with pre-eclampsia. In the present randomized controlled study 26 white women with pre-eclampsia and hypertension in pregnancy were included. Treatment was not blinded. During the initial period of intensive intravenous treatment all subjects were under constant surveillance by a physician and a nurse., Results: Effective prolonged control of blood pressure (values below 150/100 mmHg) was achieved in all patients of the two groups. In one patient of the dihydralazine group signs of lightheadedness and near syncope were noted. After this side-effect of dihydralazine the patient was treated with urapidil. At the end of the observation period the maternal heart rate in the dihydralazine group was higher than in the urapidil group., Conclusions: Since urapidil decreased the high blood pressure in patients with pre-eclampsia without serious side-effects urapidil appears preferable superior to dihydralazine. The haemodynamic effects of urapidil were more predictable than those of dihydralazine. The reduction of intracerebral pressure could be an additional advantage of urapidil in the treatment of patients with pre-eclampsia.

Objective: To compare the efficacy and safety of intravenous dihydralazine with ketanserin in the management of severe hypertension in the third trimester., Study Design: A double blind randomised controlled trial, comparing 5 mg dihydralazine with 10 mg ketanserin after an intravenous infusion of 500 ml of a crystalloid solution. Medication was repeated every 20 min till the therapeutic goal of 90 mm Hg was reached, to a maximum of 4 dosages. Main outcome measures were treatment failures and emergency deliveries for fetal distress., Results: The therapeutic goal was met more often in patients receiving dihydralazine (36/38 compared to 27/42; P < 0.01). The need for delivery for fetal distress did not differ (3 after dihydralazine, 1 after ketanserin, P = 0.29) No therapy related perinatal loss occurred, but one mother with an undiagnosed phaechromocytoma died 24 h after receiving dihydralazine., Conclusion: Ketanserin in this dosage is less effective to lower diastolic blood pressure. The place of a fluid load prior to dihydralazine needs to be further investigated, as fetal heart rate decelerations were less common than previously reported.

Hypertensive disorders are among the most common causes of maternal and perinatal mortality. Mild and uncomplicated chronic hypertension has a better prognosis than preeclampsia. The primary aims of therapy are to prevent cerebrovascular complications and to avoid the progression of chronic hypertension into superimposed preeclampsia with worse prognosis. In mild courses of the disease bedrest, whether at home or in the hospital, is commonly recommended. A special diet is not required neither for prevention nor for therapy. This also applies for the use of aspirin. Calcium supplementation during pregnancy seems to be effective in reducing the risk of hypertension and to a smaller extent of preeclampsia. Diuretic therapy is only indicated in exceptional cases. Antihypertensive drugs are recommended, if a sustained blood pressure of diastolic > or = 110 mmHg is recorded, in cases of superimposed preeclampsia even if the diastolic blood pressure is > or = 100 (> or = 90) mmHg. alpha-Methyl-dopa is the initial drug of choice for oral antihypertensive therapy. Neither short-term effects on the fetus or neonate nor long-term effects during infancy have been reported after long-term use of alpha-methyl-dopa in pregnancy. The oral application of beta-adrenergic-antagonist drugs is well-tolerated, but should be avoided in cases of severe fetal growth retardation. Dihydralazine treatment is not suitable for oral therapy, since its medication is associated with maternal side effects such as headache and tachycardia. Administration of drugs that inhibit angiotensin-converting enzyme during pregnancy is contra-indicated. Calcium-channel-blocking drugs are frequently used in the USA and in the UK as "second-line" antihypertensive medication, however there is little experience with the long-term administration of these drugs to pregnant women with hypertension. The indication for hospitalization are of particular clinical importance, since a delay in admission associated with maternal complications may lead to juridical troubles. The antihypertensive treatment is only a symptomatic therapy; the obstetrician must be aware that delivery is the ultimate cure of hypertensive disorders in pregnancy. In women with mild chronic hypertension or mild preeclampsia antihypertensive therapy is unlikely to be beneficial regarding the perinatal results, while in severe forms drug therapy is mandatory to avoid life-threatening maternal complications.

Objective: To assess maternal and perinatal outcomes of expectant management with plasma volume expansion and pharmacologic vasodilatation in patients with severe pre-eclampsia remote from term., Study Design: All women with severe pre-eclampsia between 20 and 32 weeks' gestation, not in labor and with a live, single fetus admitted to the University Hospital Rotterdam from 1985 to 1993 were managed with the intention to prolong gestation. Treatment consisted of correction of the maternal circulation with vasodilatation by means of dihydralazine and plasma volume expansion under central hemodynamic monitoring. Primary end-points of the study were prolongation of gestation, maternal antepartum and postpartum complications, and fetal and neonatal outcome., Results: Two-hundred fifty-four patients were included. The median prolongation of pregnancy was 14 (range 0-62) days. Hemodynamic treatment was associated with marked objective and subjective improvement in maternal condition. Complications of central hemodynamic monitoring were not observed. Perinatal mortality was 20.5%., Conclusion: Expectant management with plasma volume expansion and pharmacologic vasodilatation under central hemodynamic monitoring of the maternal circulation may delay delivery and enhance fetal maturity and does not appear to be associated with an increased risk of maternal morbidity and mortality.

Objective: To ascertain the change in perinatal mortality (PNM) rate over a period of 10 years in 1001 patients with severe pre-eclampsia., Methods: Patients with severe pre-eclampsia before a gestational age of 34 weeks were managed expectantly. Initial treatment consisted of the administration of magnesium sulphate to prevent convulsions and dihydralazine to reduce blood pressure. Methyldopa alone or in combination with other oral antihypertensive drugs was started soon after admission. In order to prevent fetal death from abruptio placentae, the fetal heart rate was monitored at least four times per day. Patients were delivered either at 34 weeks' gestation or when fetal or maternal indications for immediate delivery were present. The 10-year study was divided into four successive time periods and the PNM rate was calculated separately for each of these time periods., Results: Perinatal survival was low if patients were delivered before or at 26 weeks' gestation but improved rapidly if delivered thereafter. There were only 33 intrauterine deaths of babies who weighed 1000 g or more. The majority of these deaths were due to abruptio placentae which had occurred prior to admission to hospital. The PNM rate for babies of 1000 g or more decreased from 61 in the first time phase and 83 in the second to 19 in the last. The overall PNM rate during the 10-year study was 62., Conclusion: Improved knowledge about the management of patients with severe pre-eclampsia in early pregnancy resulted in a decline in the PNM rate. Although the exact cause of this reduction towards the end of the study is not known, several factors probably played a role. They are expectant management with a little gain in the gestational age, better fetal monitoring before and during labour, earlier detection of fetal distress, earlier referral to the tertiary hospital and improved neonatal care.

24-h trends in central and peripheral circulation in response to pharmacological tests were registered in 40 patients with stage II essential hypertension (EH). Rhythmic patterns of hemodynamic parameters (heart rate, systolic pressure, stroke volume, etc.) sensitivity to adelphane-esidrex were found. Hypotensive effect of this drug was maximal in morning hours because of the fall in arterial pressure due to reduced peripheral resistance. Sinepres chronotherapy given to 18 EH patients turned out superior to conventional treatment (1 pill 3 times a day) given to 20 EH patients. When taken into consideration, chronosensitivity to the above drugs may bring about a reduction in daily and course doses and earlier occurrence of a hypotensive effect.

Urapidil is an antagonist of postsynaptic alpha 1 receptors, which leads to a diminution of the increased blood pressure by reducing the peripheral vascular resistance. With this pilot study we examined, whether it is possible to reduce the pregnancy-induced-hypertension with urapidil postpartum. The postpartum dosage of dihydralazine was diminished step by step and finally discontinued. We started i.v. treatment with urapidil at a diastolic blood pressure of more than 100 mm Hg. We observed a declining blood pressure in all cases without any tachycardia or serious side effects. Further studies will have to classify the rank of urapidil in the treatment of hypertension in preeclampsia.

The relevance of the GABAergic system for the antihypertensive action of metoprolol in spontaneously hypertensive rats was studied by comparing the effect of metoprolol with the effect of dihydralazine. Chronic oral treatment with metoprolol produced the maximum effect after 49 days (-delta 34 mm Hg). This effect persisted on the same level for up to 55 days. The measurements of gamma-aminobutyric acid (GABA) synthesis and specific [3H]GABA binding were performed in the hypothalamus, the pons-medulla, the hippocampus and the striatum. Significant stimulation of GABA synthesis and turnover appeared in the hypothalamus and the pons medulla. In contrast, chronic administration of dihydralazine had no influence on GABA synthesis rate. It was also shown that metoprolol elevated significantly (P < 0.01) specific [3H]GABA binding in the hypothalamus and the pons-medulla. In the striatum this effect of metoprolol was less pronounced. Binding constant analysis revealed changes in both the receptor density and affinity. Our results suggest that the hypotensive response to chronic treatment with metoprolol might be attributed to an enhancement of GABAergic system activity.

Objective: In experimental studies differential effects of antihypertensive agents on the renal function curve have been observed: in SHR captopril lowered the slope of the renal function curve, i.e. blood pressure (BP) became salt sensitive, whereas hydralazine shifted the curve without changing its slope. To evaluate whether ACE inhibitors and vasodilators have different effects on salt sensitivity of BP in humans, we compared the effect of the ACE inhibitor cilazapril and the vasodilator dihydralazine on the renal function curve in a randomized prospective single blind cross-over study., Design: Nine patients (1 f, 8 m, mean age 41 +/- 4 y) with mild to moderate primary hypertension were put on low (20 mmol/d) and on high salt diet (200 mmol/d). Drugs were given in random low salt+cilazapril, high salt+cilazapril; low salt+dihydralazine, high salt+dihydralazine; or in reverse order., Results: All antihypertensive interventions lowered BP, but the averaged posttreatment MAP was significantly (p < 0.02) lower with cilazapril on low salt intake (83.6 +/- 2.8 mmHg) than with all of the following: cilazapril on high salt intake (86.4 +/- 2.9 mmHg), dihydralazine on low (91.6 +/- 3.2 mmHg) and high salt (90.1 +/- 3.3 mmHg) intake. Probably as a result of sympathetic activation, average daily heart rate was higher after dihydralazine on low (72.9 +/- 2.9 b/min) and high salt intake (72.4 +/- 2.8 b/min) than after cilazapril on either salt intake (68.7 +/- 3.1 and 62.7 +/- 3.2 b/min)., Conclusions: The results document that BP reduction after acute ACE inhibition is a function of salt intake, i.e. with ACE inhibitor therapy, BP is "salt sensitive". In contrast, vasodilators of the dihydralazine type have similar antihypertensive effects on low and high salt intake. To the extent that the findings of this short-term study can be extrapolated to long-term effects they suggest that intrarenal mechanisms, i.e. resetting of the pressure-natriuresis relationship, are involved in the long-term antihypertensive action of ACE inhibitors.

In 18 patients (14 men, 4 women, in the age of 37-52 years, mean = 43 years) with dilated cardiomyopathy allocated into NYHA functional classification groups III-IV, the efficacy of ambulatory long term (mean = 6 years) vasodilator therapy by means of non-invasive methods was evaluated. NITRO-MACK retard (venodilator) in the dosage of 20 mg per day and DIHYDRALAZIN (arteriodilator) in the dosage of 100-200 mg per day were combined simultaneously with continuous administration of cardiotonics and diuretics. Vasodilator therapy had a favourable effect on systolic and diastolic function of the left ventricle with the mostly marked effect at the beginning of treatment. Amidst non-invasive parameters, the diastolic amplitude time index and left ventricular hypertrophy-dilatation index had the greatest prognostic value regarding the treatment efficacy and survival of patients. This objective evidence of the efficacy of vasodilator therapy in patients with dilated cardiomyopathy coincided with the improvement of clinical status, subjective relief, moderation of decompensation, and thus with the improvement of life quality. (Fig. 1, Tab. 4, Ref. 24.).

Objective: Our aim was to assess the impact of beta-adrenergic blockade during the peripartum period on the previously observed high incidence of ventricular arrhythmias in eclamptic parturients., Study Design: An open, randomized comparison of intravenous labetalol versus dihydralazine was conducted in 40 eclamptic subjects in the peripartum period. Cardiac rhythm was assessed by blinded analysis of a 24-hour Holter record by means of the Lown classification of arrhythmias., Results: There was a significantly higher incidence of serious ventricular arrhythmias in patients receiving dihydralazine (81%) than in those receiving labetalol (17%, p < 0.0001). Patients receiving labetalol showed a significant decrease in mean heart rate (p < 0.0001), whereas patients receiving dihydralazine showed a significant increase (p < 0.0001)., Conclusion: The introduction of beta-adrenergic blockade into peripartum hypertensive management of eclampsia significantly reduced the incidence of dangerous ventricular arrhythmias. Myocardial oxygen supply/demand ratio may be improved by beta-blockade.

Tertatolol is a noncardioselective beta-blocker without intrinsic sympathomimetic activity. In a preliminary 3-month open study, it was shown that T was devoid of any atherogenic effect since HDL-cholesterol (HDL-C) and apoprotein levels did not change for 3 months of therapy. To investigate the long-term effects of tertatolol on the lipid profile and its safety in hypertensive patients with peripheral arterial disease (PAD), a 9-month, randomized, double-blind, parallel group study was carried out in 40 patients. Tertatolol 5 mg once daily was compared with metoprolol 200 mg once daily. If BP was not controlled after 2 months, a vasodilatator agent, dihydralazine, was added at the lowest dose required to control BP (diastolic BP < 90 mm Hg). Lipoprotein fractions and apoproteins were assayed before (M0) and after 2, 6 and 9 months of therapy. At the same occasions, peripheral arterial disease (PAD) was evaluated on exercise tests carried out on a treadmill and on the regional blood flow measured in the ankle arteries by the Doppler technique. Four patients were not eligible for analysis. In the tertatolol group, 1 patient with a normal BP, and 2 patients who dropped out, 1 because of persistent nausea and 1 because of personal reasons. In the metoprolol group, 1 patient refused to take dihydralazine. In the 35 fully documented patients, BP control was achieved in both groups. The mean reductions in supine systolic/diastolic BP were 31.4/14.6 and 34.7/17.1 mm Hg in the tertatolol and metoprolol groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To compare the antihypertensive effects of epoprostenol sodium (prostacyclin) with that of dihydralazine in acute hypertensive crises of pregnancy., Design: A prospective randomized study. A minimum of 20 patients per group was considered statistically acceptable (alpha = 0.05, power = 0.9)., Setting: A large urban tertiary hospital., Subjects: Forty-seven pregnant patients with diastolic blood pressures of > 100 mmHg were studied., Intervention: Lowering of high blood pressure with either dihydralazine (n = 25), the standard drug for this purpose, or epoprostenol (n = 22)., Main Outcome Measure: A significant drop in high blood pressure was regarded as a fall of 15 mmHg diastolic and 30 mmHg systolic blood pressure., Results: There were no statistically significant differences in the antihypertensive effects between the two treatment groups. Epoprostenol infusion caused less tachycardia; the mean pulse rate changed from 81.77 beats/min, before treatment to 88.36 at stabilization, compared with a change from 80.96 beats/min to 102.68 in the group treated with dihydralazine (P = 0.0024)., Conclusion: The place of epoprostenol in pregnancy might be in patients with severe hypertension and tachycardia and in those requiring acute control of severe hypertension on the operating table before general anaesthesia.

In recent years, thanks to a better understanding of the pathophysiology of congestive heart failure and progress made in the pharmacology of cardiovascular drugs, new therapeutics have been advocated in the treatment of congestive heart failure. Among them, converting enzyme inhibitors are the most useful. However, the classical association of digoxin-furosemide and general measures remains a very effective first-choice treatment in most cases. Only in particular situations, such as cardiomyopathy and decompensated atrio-ventricular insufficiency, should priority be given to converting enzyme inhibitors. Phosphodiesterase inhibitors are essentially used within the context of post-cardiac surgery intensive care. Beta-blockers which have been recently proposed for treatment of adult patients must not be used, as there is still no data available on their effectiveness and tolerance in pediatric patients.

The authors analysed 31 cases of an acute hypertensive glomerulonephritis. The antihypertensive efficacy of two medicines: a vasodilator (dihidralazine) and a diuretic (Furosemide) was underlibed an these patients. Their efficacy was evident not only in the stabilization of P.A. around normal values on three days, but also on the disappearance of signs of on hypertensive encephalopathy whereas these ones were present.

In normotensive nonpregnant women (n = 23), the plasma concentrations of immunoreactive endothelin-1 (ir-ET-1) were not different from nonpregnant women with essential hypertension (n = 15): 3.6 (2.0-5.4) ng/L (mean, range) versus 3.8 (2.4-5.8) ng/L. In normotensive pregnant women (n = 25), the plasma level of ir-ET-1 was 2.1 (1.3-3.4) ng/L (p less than 0.01) lower than in normotensive nonpregnant women. Pre-eclamptic patients (n = 25) had elevated ir-ET-1 plasma levels of 5.0 (2.1-12.4) ng/L (p less than 0.001 for normotensive pregnant women, p less than 0.01 for nonpregnant women). The low level of ir-ET-1 in normotensive pregnant women may be explained by the increase in the distribution volume of ir-ET-1 during the course of pregnancy. Damage of vascular endothelium is a consistent morphological abnormality in pre-eclampsia. Elevated ir-ET-1 in plasma might be a biochemical marker of this abnormality and may contribute to the pathogenesis of pre-eclampsia.

This study was aimed at evaluating the hemodynamic changes after acute inhibition of the renin-angiotensin system in hypertensive patients. Twenty-one subjects with essential hypertension were randomized into three groups of seven subjects each. In group I, the direct vascular vasodilator dihydralazine was administered at a dose of 4 micrograms/kg per min. Groups II and III received a continuous intravenous infusion of the angiotensin converting enzyme (ACE) inhibitor perindoprilat at a dose of 1 microgram/kg per min and 2.5 micrograms/kg per min, respectively. Brachial artery hemodynamics and aortic distensibility were evaluated non-invasively. Vascular reactivity was evaluated by the cold-pressor test. In all three groups, an identical decrease in blood pressure was observed (P less than 0.001), followed by a slight (but not significant) decrease in the heart rate in both perindoprilat groups, and an important tachycardia in the dihydralazine group (P less than 0.001). Brachial artery diameter was increased in the high-dose perindoprilate group from 0.437 +/- 0.014 to 0.479 +/- 0.013 cm (P less than 0.02), but remained unchanged in the two other groups. No significant changes in brachial artery mean blood velocity and blood flow were observed. In group III, aortic distensibility increased almost twice as much as in the two other groups, but this difference was not statistically significant. The pressor response to the cold-pressor test was not modified in the three groups; the heart rate response was almost completely abolished in groups II and III, but increased in the dihydralazine group (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial elasticity, which can be assessed by means of a piezogram, is thought to be involved in the development of hypertension. In hypertensive patients (and with aging in normal subjects), arterial elasticity is reduced. Long-term administration of spironolactone, beta blockers, or a beta-blocker/dihydralazine combination to hypertensive patients sufficiently reduced systolic and diastolic blood pressure to about the same extent; however, only spironolactone had any effect on piezoelectric indexes of arterial elasticity.

Two treatment strategies were compared in 155 women with pregnancy-induced hypertension who were also given comprehensive non-pharmacological care. The mean gestation at entry was 28 weeks. As long as the diastolic blood pressure (DBP) remained below 106 mmHg, oxprenolol, or oxprenolol plus dihydralazine, were given to the early treatment group, and matching placebos to the control group. Open antihypertensive treatment was provided for patients whose DBP rose above 105 mmHg. Proteinuria occurred in seven women in each group. In the early treatment group, 13 of the 78 women were delivered by caesarean section; the corresponding numbers in the control group were 27 of 76 (17 vs 36%, 95% confidence interval (CI) of difference: 5-33%); the sections included seven and 16 in the early treatment and control groups, respectively, for severe hypertension and/or fetal distress. There were five perinatal deaths, two in the early treatment group and three in the control group. Early treatment did not influence gestational age at birth or birthweight. Respiratory distress syndrome occurred in four infants in the early treated group and in 10 in the control group; 14 infants in the former group and 26 in the latter were in hospital for more than 10 days (18 vs 35%; 95% CI of difference 4-32%). These results indicate that early antihypertensive treatment with oxprenolol is safe for the fetus and newborn in pregnancy-induced hypertension, but has no advantage over non-pharmacological care in terms of fetal growth. However, it may prevent acute hypertension in late pregnancy and associated fetal distress, and thus reduce the number of caesarean sections.

Diabetic nephropathy is the dominant cause of hypertension in insulin-dependent diabetics, and long-term rigid antihypertensive treatment inhibits the progression of nephropathy, probably even when there is renal insufficiency. In our clinical study 14 insulin-dependent diabetics with diabetic nephropathy and renal failure (glomerular filtration rate [GFR] 0.39 +/- 0.12 ml/sec) underwent rigid blood pressure treatment. Antihypertensive therapy included furosemide, propranolol, dihydralazine and nifedipine. The whole group showed a lowering in mean blood pressures from 150.1 +/- 2.3/91.3 +/- 1.4 mm Hg to 139.8 +/- 3.1/86.5 +/- 2.0 mm Hg (p less than 0.01). During the observation period the mean decline in glomerular filtration rate decreased from -0.022 +/- 0.003 ml/sec per month to -0.010 +/- 0.007 ml/sec per month. In 10 out of 14 patients with very advanced nephropathy the further decline of GFR halted markedly. Thus, vigorous blood pressure control is able to postpone endstage renal disease even in advanced diabetic nephropathy.

Thirty-one patients with moderate and severe essential hypertension completed a comparative study of oxdralazine and dihydralazine. Treatments were administered for a 6-month period. The therapeutic regimen also included diuretic and a beta-blocking agent given at a constant daily dose. After a 4-week run-in period on diuretic plus beta blocker, which caused a mean blood pressure reduction of 17/7 mmHg, the administration of the vasodilators produced a further, more marked decrease of pressure values. After 1-month treatment mean blood pressure reductions were 26/18 mmHg on oxdralazine and 16/11 mmHg on dihydralazine. After 6 months, 10/15 patients on oxdralazine and 7/16 patients on dihydralazine had achieved a stabile diastolic pressure below 95 mmHg. These results were confirmed by an additional phase of the study, in which 21 patients had the vasodilator cross-over and were observed for a second 6-mont period. Oxdralazine and dihydralazine therapy were well tolerated: only a few patients complained of side effects that were of mild intensity and never required any change in treatment. At the first visit after the cross-over, those patients changing from oxdralazine to dihydralazine complained of side effects with a higher frequency than the patients changing from dihydralazine to oxdralazine. In one patient from the former group it was necessary to stop dihydralazine treatment.

Surgical correction of unilateral renal artery stenosis was performed in 31 hypertensive patients. Preoperative renal vein renin ratios (RVRR) before and after dihydralazine stimulation were measured in all patients. Postoperative blood pressure were normal in 12, improved in 17 and unchanged in 2 patients. Six patients did not have renin lateralization, but all were cured or improved after surgery. RVRR was a poor predictor of the results of surgery in patients with unilateral renal artery stenosis.

The effect on the fetus of lowering the maternal blood pressure with intravenous dihydralazine was studied in 33 patients with diastolic blood pressure of 110 mmHg or more. Nineteen patients showed fetal heart rate (FHR) decelerations coinciding with a fall in blood pressure. Thirteen of the 19 patients had growth-retarded fetuses, while only 1 of 14 patients who showed no FHR changes had a growth-retarded fetus (P greater than .005). Continuous FHR monitoring during the administration of dihydralazine helped identify the compromised fetus if it had been unrecognized at other observations.

Two groups of patients with hypertension ( n = 16 and 20) with comparable average age and degree of severity of clinical hypertension were controlled in an ambulatory long-term investigation for 18 months. While one group was treated with an antihypertensive standard therapy, the other group got a fixed combination of dihydralazin and propranolol. In both groups a significant decrease of the systolic and diastolic initial blood pressure was seen, which was more pronounced in the second group. Side-effects of drugs more frequently appeared in the first group. On the other hand, the total cost were higher in the second group. Nevertheless, the stronger effect, the smaller number of tablets as well as the lower rates of side-effects pleads for the combination dihydralazin-propranolol.

In order to investigate the consequences of antihypertensive therapy on hormonal and renal parameters in one-clip, two kidney renovascular hypertension, we compared the effects of converting enzyme inhibition (CEI) with those of tripletherapy (clonidine, dihydralazine and furosemide) in this experimental model in rats. The treatment period was initiated four weeks after application of the clip and was continued for five weeks. In plasma, renin was increased and renin substrate was negatively correlated to plasma renin. Hypertension was associated with activation of the renin angiotensin system in both plasma and kidney. The degree of activation of the renin-angiotensin system in the clipped kidney and its suppression in the unclipped kidney was evaluated by two methods, renal renin content and semi-quantification of juxtaglomerular hyperplasia by immunofluorescent renin. These two methods were correlated. During the treatment period, average systolic blood pressure was 144 +/- 13 mmHg in the CEI treated group (HT1) which was not significantly different from the value found in the sham-operated group (139 +/- 4 mmHg; C2). Blood pressure, however, was lowered only to 173 +/- 18 mmHg in the group treated with tripletherapy (HT2). In control hypertensive animals, the wt of the clipped kidney did not decrease whereas significant hypertrophy was present in the unclipped kidney. Tripletherapy did not alter this relationship, whereas converting enzyme inhibition decreased kidney wt in the clipped kidney and increased further the hypertrophy of the contralateral unclipped kidney. A histological examination revealed that hypertensive microangiopathy was a predominant feature in the unclipped kidney of the untreated hypertensive group and of the group treated with tripletherapy, these lesions were completely absent in the CEI treated group. In the CEI treated group, however, ischemic lesions during this treatment were found to be decreased in the contralateral unclipped kidney and increased in the clipped kidney by comparison with untreated hypertensive rats. These renal lesions observed in the clipped kidney were most likely related to the normalization of blood pressure or to a disturbance of intrarenal mechanisms normally mediated by the renin-angiotensin system during stenosis of a renal artery.

17 patients with severe chronic heart failure (class III and IV) were prescribed hydralazine, an arterial vasodilatator, orally at doses of 150 mg to 400 mg/day. Considerable clinical improvement was observed in most patients. After 24 to 48 hours the cardiac index rose 79 p. 100, the systolic index by 67 p. 100 and left ventricular work by 73 p. 100, whilst systemic and pulmonary resistances fell by 51 p. 100 and 34 p. 100 respectively. There was no significant change in systemic blood pressure or in heart rate. These results were confirmed at 4 months. Mean pulmonary capillary pressure varied little at the start of treatment but decreased by 52 p. 100 at medium term (4 and 12 months) in this series. No cases of systemic lupus erythematosis were observed. The main, but not the only, indication of therapy with dihydralazine is low output heart failure with little elevation in the pulmonary capillary pressure, especially in primary cardiomyopathy and valvular regurgitation. At present, treatment should be based on the results of cardiac catheterisation and the dosage adjusted according to the rate of hepatic acetylation.