Disease relevance of DIHYDRALAZINE

• Vascular effects of dihydralazine during prevention of genetic hypertension development in SHR rats [1].
• Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats [2].
• The strong heterogeneity in the expression of P4501A enzymes in human liver and the capacity of these enzymes for induction by dihydralazine and by other compounds might be predisposing factors in this autoimmune disease [3].
• Acute and long-term supplementary therapy with dihydralazine was therefore compared with placebo in 14 patients with severe congestive heart failure (classes III and IV) due to congestive cardiomyopathy [4].
• A comparison between the haemodynamic effects of oral nifedipine and intravenous dihydralazine in patients with severe pre-eclampsia [5].

High impact information on DIHYDRALAZINE

• Since these studies demonstrate that hydralazine and dihydralazine damage DNA in mammalian cells, these drugs should be viewed as potential human carcinogens [6].
• Sera from patients with dihydralazine-induced hepatitis were shown to contain anti-liver microsomal autoantibodies (anti-LM) by indirect immunofluorescence [7].
• Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis [7].
• The results contrasted with those observed after dihydralazine, which induced a sustained increase in cardiac index and heart rate [8].
• The caliber of the brachial artery decreased significantly (P less than 0.001) after dihydralazine and increased significantly after diltiazem (P less than 0.01) [8].

Chemical compound and disease context of DIHYDRALAZINE

• 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 [9].
• Compared myocardial and vascular effects of captopril and dihydralazine during hypertension development in spontaneously hypertensive rats [10].
• Ketanserin versus dihydralazine in the management of severe early-onset preeclampsia: maternal outcome [11].
• 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) [12].
• Acute effects of dihydralazine mesylate, furosemide, and metoprolol on maternal hemodynamics in pregnancy-induced hypertension [13].

Biological context of DIHYDRALAZINE

• Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached [2].
• To assess whether carotid artery circulation could influence the baroreceptor reflex response to arteriolar vasodilation, carotid artery and brachial artery hemodynamics were measured in immediate succession in normotensive and hypertensive subjects before and after oral administration of cadralazine, a dihydralazine derivative [14].
• Following the acute administration of 25 mg i.v. (n = 10) or 100 mg oral dihydralazine (n = 8), cardiac output increased significantly from 4.0 to 6.7 l min-1 and from 4.7 to 7.7 l min-1 respectively (2P less than 0.001) [4].
• Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF [2].
• The LD50 values of 7c and dihydralazine are very similar [15].

Anatomical context of DIHYDRALAZINE

• To understand the first steps leading to this immune reaction, we studied the covalent binding fo dihydralazine metabolites to microsomes from rat and human livers [16].
• In human hepatocytes, dihydralazine produced a dose-dependent increase in the level of P4501A up to 0.1 mM; induction of P4501A was less strong at 0.2 mM and disappeared at 0.5 mM [3].
• Mechanism-based inactivation of cytochrome P450s 1A2 and 3A4 by dihydralazine in human liver microsomes [17].
• Anti-cytochrome P450 (CYP)1A2 autoantibodies are found in dihydralazine-induced hepatitis, and CYPs2B and 2C have been shown to follow vesicular flow to the plasma membrane (PM) [18].
• 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 [19].

Associations of DIHYDRALAZINE with other chemical compounds

• Hemodynamic responses after urapidil were compared with those after dihydralazine in placebo-controlled, double-blind studies after cumulative intravenous doses [20].
• Upon incubation with NADPH and microsomes, dihydralazine formed metabolites that reacted with heme (as evidenced by destruction of heme, formation of 445-nm light-absorbing complexes, and covalent binding of heme to P450 apoprotein) and covalently bound to microsomal proteins [16].
• This study analyzes the effects of the converting enzyme inhibitor lisinopril, which specifically interferes with the renin-angiotensin system, and the direct vasodilator dihydralazine on the renal and extrarenal expression of renin and angiotensinogen [21].
• PATIENTS: Twenty-seven early-onset, pre-eclamptic patients with a median gestational age of 27 weeks 1 day (range, 21 weeks 2 days-32 weeks 4 days) with treatment failure on standard intravenous antihypertensive drugs (ketanserin, dihydralazin or labetalol) [22].
• Ten patients chewed a 10-mg capsule of nifedipine and 10 patients received dihydralazine by intravenous infusion at a rate of 1-3 mg/h. Arterial pressures, heart rate, cardiac output and pulmonary capillary wedge pressure were determined before and after drug administration [5].

Gene context of DIHYDRALAZINE

• Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis [23].
• Subgroups of rats received either human (rh)Epo alone or in combination with unspecific antihypertensive treatment (dihydralazine plus furosemide) in order to control the Epo induced rise in blood pressure [24].
• A similar mechanism has been described for dihydralazine induced hepatitis, where autoantibodies are directed against P450 1A2 (LM) [25].
• Dihydralazine is known to induce immunoallergic hepatitis, and the anti-liver microsome (anti-LM) autoantibodies found in the serum of the patients have been reported to react with cytochrome P450 1A2 (CYP1A2) [26].
• The lesions induced by ET-1 were prevented by coinjection with dihydralazine, a vasodilator drug [27].

Analytical, diagnostic and therapeutic context of DIHYDRALAZINE

• After preconstriction with U46619, magnesium sulphate (1.5 x 10(-3) to 6 x 10(-3) mol/l) induced a decrease in perfusion pressure, while dihydralazine (10(-6) to 10(-4) mol/l) or labetalol (10(-7) to 10(-4) mol/l) enhanced the perfusion pressure [28].
• Detection of some antihypertensive drugs and their metabolites in urine by thin-layer chromatography: II. A further five beta blockers and dihydralazine [29].
• 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 [30].
• Subcutaneous injections of dihydralazine in rats produced a local as well as a general toxic effect [31].
• Hydralazine and dihydralazine, chelators of Fe2+, Fe3+ and Mn2+ ions, inhibited collagen biosynthesis in organ culture of chicken embryo tibiae [31].

References