Antihypertensive therapy in patients with pre-eclampsia: A prospective randomised multicentre study comparing dihydralazine with urapidil.

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.

Hypertension in children with chronic renal failure.

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.

Ketanserin versus dihydralazine for the treatment of severe hypertension in early-onset preeclampsia: a double blind randomized controlled trial.

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.

Vascular effects of intravenous infusion of the angiotensin converting enzyme inhibitor perindoprilat.

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)

Peripheral action of spironolactone: improvement in arterial elasticity.

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.

Baroreflex response and vasodilating drugs in essential hypertension.

Blood pressure, heart rate, and arterial diameter of the brachial artery were studied in patients with sustained essential hypertension before and after administration of three vasodilating drugs: dihydralazine, diltiazem, and dinitrate isosorbide (ISDN). The diameter of the brachial artery was measured using a pulsed Doppler device, enabling the angle between the ultrasound beam and the vessel axis to be evaluated with a precision inferior to 2 percent. The three drugs had similar effects in decreasing the blood pressure and the forearm vascular resistance. Dihydralazine reduced the arterial diameter (p less than 0.001) and increased heart rate. Diltiazem and ISDN increased markedly the arterial diameter (p less than 0.001) but did not change heart rate. Dihydralazine decreased the tangential tension of the arterial wall, while diltiazem and ISDN did not. The study provided evidence that, with vasodilating drugs, the changes in the caliber of peripheral large arteries, which are a determinant of wall arterial tension, can influence the baroreflex-mediated tachycardia caused by use of the drugs.

Myocyte loss in early left ventricular hypertrophy of experimental renovascular hypertension.

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.

Hypertensive crisis immediately after complete removal of phaeochromocytoma.

A hypertensive crisis with an arterial blood pressure of 280/180 mmHg developed immediately after an apparently successful removal of a phaeochromocytoma. The blood pressure could not be lowered by phentolamine and not until the administration of dihydralazine and furosemide was the systemic pressure normalized. In addition to residual high concentrations of vasoactive substances, the hypertension may have been due to an overloaded vascular bed. Careful peroperative volume substitution in patients treated preoperatively with modern sympathetic blocking agents appears to be of great importance.

Effect of dihydralazine on the fetus in the treatment of maternal hypertension.

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.

Enhancement of GABAergic system activity by metoprolol in spontaneously hypertensive rats.

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.

Maternal and perinatal outcome of temporizing management in 254 consecutive patients with severe pre-eclampsia remote from term.

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.

Dihydralazine or ketanserin for severe hypertension in pregnancy? Preliminary results.

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.

Acute onset of blindness during labor: report of a case of transient cortical blindness in association with HELLP syndrome.

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.

Liminal therapy: a strategy for the complete and selective destruction of malignant tissue in situ.

The property of aerobic glycolysis commonly possessed by malignant cells points to a weakness in oxidative metabolism which has been equated in some tumours with partial uncoupling of oxidative phosphorylation. The suggestions are made, first, that this endogenous defect may account for spontaneous cell death in situ, and, second, that its accentuation would inflict extensive tumour injury upon sensitive neoplasms. Certain drugs not in current use for the treatment of malignant disease are known to be able to interfere selectively with energy metabolism in sensitive tumours to such an extent that widespread necrotization ensues. The drugs activate an endogenous destructive mechanism that appears to require oxygen. Liminal therapy, the maintenance of continuous destructive pressure on sensitive growths in such a manner that maximal anti-tumour activity in terms of interference with energy production is not achieved at any one time, and under conditions in which the oxygen supply is only partly depleted, is put forward as a possible means of achieving complete and selective tumour destruction in vivo.

[Long-term treatment of arterial hypertension with propranolol. Combination with diuretics and dihydrazinophthalazine]. / Trattamento cronico dell'ipertensione arteriosa con propranololo. Associazione con diuretici e diidrazinoftalazina.

The effect of long-term treatment of hypertension with propranolol, alone or in combination with hydrochlorothiazide and/or dihydralazine, was investigated in 93 patients with various types of hypertension. Normalisation of the B. P. was obtained within two-four weeks of treatment with propranolol alone in all cases with mild hypertension, and in 77% and 44% of moderate and severe forms respectively. These percentages were even higher when propranolol was employed with hydrochlorothiazide and/or dihydralazine. The rationale of this combination and the mechanism of the hypotensive effect of propranolol are discussed. The drug was well tolerated; major side effects did not occur.

[Penbutolol and arterial hypertension]. / Penbutololo e ipertensione arteriosa.

Penbutolol has proved particularly effective and suitable for the treatment, even on a long-term basis, of recently developed hypertension, especially in its hyperkinetic forms. The drug produces minimal side effects, is well tolerated and gives an early therapeutic response. In addition penbutolol does not cause any significant alterations in the biohumoral parameters of the patients treated and is ideal for combination with dihydralazine, reserpine and dihydrochlorotiazide in the treatment of more stubborn cases, making it possible to reduce the doses of the other drugs without causing bradycardia.

[Treatment of hypertension with a drug combination, consisting of bemetizide, triamterene, dihydralazine and bupranolol (author's transl)]. / Hypertoniebehandlung mit einem Kombinationspräparat, bestehend aus Bemetizid, Triamteren, Dihydralazin und Bupranolol.

The optimal daily dose and dose regimen of a new drug combination (Pertenso), consisting of 10 mg bemetizide, 20 mg triamterene, 20 mg dihydralazine and 20 mg bupranolol were tested in 14 hypertensive outpatients (WHO I to III) in a single blind crossover trial. The mean blood pressure before treatment was 183/107 +/- 5/2 mm Hg (+/-SEM) and was lowered to a mean blood pressure of 147/89 +/- 4/4 mm Hg (+/- SEM; p less than 0,005) during a multiple dose regimen and to 141/84 +/- 3/3 mm Hg (+/- SEM; p less than 0,005) during a single dose regimen. The results indicate that even in hypertension which requires a combination of diuretics, vasodilators and beta-adrenergic blocking agents for treatment, a fixed combination of these substances could be given for effective blood pressure control. The data suggest the possibility of a single dose regimen of the fixed drug combination.

[Prostacyclin therapy in EPH gestosis (preliminary report)]. / Prostazyklintherapie der EPH-Gestose (Vorläufige Mitteilung).

EPH-gestosis is still today one of the most dangerous complications of pregnancy, threatening both, maternal and fetal life. Until now only symptomatic treatment was possible. A new mode of treatment of EPH-gestosis may evolve from the use of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. We tried prostacyclin therapy in three patients with severe gestosis. The results of prostacyclin infusion on this condition, the pregnancy, the fetus, the placenta and the morphology of the umbilical artery are discussed.

[Treatment of severe chronic cardiac insufficiency with dihydralazine. Short-and median-term results]. / Traitement de l'insuffisance cardiaque chronique sévère par la dihydralazine. Résultants à court et moyen termes.

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.

[Comparative hemodynamic effects of 2 vasodilators: dihydralazine and diltiazem in permanent essential arterial hypertension]. / Effets hémodynamiques comparés de deux vasodilatateurs: la dihydralazine et le diltiazem dans l'hypertension artérielle permanente essentielle.

Cardiac hemodynamic and diameter, blood flow velocity, volumic flow of the brachial artery measured by pulsed Doppler, were studied before and after diltiazem administration in comparison with dihydralazine in hypertensive patients. After diltiazem administration, blood pressure and total peripheral resistance significantly decreased (P less than 0.001) while cardiac index and heart rate increased (P less than 0.01). After 25 minutes perfusion cardiac output and heart rate returned toward control values, while blood pressure and total peripheral resistance remained decreased. The result contrasted with those observed after dihydralazine, which induced an increase in cardiac index and heart rate. The caliber of the brachial artery decreased significantly (P less than 0.001) after dihydralazine and increased after diltiazem (P less than 0.01). This study shows that 1). The antihypertensive effect of diltiazem was due to a fall in total peripheral resistance associated with a transient baroreflex mediated tachycardia, and 2) diltiazem dilated also large arteries.