The Effect of Methyl Dopa, Nifedipine and Labetalol Treatment on Uterine, Umbilical and Fetal Middle Cerebral Artery Blood Flows in Cases Suffered from Pregnancy Induced Hypertension

Background: Treatment of severe maternal hypertension is strongly indicated for the prevention of maternal complications, such as cerebrovascular accidents and placental abruption, for avoiding extreme pre maturity. The selection criteria for the various antihypertensive drugs are somewhat unclear, and although vasodilator agents reducing peripheral vascular resistance (e.g., methyldopa, nifidipine and labetalol) have been accepted for general obstetric use. The aim of the study is to compare the effect of methyl dopa, nifedipine and labetalol treatment on the doppler indices of uterine, umbilical and fetal middle cerebral artery blood flows in cases suffered from pregnancy induced hypertension. Methods: This prospective randomized comparative clinical trial study was carried out on 75 pregnant women suffered from pregnancy-induced hypertension. The patients were divided into three equal groups: Group I: received alpha methyldopa750 mg-2000 mg per day, Group II: received labetalol 100 mg twice per day and Group III: received nifedipine oral sustained tablets 20-120mg per day. Results: Follow up of the patients was done with assessment of the outcome measures and statistical analysis was done and revealed that the use of alpha methyldopa, nifedipine and labatalol in pregnancy induced hypertension cases produce significant reduction of blood pressure ,prolong pregnancy duration, decrease the need for maternal admission to the ICU due to uncontrolled severe hypertension, decrease insignificantly the progression of mild preeclampsia to severe preeclampsia without producing negative effect on the mother or the fetus because these drugs did not impair the uteroplacental or middle cerebral blood flow documented by Doppler studies. Conclusions: Use of methyl dopa, nifidipine and labetalol treatment in PIH cases make an improvement of uteroplacental and middle cerebral blood flow which indicated by maternal uterine, umbilical and fetal middle cerebral arteries doppler indices (resistive index, pulatility index and S/D ratio). Labetalol is ideal first line of treatment because it has potent and fast hypotensive effect without producing significant side effects on the mother or fetus.

Oxidative cyclization of N-methyl-dopa by a fungal flavoenzyme of the amine oxidase family

Flavin-dependent enzymes catalyze many oxidations, including formation of ring structures in natural products. The gene cluster for biosynthesis of fumisoquins, secondary metabolites structurally related to isoquinolines, in the filamentous fungus Aspergillus fumigatus harbors a gene that encodes a flavoprotein of the amine oxidase family, termed fsqB (fumisoquin biosynthesis gene B). This enzyme catalyzes an oxidative ring closure reaction that leads to the formation of isoquinoline products. This reaction is reminiscent of the oxidative cyclization reported for berberine bridge enzyme and tetrahydrocannabinol synthase. Despite these similarities, amine oxidases and berberine bridge enzyme–like enzymes possess distinct structural properties, prompting us to investigate the structure–function relationships of FsqB. Here, we report the recombinant production and purification of FsqB, elucidation of its crystal structure, and kinetic analysis employing five putative substrates. The crystal structure at 2.6 Å resolution revealed that FsqB is a member of the amine oxidase family with a covalently bound FAD cofactor. N-methyl-dopa was the best substrate for FsqB and was completely converted to the cyclic isoquinoline product. The absence of the meta-hydroxyl group, as e.g. in l-N-methyl-tyrosine, resulted in a 25-fold lower rate of reduction and the formation of the demethylated product l-tyrosine, instead of a cyclic product. Surprisingly, FsqB did not accept the d-stereoisomer of N-methyltyrosine, in contrast to N-methyl-dopa, for which both stereoisomers were oxidized with similar rates. On the basis of the crystal structure and docking calculations, we postulate a substrate-dependent population of distinct binding modes that rationalizes stereospecific oxidation in the FsqB active site.