Dihydralazine Research Articles

Thermodynamic and Kinetic Studies of the Radical Scavenging Behavior of Hydralazine and Dihydralazine: Theoretical Insights.

Hydralazine (HZ) and dihydralazine (DHZ) are phthalazine derivatives substituted at position 1 (HZ) or positions 1 and 4 (DHZ) by a hydrazinyl substituent. These compounds are widely used for treating hypertension and heart failure, essentially acting as vasodilators on the arteries and arterioles. In this study, the antioxidant activity of HZ and DHZ in the gas phase and in physiological environments was investigated by thermodynamic and kinetic calculations. It was found that the HOO• radical scavenging activity of these compounds follows the formal hydrogen transfer (FHT) mechanism. The H abstraction of the N9-H bond plays a deciding role in the HOO• radical scavenging of HZ-1 and DHZ-1, whereas the HOO• radical scavenging activities of HZ-2 and DHZ-2 are defined by the dissociation of the N10-H and N11-H bonds, respectively. The rate constants for the HOO• radical scavenging of the HZ and DHZ in the gas phase are in the range of 9.64 × 106 to 4.52 × 108 M-1 s-1, whereas in aqueous solutions and the lipid medium they are in the range of 2.62 × 104 to 5.13 × 107 M-1 s-1 and 5.75 × 104 to 6.66 × 106 M-1 s-1, respectively. The HOO• radical scavenging of DHZ-1 and DHZ-2 is thus faster than that of the reference antioxidant compound Trolox in all the studied environments. Consistently, DHZs are not only vasodilators but also potent antioxidants.

The Blocking on the Cathepsin B and Fibronectin Accumulation in Kidney Glomeruli of Diabetic Rats.

Hyperglycemia results in the activation of tissue angiotensin II. Angiotensin II stimulates the synthesis of ECM proteins and causes a decrease activity of proteolytic enzymes. The aim of this study was to assess the impact of multilevel blocking of the RAAS, cathepsin B activity, and fibronectin accumulation in the glomerular in the rats diabetes model. Sixty male Wistar rats were initially included. Diabetes was induced by intravenous administration of streptozotocin. The animals were randomized to six groups of ten rats in group. Rats in the four groups were treated with inhibitors of the RAAS: enalapril (EN), losartan (LOS), enalapril plus losartan (EN + LOS), and spironolactone (SPIR); another group received dihydralazine (DIH) and the diabetic rats (DM) did not receive any drug. After six weeks, we evaluated blood pressure, 24 h urine collection, and blood for biochemical parameters and kidneys. In this study, fluorometric, ELISA, and immunohistochemical methods were used. Administration of EN + LOS increased activity of cathepsin B in homogenates of glomeruli compared to DM. Losartan treatment resulted in reduction of the ratio kidney weight/body weight compared to untreated diabetic rats. SPIR resulted in the increase activity of cathepsin B in the homogenate of glomeruli. The values of cathepsin B in the plasma of rats in all studied groups were similar and showed no tendency.

The impact of maternal plasma volume expansion and antihypertensive treatment with intravenous dihydralazine on fetal and maternal hemodynamics during pre-eclampsia: a clinical, echo-Doppler and viscometric study.

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. 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. 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. 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.

Simultaneous spectrophotometric determination of diuretics by using multivariate calibration methods

The wavelength range and number of factors used in partial least-squares (PLS) calibration for the resolution of the dihydralazine (DHZ)–hydrochlorothiazide (HCT) binary mixture and the dihydralazine–hydrochlorothiazide–reserpine ternary mixture were optimized in terms of the relative standard error (R.S.E.) and relative mean standard error (R.M.S.E.). Under the optimum conditions thus established, synthetic mixtures of the analytes can be resolved with errors and relative standard deviations (R.S.D) less than 4.5 and 1.0%, respectively. The ensuing method, which was validated by comparison with high performance liquid chromatography (HPLC), also gives good results with real samples (pharmaceutical preparations).

Anti-cytochrome P450 autoantibodies in drug-induced disease.

Drugs may induce hepatitis through immune mechanisms. In this review we have used the examples of 2 drugs to elucidate the first steps leading to the triggering of such disease, namely tienilic acid (TA) and dihydralazine (DH). These drugs are transformed into reactive metabolite(s) by cytochrome P450 (2C9 for TA and 1A2 for DH) (step 1). The reactive metabolites produced are very short-lived and bind directly to the enzymes which generated them (step 2). A neoantigen is thus formed which triggers an immune response (step 3), characterized by the presence of autoantibodies in the patient's serum (step 4). The autoantibodies are directed against the cytochrome P450 which generated the metabolite(s). Although the process by which TA and DH induce-hepatitis has been elucidated, further studies are necessary to generalize this mechanism. In addition, an animal model will also be useful to fully understand the immune mechanism of this type of disease.

Studies on the Role of Activa Oxygen Species in mutagenicty and ganotoxicity induced by dihydralazine

Studies on the Role of Activa Oxygen Species in mutagenicty and ganotoxicity induced by dihydralazine

Deleterious effects of inhibition of the renin-angiotensin system in neonatal rats.

The angiotensin I converting enzyme inhibitor (ACEI) perindopril (2 mg/kg body weight), the peripheral vasodilator dihydralazine (DHL) (25 mg/kg body weight) or distilled water was given daily from birth to day 14 to neonatal rats. Blood pressure, plasma creatinine, plasma renin activity (PRA), substrate (PRS) and concentration (PRC) and renin content of kidney tissue sections were evaluated on days 14 and 28. By day 14, a high mortality in the ACEI group was observed. ACEI, but not DHL, led to a significant fall (P < 0.01) in blood pressure, 57 +/- 11 versus 89 +/- 25 in the DHL group and 103 +/- 24 mmHg in controls, and to a dramatic increase in plasma creatinine. PRA and PRS were undetectable in ACEI-treated rats; in contrast, PRC and renal staining with anti-renin antibody were significantly increased in ACEI rats. On day 28, the blood pressure was normal in all groups and plasma creatinine returned to the normal range in ACEI rats. PRA, PRS and PRC were not significantly different in the ACEI group and controls. These results suggest that the renin-angiotensin system (RAS) plays a major postnatal role in the neonatal rat. Inhibition of the RAS during the first 2 weeks of life leads to high mortality, severe hypotension, reversible renal failure and a defect in circulating angiotensinogen.

Comparison of the effectivity and safety of ketanserin versus dihydralazine in the treatment of severe early-onset peeclampsia

Comparison of the effectivity and safety of ketanserin versus dihydralazine in the treatment of severe early-onset peeclampsia

Dihydralazine

Dihydralazine

Pyrazoles Derived from Dihydralazine

Pyrazoles Derived from Dihydralazine

Dihydralazine⋆

Dihydralazine⋆

METHOHEXITONE ANAESTHESIA FOR MICROLARYNGOSCOPY: CIRCULATORY MODULATION WITH METROPROLOL AND DIHYDRALAZINE

Anaesthesia for microlaryngoscopy was induced and maintained with fentanyl 3 micrograms kg-1 and methohexitone (initial bolus of 1-1.5 mg kg-1 plus subsequent infusion of 4 mg kg-1 h-1). Suxamethonium was used to induce neuromuscular blockade. Twenty minutes before induction of anaesthesia, previously normotensive patients (n = 35), and patients with hypertension well controlled by beta-receptor antagonists (n = 16) were pretreated with metoprolol (M) 0.2 mg kg-1 i.v. and dihydralazine (DH) 0.2 mg kg-1 i.v., dihydralazine 0.2 mg kg-1 i.v. alone, or saline. Arterial pressure (AP) and heart rate (HR) were monitored: any arrhythmia and ST60-T changes were noted. After the methohexitone infusion was stopped, the times for emergence and full recovery were short (median 2 min 15 s and 5 min later, respectively). Pretreatment with M + DH abolished increases in AP and HR during endoscopy. Arrhythmias were observed in fewer pretreated patients than in controls (P less than 0.05). ST60-T changes in the ECG indicating myocardial ischaemia were found in two of 19 M + DH and in six of 21 saline-pretreated patients. One of these six patients developed a myocardial infarction. Pretreatment with dihydralazine alone attenuated the pressor response to microlaryngoscopy, but was associated with consistently high HR and an incidence of arrhythmias as well as ST60-T changes similar to that found after saline.