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Background: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy., Methods: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy., Results: Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes., Conclusions: Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Rationale: Unraveling immune-driven vascular pathology in pulmonary arterial hypertension (PAH) requires a comprehensive understanding of the immune cell landscape. Although patients with hereditary (H)PAH and bone morphogenetic protein receptor type 2 (BMPR2) mutations have more severe pulmonary vascular pathology, it is not known whether this is related to specific immune cell subsets. Objectives: This study aims to elucidate immune-driven vascular pathology by identifying immune cell subtypes linked to severity of pulmonary arterial lesions in PAH. Methods: We used cutting-edge multiplexed ion beam imaging by time of flight to compare pulmonary arteries (PAs) and adjacent tissue in PAH lungs (idiopathic [I]PAH and HPAH) with unused donor lungs, as controls. Measurements and Main Results: We quantified immune cells' proximity and abundance, focusing on those features linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells. Distinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In patients with HPAH, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving T cell immunoglobulin and mucin domain-3 (TIM-3) +  T cells. This correlated with an expanded DC subset expressing indoleamine 2,3-dioxygenase 1, TIM-3, and SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1, alongside increased neutrophils, SMCs, and alpha-smooth muscle actin (ACTA2) + endothelial cells, reinforcing the heightened severity of pulmonary vascular lesions. Conclusions: This study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared with IPAH. Our findings emphasize the therapeutic potential of targeting monocyte-derived dendritic cells, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.

Hypoxia-induced vasoconstriction and vascular remodelling are the main pathological features of hypoxic pulmonary arterial hypertension (HPAH), and inflammation is participated in the occurrence of pulmonary vascular remodelling (PVR). Matrine is an alkaloid with the effects of anti-inflammation, antifibrosis and antitumour. But, few studies have explored the role of matrine in regulating PVR, and the related mechanisms are still unknown. In this study, we found that hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibited its apoptosis, reduced the expression of ribosomal protein s5 and activated the nuclear factor kappa-B (NF-κB) signalling. Matrine, sildenafil and NF-κB inhibitor Bay 11-7082 could reverse these changes and impel the cell cycle in phase S retardation, and reduced the expression of p50, p65, proliferating cell nuclear antigen (PCNA), Bcl-2. In addition, matrine could lower right ventricular systolic pressure and mean pulmonary artery pressure of rats, α-smooth muscle actin and PCNA expression in pulmonary artery media, the levels of tumor necrosis factor-α and interleuki-1β, thus improved hypoxia-induced PVR. This study indicated that matrine could alleviate inflammation and improve PVR through reversing the imbalance of proliferation and apoptosis of PASMCs, thus it had a therapeutic effect on HPAH., (© 2023 Wiley Periodicals LLC.)

The neovascularization of atherosclerotic lesions is involved in plaque development and may contribute to intraplaque hemorrhage and plaque fragilization and rupture. Among the various proangiogenic agents involved in the neovascularization process, proatherogenic oxidized LDLs (oxLDLs) contribute to the formation of tubes via the generation of sphingosine 1-phosphate (S1P), a major mitogenic and proangiogenic sphingolipid mediator. In this study, we investigated whether 4-hydroxynonenal (4-HNE), an aldehydic lipid oxidation product abundantly present in oxLDLs, contributes to their proangiogenic properties. Immunofluorescence analysis of human atherosclerotic lesions from carotid endarterectomy showed the colocalization of HNE-adducts with CD31, a marker of endothelial cells, suggesting a close relationship between 4-HNE and neovessel formation. In vitro, low 4-HNE concentration (0.5-1  µ M) elicited the formation of tubes by human microvascular endothelial cells (HMEC-1), whereas higher concentrations were not angiogenic. The formation of tubes by 4-HNE involved the generation of reactive oxygen species and the activation of the sphingolipid pathway, namely, the neutral type 2 sphingomyelinase and sphingosine kinase-1 (nSMase2/SK-1) pathway, indicating a role for S1P in the angiogenic signaling of 4-HNE. Carbonyl scavengers hydralazine and bisvanillyl-hydralazone inhibited the nSMase2/SK1 pathway activation and the formation of tubes on Matrigel® evoked by 4-HNE. Altogether, these results emphasize the role of 4-HNE in the angiogenic effect of oxLDLs and point out the potential interest of pharmacological carbonyl scavengers to prevent the neovascularization process.

Reactive oxygen species (ROS) generated within the vascular wall trigger low-density lipoprotein (LDL) oxidation, lipid peroxidation, and carbonyl stress that are involved in atherogenesis. We recently reported that the antihypertensive drug, hydralazine, exhibits carbonyl scavenger and antiatherogenic properties, but only moderate antioxidant activity, so that high concentrations are required for inhibiting LDL oxidation. We aimed to develop agents sharing both antioxidant and carbonyl scavenger properties. We have synthesized a new hydralazine derivative, the bisvanillyl-hydralazone (BVH). BVH strongly inhibited LDL oxidation induced by copper and by human endothelial cells (HMEC-1), and prevented the formation of macrophagic foam cells. BVH reduced both the extracellular generation of ROS (superoxide anion and hydrogen peroxide) induced by oxidized LDL (oxLDL), as well as intracellular oxidative stress and proteasome activation, NFkappaB activation, and oxLDL-mediated proinflammatory signaling. In parallel, BVH prevented the carbonyl stress induced by oxLDL on cellular proteins, and blocked the apoptotic cascade as assessed by the inhibition of Bid cleavage, cytochrome C release, and DEVDase activation. Lastly, BVH prevented atherogenesis and carbonyl stress in apoE(-/-) mice. In conclusion, BVH is the prototype of a new class of antioxidant and carbonyl scavenger agents designed for new therapeutical approaches in atherosclerosis.

This mini-review highlights the chemical and cytoprotective properties of various hydralazine analogues that block the induction of cell death by acrolein, a highly toxic contributor to "carbonyl stress" during a diverse range of human diseases. Recent work on the action of hydralazine against various carbonyl-mediated pathologies is also reviewed.

Background/aims: The aim of this study was to investigate the precise mechanism of liver failure by hydralazine derivatives, with special reference to liver regeneration failure., Methods: Histone acetylation and proliferation of hepatocytes were evaluated by immunohistochemistry with anti-acetylated histone H4 and proliferating cell nuclear antigen (PCNA). Inhibition of histone acetylation by drugs was determined by in vitro histone acetylation assay. Mice livers fed with todralazine for 1 or 4 months were subjected to immunohistochemistry and Western blotting. Todralazine-fed mice were challenged with anti-Fas to check liver regeneration failure., Results: On immunohistochemistry, histone acetylation in the hepatocytes was significantly impaired in patients with hydralazine derivatives. In an in vitro acetyl transferase assay, histone acetylation was inhibited by hydralazine derivatives in a dose-dependent manner. Mice fed with todralazine (3mg/day) for 4 months showed impairment of histone acetylation in hepatocytes whereas no inhibition was observed in mice fed with todralazine for 1 month. Anti-Fas challenge to todralazine-fed mice resulted in impairment of liver regeneration in respect of liver weight loss with impairment of histone acetylation in hepatocytes., Conclusions: Todralazine could inhibit catalysis of histone acetyltransferase and long-term administration of todralazine may impair histone acetylation of the hepatocytes, resulting in liver regeneration failure.

Drug-induced lupus is a serious side effect of certain medications, but the chemical features that confer this property and the underlying pathogenesis are puzzling. Prototypes of all six therapeutic classes of lupus-inducing drugs were highly cytotoxic only in the presence of activated neutrophils. Removal of extracellular hydrogen peroxide before, but not after, exposure of the drug to activated neutrophils prevented cytotoxicity. Neutrophil-dependent cytotoxicity required the enzymatic action of myeloperoxidase, resulting in the chemical transformation of the drug to a reactive product. The capacity of drugs to serve as myeloperoxidase substrates in vitro was associated with the ability to induce lupus in vivo.

Hydralazine, dihydralazine and todralazine were tested in the aspect of their mutagenic potency, and the influence upon the mutagenicity of standard promutagen--B(a)P. Hydralazine exhibited strong mutagenic activity in the Ames test while mutagenic activity of dihydralazine was relatively weak. Todralazine had no mutagenic activity, and significantly decreased mutagenicity of B(a)P. It was concluded that todralazine could be a good antimutagenic substance.

Z-2-amino-5-chlor-benzophenon-amidin-hydralazin is a new chemical potential antiarrhythmic substance. The blood levels were investigated after different dosages and forms of administration in patients and volunteers. The determination of the substance can be performed by high-pressure liquid chromatography. In addition the pharmacokinetic parameters were calculated. The pharmacokinetic profile is similar in humans and animals.

The present study was undertaken to elucidate the anti-tachycardic effect of a direct-acting vasodilator, budralazine, using an electrophysiological technique. Normotensive male Wistar rats were used. Rats were anesthetized intraperitoneally with urethane and alpha-chloralose. Intravenous administration of budralazine (0.5-5.0 mg/kg) produced a dose-dependent reduction of mean arterial pressure in anesthetized rats. At doses of 0.5 and 1.0 mg/kg, budralazine induced bradycardia accompanied with a decrease in cardiac sympathetic nerve activity (ICNA). Preganglionic adrenal sympathetic nerve activity (ASNA) was also reduced by budralazine (1.0 mg/kg). A 0.5 mg/kg of budralazine neither influenced carotid sinus nerve activity nor augmented aortic depressor nerve activity (ADNA). On the contrary, at dose of 5.0 mg/kg, budralazine produced a tachycardia accompanied with increases in both ICNA and ASNA. The ADNA was decreased by budralazine (5.0 mg/kg) significantly. These findings suggest that the central sympathoinhibitory action of budralazine may be responsible for the anti-tachycardic effect of budralazine and baroreceptor-mediated tachycardia occurred after high dose of budralazine.

The effects of antihypertensive drugs on ischemic cerebral damage were investigated using the bilateral carotid artery occlusion (BCAO) model in SHR. Oral budralazine and nifedipine, at doses that increased cerebral blood flow (CBF) in SHR in our previous study (Tanaka, S. et al., Folia Pharmacol, Japan, 87, 1986), significantly improved cerebral energy failure after the BCAO, but prazosin which does not increase CBF had no effect on the energy failure. These results suggest that the amelioration by these antihypertensive drugs of the energy failure after the BCAO results from its CBF-increasing effects in SHR.

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.

The hemodynamic effects of the calcium antagonist isradipine (code name PN 200-110) and the arteriolar vasodilator dihydralazine were compared in atherosclerotic (cholesterol-fed) and normal conscious rabbits with implanted catheters. Regional blood flows were measured using the microsphere technique. Cardiac output and blood flow to several organs, especially to the gastrointestinal system, but not to the heart and brain, were lower in atherosclerotic rabbits than in normal ones. Intravenous isradipine (10 and 30 micrograms/kg) increased heart rate less in atherosclerotic than in normal rabbits. Isradipine had no effect on the surface electrocardiogram (ECG). In contrast, 0.4 mg/kg dihydralazine caused depression of the ST segment while decreasing blood pressure similarly. This was explained partly by an intramyocardial maldistribution of coronary blood flow (using microspheres). Isradipine increased and dihydralazine decreased flow to the brain. Isradipine redistributed cardiac output in atherosclerotic and normal animals in favor of the heart, brain, and skeletal muscle. However, in atherosclerotic animals, the high dose was less effective than the low dose in some vascular beds. Thus, isradipine is not a general vasodilator in either atherosclerotic or in normal animals, but favors the vital organs. This redistribution of cardiac output contrasts favorably with that induced by dihydralazine.

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.

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.

One of the principal uses suggested for the microencapsulation of pharmaceuticals has been the preparation of the sustained release dosage form. The finished microcapsules have usually been presented in the form of suspensions or gels, but in order to obtain greater sustained release effect a non-disintegrating tablet would be a better formulation. Dihydralazine sulphate (Nepresol) is a dihydralazine-1,4-phthalazine derivative and used as an antihypertensive drug. This work was planned to prepare sustained action preparations of dihydralazine sulphate by microencapsulation and by tabletted microcapsules. Microcapsules were prepared from the microcapsule fractions using biconvex punches with 0.81 cm diameter fitted into a single punch by hand compressor. Avicel PH 101 and lactose were used as disintegrating materials in tablets having 2 kg hardness. Dissolution from both suspended microcapsules and the tablets was studied using the USP XX basket method. A study of in vitro release for both the free and tabletted microcapsules showed basically the same pattern but the time for the release was extended in the case of the tabletted preparations. Dissolution of dihydralazine sulphate was found to be governed by the core: wall ratio, microcapsule size, and the amount and kind of disintegrating agents. Dissolution kinetics were studied and evaluated.

Antihypertensive and general pharmacological properties of 1-[2-(1,3-dimethyl-2-butenylidene)hydrazino]phthalazine (budralazine) were studied in comparison with those of hydralazine. Single oral administration of budralazine (4--15 mg/kg) to DOCA/saline hypertensive rats resulted in a dose-related and sustained antihypertensive effect which was 2--3 times less potent than that of hydralazine. However, there were no remarkable differences between both drugs in the hypotensive magnitude after the 4-week treatment of spontaneously hypertensive rats (SHR) with their higher doses. After single oral administration, budralazine was about 8 times less potent than hydralazine in increasing plasma renin activity in normotensive rats. At effective antihypertensive doses, budralazine inhibited spontaneous motor activity (mice), gastrointestinal propulsion (mice), gastric emptying rate (rats), gastric secretion (rats), urine output and urinary electrolyte excretion (rats) as well as carrageenan-induced paw edema formation (rats), which were essentially less potent than those produced by hydralazine. Budralazine at 6 mg/kg i.v. exhibited a slowing of neocortical EEG (cats) and a slight increase in spinal monosynaptic potentials (cats) and inhibited gastrointestinal motility (dogs). The same dose of hydralazine produced an increase in occurrence of the neocortical fast waves, an inhibition of the monosynaptic potentials and the carotid sinus reflex (dogs) and a stimulation of intestinal motility followed by prolonged and marked reduction. Budralazine (10(-5) g/ml) slightly potentiated contractile response of isolated guinea-pig vas deferens to noradrenaline, whereas hydralazine (10(-4) g/ml) inhibited the response. Budralazine (10(-5) g/ml), like hydralazine (10(-4) g/ml), produced a nonspecific antagonism against the contractile response of isolated guinea-pig ileum to various spasmogens, and both drugs (10(-4) g/ml) reduced either spontaneous motility or oxytocin-induced motility in isolated rat uterus.

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.

The pharmacokinetics of hydralazine acetone hydrazone (HAH), which is a metabolite of hydralazine (HP), was investigated after iv administration to rats. Plasma concentrations of HAH, HP, and hydralazine pyruvic acid hydrazone (HPH) were simultaneously determined by a specific HPLC method. A five-compartment pharmacokinetic model was presented to elucidate the disposition of HAH and two products, HP and HPH. The parameters used in the model were obtained by administering each of the three compounds (10 mg/kg) separately. The proposed model described the experimental data well and the model parameters were close to the model-independent values. After HP administration, HPH appeared rapidly in plasma, but the HPH availability from HP amounted to only 17.8 +/- 3.7%, based on the comparison between the area under the plasma concentration curves of formed and iv HPH. The formation of HP from HAH in the systemic circulation was demonstrated, but formed HP disappeared rapidly. The fraction of HAH available to the systemic circulation as HPH was extremely low (7.8 +/- 2.2%), indicating that the conversion of HAH to HP was not so extensive. The present results support the hypotheses that HPH is formed via the direct reaction of HAH with pyruvic acid and that the secondary formation is mediated by conversion to HP.

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.

When administered to young spontaneously hypertensive rats (SHRs), dihydralazine (25 mg kg-1, daily) and captopril (100 mg kg-1, daily) prevent with the same efficacy genetic hypertension development (GHD). Dihydralazine treatment increased vascular mesenteric compliance, as shown by a significant decrease in the stiffness of the vessels (-27%), and induced slight reductions in contractility (-12%) and in wall to lumen (W/L) ratio (-15%). After treatment withdrawal, all these parameters returned to control values within 7 weeks, as did blood pressure. Captopril treatment also strongly increased the mesenteric vessels compliance, vessel stiffness being decreased by 16%, and reduced their contractility (-15%) and their W/L ratio (-30%). These effects as well as those exerted on blood pressure persisted up to 7 weeks after treatment ceased although there was a slight trend to a progressive reduction in the intensity of both phenomena. These experiments show that captopril but not dihydralazine has a long-lasting effect in opposing the functional and morphological vascular alterations occurring during GHD in SHRs and this phenomenon probably contributes to a large extent to the sustained preventive effects of the drug against GHD.

Effects of budralazine, a new antihypertensive drug, on regional circulation in various sites of brain and extracranial skeletal muscle and skin in curarized, artificially respirated cats were studied using the thermoelectrical method. Budralazine produced an increase in blood flow in the cerebral cortex and hippocampus. Effects of the drug on blood flow in the hypothalamus and amygdala were inconsistent. Budralazine produced an apparent increase in muscular blood flow, whereas the drug did not consistently alter dermal blood flow. Budralazine produced a mild and sustained fall in blood pressure, particularly after the repeated administration. Thus, the action of budralazine seems to be mainly one of a smooth muscle relaxant effect. The mode of action of the drug seems to differ from that of papaverine or hydralazine.

The acute haemodynamic effects of 40 mg isosorbide dinitrate (10 subjects), 4 mg prazosin (20 subjects) and 50 mg dihydralazine (8 subjects) were compared in 24 patients with the clinical picture of chronic therapy-resistant cardiac failure (NY Heart Association stages III-IV). There was a fall in left-ventricular filling pressure of about 15% and right-atrial mean pressure of 21 and 24%, respectively, with isosorbide dinitrate and prazosin, while there was no change with dihydralazine. Cardiac output rose by 23% with dihydralazine and 20% with prazosin, but remained unchanged with isosorbide dinitrate. These data indicate that a reduction in pulmonary and systemic-venous congestion due to chronic decompensated cardiac failure can be achieved with isosorbide dinitrate and prazosin, while cardiac output can be improved only with prazosin and dihydralazine.

1. Two female and two male patients with essential hypertension were given dihydralazine plus saline or dihydralazine plus diclofenac intravenously on two separate occasions. The dihydralazine dose (range: 16.2--32.4 mg/2 h) was chosen individually to reduce systolic blood pressure by 20 mmHg from the control value before the investigation; the intravenous diclofenac dose was 75 mg/20 ml of saline for all patients. 2. Dihydralazine decreased diastolic blood pressure more than systolic blood pressure and increased heart rate; diclofenac reduced both of these effects. 3. Dihydralazine increased urinary volume and sodium clearance; both these effects were antagonized by concomitant treatment with diclofenac. 4. Whereas dihydralazine did not influence creatinine clearance appreciably, concomitant administration of diclofenac reduced creatinine clearance. 5. Urinary prostaglandin E2 was reduced by diclofenac. 6. We suggest that dihydralazine-mediated vasodilation is reduced by cyclo-oxygenase inhibition.

Dihydralazine (0.1 mg/kg), injected intravenously into male Sprague-Dawley rats, caused a decrease in mean arterial blood pressure and an increase in renal plasma flow, while urine volume remained unchanged. Dihydralazine had no effect on kallikrein excretion in the urine and on kallikrein activity in the renal cortex. No correlation was found between renal kallikrein and either renal plasma flow or mean arterial blood pressure. The excretion of kinins in the urine rose markedly after the administration of dihydralazine; no correlation between urinary kinins and urinary or renal kallikrein was observed. Dihydralazine had no influence on the kininogen content of blood-free renal cortex. The enzymatic activity of kininase II in renal cortex was not impaired by dihydralazine. It is suggested that the increased formation of kinins within the kidney could be involved in the vasodilating and blood pressure lowering effect of dihydralazine.

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.

The hemodynamic effects of intravenously infused dihydralazine (incremental doses up to 125 micrograms per minute during 60 minutes) were studied in ten women with acute or superimposed severe preeclampsia. The intervillous and umbilical vein blood flow were measured before and during dihydralazine infusion with 133Xenon method and with a combination of real-time and Doppler ultrasonic equipment, respectively. Maternal blood pressure decreased and pulse rate increased during the infusion. Dihydralazine did not change the intervillous blood flow but it increased the blood flow in umbilical vein. No effect on the 6-ketoprostaglandin F1 alpha in maternal plasma and urine or thromboxane B2 in maternal serum was observed. The results indicate that dihydralazine affects the placental and fetal circulations differently.

Ten patients with gestational proteinuric hypertension were studied with a Swan-Ganz thermodilution haemodynamic catheter before, during and after plasma volume expansion. Five patients were treated with dihydralazine before volume expansion and five after volume expansion. Before treatment all patients had a low pulmonary capillary wedge pressure (PCWP), low cardiac index (CI) and high systemic vascular resistance (SVR). Following volume expansion the PCWP and CI increased, the SVR decreased but the blood pressure (BP) was unchanged. Administration of dihydralazine following volume expansion led to a decrease in PCWP, an increase in CI and a decrease in SVR and BP. Dihydralazine alone caused an increase in heart rate, PCWP, and CI, and a decrease in SVR and BP. Volume expansion, by increasing CI and decreasing SVR, may be of therapeutic benefit in the severely hypertensive pregnant patient with a low cardiac index.

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.

In 61 out-patients with essential hypertension, grade I or II, propranolol was administered alone in increasing doses (3 x 40 mg/d or 3 x 80 mg/d) or, if there was insufficient response, with a double or triple combination consisting additionally of spironolactone (50 mg/d)-thiabutazide (5 mg/d) and dihydralazine (3 x 25 mg/d). This treatment schedule achieved normal pressures in 51 patients, in 22 on 40 mg, in 7 on 80 mg propranolol, in 16 after the addition of the diuretic, and in 6 with the triple combination. Four patients had to be excluded from the study because they developed either marked bradycardia or anxiety states or paraesthesias after propranolol (3 x 40 mg/d). On chronic beta-adrenergic blockade the serum potassium level increased slightly, but remained within normal limits. The initial value of plasma-renin activity was highest in the group of those who responded to the propranolol treatment.

Acute volume loading increases plasma atrial natriuretic factor (ANF) levels in man and animals. In the present work we have compared the effects of a 1-week oral application of clonidine (2 x 0.075 mg/day) to dihydralazine (2 x 25 mg/day) in eight healthy volunteers on changes in plasma ANF and plasma and urine cyclic GMP levels after acute volume loading with 2 I physiological saline i.v. Basal plasma ANF levels before infusion were decreased by clonidine to 65% of the untreated controls and remained unaltered with dihydralazine. Volume loading increased plasma ANF levels by about 40% in the control and 30% in the dihydralazine treated group, whereas plasma ANF remained unchanged by volume loading in the clonidine-treated group. Dihydralazine increased basal cyclic GMP levels and urinary cyclic GMP excretion by 30 and 90%, respectively. Basal cyclic GMP levels were identical without treatment and after clonidine treatment. Saline infusion increased cyclic GMP levels by 40% in the control and clonidine-treated groups, and by 25% in the dihydralazine-treated group. Urinary cyclic GMP excretion increased by 2.1-, 1.6-, and 1.2-fold, respectively, in the controls, after clonidine, or after dihydralazine. The results of this study suggest that ANF is involved in the hormonal and hemodynamic effects that are induced by clonidine, but not in those induced by dihydralazine.

1 The 0-24 h urine from hypertensive patients treated with hydralazine (100 mg twice daily) has been analysed by gas chromatography and high pressure liquid chromatography. 2 4-N-Acetylhydrazinophthalazine-1-one (NAcHPZ), s-triazolo [3, 4-a] phthalazine (TP), phthalazinone (PZ) and hydralazine (free, H; acid-labile hydrazones, HH) were detected and assayed. 3 The results indicate that slow acetylators excrete less NAcHPZ and TP than rapid acetylators but more PZ and HH. 4 Free hydralazine was present in low levels and was only detected in some urine samples. 5 The ratios of the metabolites NAcHPZ/HH; TP/HH; NAcHPZ/PZ and PZ/TP are different in the two acetylator phenotypes. 6 It is possible the ratio PZ/TP may be used for determination of acetylator phenotype. 7 It is concluded that hydralazine metabolism is dependent on the acetylator phenotype.

Cardiac presynaptic and vascular postsynaptic alpha-adrenergic effects of 1-[2-(1,3-dimethyl-2-butenylidene)hydrazino]phthalazine (budralazine) were studied in comparison with those of hydralazine. Budralazine was about 3 times less potent than hydralazine in producing tachycardia in spontaneously hypertensive and normotensive rats when compared at equihypotensive doses. In normotensive pithed rats, budralazine at 3 mg/kg i.v. affected neither the tachycardiac response to cardioaccelerator nerve stimulation nor the inhibition of clonidine of the stimulation-induced tachycardia. As the dose was increased to 6 and 12 mg/kg i.v., however, budralazine not only inhibited transiently the sympathetic tachycardia but also enhanced the clonidine bradycardia, although this drug was almost without effect on resting heart rate. These effects of budralazine on the heart rate response in the stimulated rats were partially but significantly antagonized by pretreatment with phentolamine. Hydralazine (3 mg/kg i.v.) differed from budralazine in that its transient inhibition of the stimulation-induced tachycardia was not modified by phentolamine and it produced an acceleration of the recovery of clonidine bradycardia as well as an increase in resting heart rate. Budralazine (3--12 mg/kg i.v.), like hydralazine (0.3 and 3 mg/kg i.v.), antagonized pressor responses to noradrenaline and phenylephrine but did not affect the tachycardia produced by both agonists in normotensive pithed rats. Based on these results, a possible mechanism of hypotensive and weak tachycardiac actions of budralazine is discussed in relation to that of hydralazine.

We studied the effect of chronic antihypertensive treatment with budralazine on the lower blood pressure limit of cerebral blood flow autoregulation using spontaneously hypertensive rats. Cerebral blood flow in the parietal cortex and caudate nucleus was measured to determine the lower limit using the hydrogen clearance method. The lower limit in both cerebral regions was significantly higher in 10 untreated spontaneously hypertensive rats than in 10 Wistar-Kyoto rats. The upward-shifted lower limit was restored to close to normal in the caudate nucleus and was partially restored in the parietal cortex of nine rats by 9 weeks of treatment with the high dose (50-68 mg/kg/day) of budralazine, which kept blood pressure constant at approximately normotension during the treatment period; the lower limit was slightly restored in both cerebral regions of seven rats by 4 weeks of treatment with the high dose. However, 9 weeks of treatment with the low dose (19-27 mg/kg/day) of budralazine, which produced moderate continuous hypotension in nine rats, did not apparently influence the lower limit. Our results suggest that long-term antihypertensive therapy with budralazine reduces the upward-shifted lower blood pressure limit of cerebral blood flow autoregulation toward normal and that the restoration induced by budralazine depends on the degree of blood pressure reduction as well as on the duration of the therapeutic period.

The diameters of pial vessels in the cat were measured through a closed cranial window after i.v. injection of dihydralazine (250 microgram or 1 mg x kg-1). The intracranial pressure was recorded from a needle in the cisterna magna. In 7 cats given 1 mg x kg-1 dihydralazine, arterial vessels with a resting diameter of 72 +/- 24 micron (SD) dilated by 58 +/- 21% (p < 0.01), with no significant change seen in the veins. The intracranial pressure increased by 95 +/- 30%. The maximum increase in intracranial pressure and arterial diameter was observed before the blood pressure had reached its lowest level. The dilatation far exceeded the autoregulatory dilatation observed at corresponding pressure reductions induced by bleeding. It is concluded that dihydralazine dilates pial arterial vessels.

Authors studied a 56 year old male and a 47 year old female patient having taken an antihypertonic drug for two and a half month and one year respectively observed acute HBsAg-negative liver disease. In the needle biopsy specimen obtained on the 8th day (at the male patient) and on the 10th day (at the female) of the onset of jaundice severe centrilobular liver cell necrosis was found, which in the first case was accompanied by "bridging" necrosis. In the necrosis-free areas hydropic and fatty degeneration of different degree and also cholestasis occurred. The mild local and portobiliar inflammatory reaction consisted of mononuclear cells, neutrophil- and eosinophil granulocytes. Pathogenetic role of the drug has been proved by a provocation test. Authors call attention to the fact, that Depressan represents another drug, being in use in this country, which causes centrilobular liver cell necrosis.

The effects on the fetus of the acute lowering of blood pressure in maternal hypertension with dihydralazine 6.25 mg were studied in 27 Black patients with diastolic blood pressures of 110 mmHg or more. The fetus was found to be growth-retarded in 13 of the 14 cases in which fetal heart rate decelerations coincided with a fall in maternal blood pressure. Only 2 of the 13 fetuses without heart rate changes were growth-retarded (P less than 0.001). Continuous fetal heart monitoring during the lowering of the blood pressure helped in recognizing the 'comprised' fetus if this had been missed by other observations.