Inhibition of brain acetylcholine biosynthesis by methyldopa in spontaneously hypertensive rats

The formation of 3H-acetylcholine was measured in several brain regions of spontaneously hypertensive (SH) rats following intracerebroventricular injection of 3H-choline. Endogenous acetylcholine (ACh) also was measured and specific activity-time curves for brain ACh generated for control SH rats and for SH rats pretreated with methyldopa (100-200 mg/kg, IV). The relative turnover rates for ACh in several brain regions was estimated from the specific activity-time curves. The turnover rates of ACh in rostral hypothalamus, caudal hypothalamus, medulla oblongata and pons were reduced by 34-54%. Apparently synthesis was inhibited also since methyldopa produced relatively little effect on ACh levels. More rostral brain regions, thalamus-septum, midbrain and striatum, were not significantly affected by methyldopa. Methyldopa also reduced arterial pressure by 53/28 mmHg. The ability of methyldopa to inhibit the function of cholinergic neurons in selective brain regions may be responsible for its common "anticholinergic" side effects. Since centrally-acting anticholinergic drugs reduce arterial pressure in SH rats, it is possible that inhibition of brain ACh synthesis by methyldopa also may contribute to its antihypertensive action in experimental genetic hypertension.     

Pharmacokinetics of methyldopa in healthy man

Summary The pharmacokinetics of 2-¹⁴C-L--methyldopa have been investigated in five healthy volunteers following intravenous and oral administration. In the intravenous study a bi-phasic plasma concentration curve was found both for chemically determined -methyldopa and for radioactivity. The plasma level of radioactivity differed significantly from chemically determined drug, a pattern which was also found in urine. This suggests the presence of unidentified metabolite(s). The difference between plasma disappearance and urine recovery of -methyldopa and radioactivity during the first 4 h after injection suggests distribution to an extravascular compartment. Plasma half-lives of total radioactivity and of unchanged drug were calculated. In three subjects, pharmacokinetic parameters for a two-compartment open body model were calculated from urine and plasma data. Urinary recovery of radioactivity was almost complete within 48 h after intravenous administration. After oral administration, however, only about 40 per cent of the radioactive dose was recovered in the urine, and it contained approximately equal amounts of unconjugated methyldopa, acid-labile conjugated methyldopa and unidentified metabolite(s). The acid-labile conjugate was found only after oral administration, which supports the theory of a mucosal conjugation process. The lack of acid-labile conjugated drug either in the plasma or urine after intravenous injection indicates that there is no enterohepatic circulation of this drug.     

国产甲基多巴治疗高血压的临床疗效观察

本文用国产甲基多巴口服治疗32例高血压病人,疗程37天。结果显效90.6%,有效9.4%,27例血压恢复正常,总有效率100%。病人尿量及肌酐清除率增加。剂量范围为0.5～3g/日,平均有效剂量为0.92g/日,平均显效剂量为1.25g/日。副作用主要有乏力、嗜睡、口干等,一般不严重,而且部分病例可在继续用药过程中减轻或消失。     

Studies on the mechanism of the cardiovascualr effects of methyldopa.

Oral administration of methyldopa (100 mg/kg, twice daily for 3 days) to mongrel dogs produced a significant decrease in blood pressure and heart rate. The drug treatment affected neither the resting venous tone nor the cardiac output. Thus, the hypotensive effect of the drug was predominantly due to a reduction in total peripheral resistance. Vasoconstrictor responses of the renal vasculature to sympathetic nerve stimulation were significantly impaired after methyldopa at all the frequencies, while mesenteric vasoconstrictor responses to sympathetic nerve stimulation were impaired only at the lower stimulation frequencies. In addition, methylnorepinephrine was a significantly less potent vasoconstrictor than norepinephrine in the renal vasculature, but was equipotent to norepinephrine in the mesentery. The finding of a reduction in the renal vascular resistance of methyldopa-treated dogs, with no such alteration in the mesenteric vascular resistance, is consistent with the nerve stimulation studies. Therefore, the results of the present investigation indicate that in addition to the existing evidence favoring a central site of action for methyldopa, the impairment of peripheral sympathetic neuronal function is also of importance in accounting for the hemodynamic alterations observed following treatment with methyldopa.     

A crossover comparison of a timolol/bendrofluazide combination and methyldopa in essential hypertension

Summary

A crossover study was carried out in 24 hypertensive patients being treated solely with methyldopa on entry to compare the effectiveness and side-effects of treatment with timolol maleate combined with bendrofluazide (4:1 dosage ratio). On entry, only 8 of the patients were controlled and receiving an optimum dose of methyldopa. A further 7 patients were controlled during a 4-week methyldopa titration period. After 4 weeks on placebo, patients were crossed over for a final 4-weeks to active treatment with timolol plus bendrofluazide, and 22 of the 24 patients were controlled on the combination therapy, 18 of them on 40?mg timolol plus 10?mg bendrofluazide or less per day. The reduction in blood pressure with the combination therapy was significantly greater than with methyldopa, and there was a lower incidence of side-effects.     

The correlation of changes in systolic blood pressure with regional anatomical regression of hypertensive left ventricular hypertrophy in patients on chronic antihypertensive therapy (>1 year): Alpha-methyldopa compared to propranolol

Summary

Twenty patients with mild to moderate hypertension and evidence of left ventricular hypertrophy (relative wall thickness ?0.45), who previously had not received either alpha-methyldopa or propranolol, were allocated at random to treatment with one or other of these drugs as monotherapy after a 2-week baseline period on no medication. Dosage was titrated until normotension was attained and patients were then maintained on this treatment for a yeac Analysis of blood pressure measurements and echocardiograms taken before and during maintenance therapy showed that there were significantly correlated changes in systolic blood pressure and heart rate with left ventricular cavity and regional wall changes during chronic drug administration. In the alpha-methyldopa group there were significant correlations between changes in erect and supine systolic blood pressure and the posterior wall index, and in erect systolic blood pressure and left ventricular mass. In the propranolol group, there were significant correlations between changes in supine systolic blood pressure and interventricular septal thickness, and in erect heart rate and supine systolic blood pressure with the percentage change in internal diameter of the left ventricle. It is suggested that these observations may have important therapeutic implications for hypertensive patients with documented left ventricular hypertrophy.     

甲基多巴联合拉贝洛尔治疗妊娠期高血压的疗效观察

目的观察甲基多巴联合拉贝洛尔治疗妊娠期高血压的临床疗效。方法将84例妊娠期高血压患者根据治疗方法不同分为对照组和观察组,各42例。对照组采用常规治疗及硫酸镁治疗,观察组在对照组基础上采用甲基多巴联合拉贝洛尔治疗。两组均连续治疗7 d,比较两组的心脏指数(CI)、总外周阻力(TPR)、脐动脉血流S/D及不良反应情况。结果治疗后,两组的CI高于治疗前,TPR、脐动脉血流S/D均低于治疗前,且观察组的CI高于对照组,TPR、脐动脉血流S/D均低于对照组(P均<0.05)。两组的不良反应发生率比较,差异无统计学意义(P>0.05)。结论甲基多巴联合拉贝洛尔治疗妊娠期高血压的效果显著,有利于提高患者的CI,降低TPR及脐动脉血流S/D,且不会增加不良反应。     

Influence of Calcium on Vascular Reactivity in Pregnant Rats

Objective: To examine fetal (FHR) and neonatal heart rate patterns following use of common oral antihypertensives in pregnancy. Methods: A systematic review of randomized controlled trials (RCTs), observational studies (N ≥ 6 women), and animal studies. Data were abstracted (two reviewers) to determine relative risk (RR) (or risk difference (RD) for low event rates) and 95% CI. Results: Eighteen RCTs (1858 women), one controlled observational study (N = 22), and seven case series (N = 117) were reviewed. Most hypertension was pregnancy‐induced (N = 14 studies). The FHR was assessed by cardiotocogram (CTG) (N = 17 studies (visual interpretation); 1 study (computerized CTG), or umbilical artery velocimetry (N = 4). Four studies examined neonatal heart rate. In placebo‐controlled RCTs (N = 192 women), adverse FHR effects did not differ between groups [9/101 (drugs) vs. 7/91 (placebo); RD 0.02, 95% CI (? 0.06, 0.11); χ² = 1.02]. In six drug vs. drug RCTs (295 women), adverse FHR effects did not differ between groups [29/144 (methyldopa) vs. 42/151 (other drugs); RR 0.72, 95% CI (0.49, 1.07); χ² = 0.69]. In one labetalol vs. placebo trial, neonatal bradycardia did not differ between groups [4/70 (labetalol) vs. 4/74 (placebo); OR 1.06, 95% CI (0.26, 4.39)], while in three drug vs. drug RCTs, neonatal bradycardia was not observed (0/24 vs. 0/26). Conclusions: Available data are inadequate to conclude whether oral methyldopa, labetalol, nifedipine, or hydralazine adversely affect fetal or neonatal heart rate and pattern. Until definitive data are available, FHR changes cannot be reliably attributed to drug effect, but may be due to progression of the underlying maternal or placental disease.     

Sensitive colorimetric assay of carbidopa and methyldopa using tetrazolium blue chloride in pharmaceutical products

A colorimetric method for the assay of carbidopa and methyldopa either in pure form or in pharmaceutical preparations is described. The method is based on the reduction of tetrazolium blue chloride in a non-aqueous alkaline medium by the substances analysed, and the measurement of the absorbance of the pink-coloured diformazan solution, which is caused by this reduction. The spectra of the aforesaid solutions exhibit an absorption maximum at= 525 nm. The apparent molar absorptivities and Sandell's sensitivities (in 1·mol^–1 ·cm^–1 and ng· cm^–2, respectively) are 1.2·10⁵ and 1.9 for carbidopa and 7.07· 10⁴ and 3.0 for methyldopa. The solution of diformazan formed obeys Beer's law in the concentration range of 0.05–4.0 ppm for carbidopa and 0.1–6.0 ppm for methyldopa. The slope and intercept of the corresponding regression line equation were obtained with a correlation coefficient of 0.9999 for carbidopa and 0.9994 for methyldopa. The variables affecting the development of the colour are investigated and the conditions are optimized. Compared with other procedures this method showed to be more simple and rapid, highly sensitive, precise and accurate. Results obtained by application of the proposed method and the official one, were in good agreement, while statistical comparison by the Student's t-test shows no significant difference between the two sets of the results.     

Central Monoamine Systems and New Antihypertensive Agents

This review describes the relationship between central monoamine pathways and centrally acting antihypertensive agents. By using antagonists with affinity for α₂-adrenoceptors and also imidazoline receptors we have found that the first generation agents clonidine and α-methyldopa activate α₂-adrenoceptors while the newer second generation antihypertensive agents rilmenidine and moxonidine activate imidazoline receptors. Despite the difference in receptors activated, the hypotension produced by central administration of all agents was attenuated after chemical lesioning of the brainstem noradrenergic or serotonergic pathways suggesting a similar dependence on central monoamine pathways. Since the acute 6-hydroxydopamine-induced release of noradrenaline in the brainstem produces hypotension it suggests that these agents normally mimic brainstem noradrenergic function. By contrast the pressor response shortly following 5,6-dihydroxytryptamine suggests serotonergic neurones in the brainstem are pressor and that part of the anti-hypertensive action of centrally acting antihypertensive agents is mediated by inhibition of bulbar serotonergic pathways. We suggest that the similar haemodynamic and baroreflex effects of the two generations of agents can be explained by the α₂-adrenoceptors and the imidazoline receptors being in series along the noradrenergic and serotonergic pathways.