Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action.

BACKGROUND: the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)2]·H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD. METHODS: ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91phox and p47phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis. RESULTS: The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment. CONCLUSION: Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

The "Preeclampsia and Hypertension Target Treatment" study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings.

BACKGROUND: Despite major advances in the pharmacologic treatment of hypertension in the nonpregnant population, treatments for hypertension in pregnancy have remained largely unchanged over the years. There is recent evidence that a more adequate control of maternal blood pressure is achieved when the first given antihypertensive drug is able to correct the underlying hemodynamic disorder of the mother besides normalizing the blood pressure values. OBJECTIVE: This study aimed to compare the blood pressure control in women receiving an appropriate or inappropriate antihypertensive therapy following the baseline hemodynamic findings. STUDY DESIGN: This was a prospective multicenter study that included a population of women with de novo diagnosis of hypertensive disorders of pregnancy. A noninvasive assessment of the following maternal parameters was performed on hospital admission via Ultrasound Cardiac Output Monitor before any antihypertensive therapy was given: cardiac output, heart rate, systemic vascular resistance, and stroke volume. The clinician who prescribed the antihypertensive therapy was blinded to the hemodynamic evaluation and used as first-line treatment a vasodilator (nifedipine or alpha methyldopa) or a beta-blocker (labetalol) based on his preferences or on the local protocols. The first-line pharmacologic treatment was retrospectively considered hemodynamically appropriate in either of the following circumstances: (1) women with a hypodynamic profile (defined as low cardiac output [≤5 L/min] and/or high systemic vascular resistance [≥1300 dynes/second/cm2]) who were administered oral nifedipine or alpha methyldopa and (2) women with a hyperdynamic profile (defined as normal or high cardiac output [>5 L/min] and/or low systemic vascular resistances [<1300 dynes/second/cm2]) who were administered oral labetalol. The primary outcome of the study was to compare the occurrence of severe hypertension between women treated with a hemodynamically appropriate therapy and women treated with an inappropriate therapy. RESULTS: A total of 152 women with hypertensive disorders of pregnancy were included in the final analysis. Most women displayed a hypodynamic profile (114 [75.0%]) and received a hemodynamically appropriate treatment (116 [76.3%]). The occurrence of severe hypertension before delivery was significantly lower in the group receiving an appropriate therapy than in the group receiving an inappropriately treated (6.0% vs 19.4%, respectively; P=.02). Moreover, the number of women who achieved target values of blood pressure within 48 to 72 hours from the treatment start was higher in the group who received an appropriate treatment than in the group who received an inappropriate treatment (70.7% vs 50.0%, respectively; P=.02). CONCLUSION: In pregnant individuals with de novo hypertensive disorders of pregnancy, a lower occurrence of severe hypertension was observed when the first-line antihypertensive agent was tailored to the correct maternal hemodynamic profile.

Different culture media containing methyldopa for melanin production by Cryptococcus species / Avaliação de diferentes meios de cultura contendo metildopa para a produção de melanina por espécies de Cryptococcus

INTRODUCTION: Melanin production by species of Cryptococcus is widely used to characterize C. neoformans complex in mycology laboratories. This study aims to test the efficacy of methyldopa from pharmaceutical tablet as a substrate for melanin production, to compare the production of melanin using different agar base added with methyldopa, and to compare the melanin produced in those media with that produced in Niger seed agar and sunflower seed agar by C. neoformans, C. laurentii, and C. albidus. Two isolates of each species, C. neoformans, C. laurentii, and C. albidus, and one of Candida albicans were used to experimentally detect conditions for melanin production. METHODS: The following media were tested: Mueller-Hinton agar (MHA), brain and heart infusion agar (BHIA), blood agar base (BAB), and minimal medium agar (MMA), all added with methyldopa, and the media Niger seed agar (NSA) and sunflower seed agar (SSA). RESULTS: All isolates grew in most of the culture media after 24h. Strains planted on media BAB and BHIA showed growth only after 48h. All isolates produced melanin in MMA, MHA, SSA, and NSA media. CONCLUSIONS: Methyldopa in the form pharmaceutical tablet can be used as a substrate for melanin production by Cryptococcus species; minimal medium plus methyldopa was more efficient than the BAB, MHA, and BHIA in the melanin production; and NSA and SSA, followed by MMA added with methyldopa, were more efficient than other media studied for melanin production by all strains studied.

INTRODUÇÃO: A produção de melanina por espécies de Cryptococcus é uma característica amplamente utilizada em laboratórios de micologia para caracterização do complexoC. neoformans. O objetivo deste estudo foi verificar a eficácia da metildopa na forma farmacêutica de comprimido, como substrato para a produção de melanina por Cryptococcus, comparar diferentes bases de meios de cultura acrescidas de metildopa para produção de melanina e comparar o pigmento produzido nestes meios com o produzido em ágar Níger e ágar girassol por C. neoformans, C. laurentii e C. albidus. MÉTODOS: Foram testados dois isolados de cada uma das espécies, C. neoformans, C.laurentii e C.albidus, e um de C. albicans para avaliar a produção de melanina nos meios de cultura ágar Müeller-Hinton (MH), ágar brain heart infusion (BHI), ágar base sangue (BS), meio mínimo (MM), todos acrescidos de metildopa, e ainda ágar girassol e ágar Níger. RESULTADOS: Todos os isolados cresceram na maioria dos meios após 24h. O crescimento nos meios BS e BHI somente ocorreu após 48h. Todos os isolados produziram melanina nos meios MM, MH, girassol e Niger. CONCLUSÕES: A metildopa de origem farmacêutica pode ser utilizada como substrato para a produção de melanina por espécies de Cryptococcus; o MM acrescido de metildopa mostrou-se mais eficiente na produção de melanina do que os meios BS, MH e BHI; ágar girassol e ágar Níger seguidos de MM acrescido de metildopa foram os mais eficientes na produção de melanina pelos isolados estudados.

Effects of the antihypertensive drugs Ó-methyldopa and hydralazine on the performance of spontaneously hypertensive rats in the elevated plus-maze

The effects of antihypertensive drugs on the performance of spontaneously hypertensive rats (SHR) in the elevated plus-maze were determined. Male SHR (3 months old) were submitted to long-term treatment (15 days) with Ó-methyldopa (ÓMD, 5g/l, N = 10) and hydralazine (HYD, 100 mg/l, N = 10) given orally, diluted in water. After the drug treatment, the performance of the rats in the plus-maze was observed for 5 min in a single test and mean arterial pressure (MAP) and heart rate (HR) were then measured. The antihypertensive drugs reduced MAP significantly (mean ñ SEM:CON = 176.2 ñ 5.2, ÓMD = 157.8 ñ 4.6 and HYD = 150 ñ 4.4 mmHg) and only ÓMD increased HR significantly (mean ñ SEM:CON = 391.7 ñ 13.8, ÓMD = 453.3 ñ 14 and HYD = 368.8 ñ 18.9 bpm). The ÓMD group presented a lower total number of entries (mean ñ SEM:CON = 12.7 ñ 0.7, ÓMD = 8.7 ñ 0.9 and HYD = 12 ñ 0.9) and spent less time in the open arms than the CON (N = 10) and HYD groups (mean ñ SEM:CON = 0.69 ñ 0.04, ÓMD = 0.48 ñ 0.07 and HYD = 0.65 ñ 0.06 s). ÓMethyldopa acts centrally and hydralazine acts peripherally. The behavioral change of SHR treated with Ó-methyldopa suggests that hypertension seems to be related to central nervous dysfunctions that are affected by an antihypertensive drug with central noradrenergic action

Efecto de la alfa metildopa sobre el corazón en la hipertensión renovascular / Effect of alpha methyldopa on heart in renovascular hypertension

Resultados previos mostraron que la hipertrofia cardíaca (HC) y la respuesta contráctil al Isoproterenol (I) en el modelo 2R Ic, se normalizagba tres semanas sdespués del descenso de la presión arterial (PA) por el declipado de la arteria renal. En el presente trabajo se estudió el efecto de la Alfa Metidopa (aMD) sobre la PA, HC y la respuesta al I. Con ese propósito, a 43 ratas macho Wistar, de 280 gramos, se las dividió en: a) Grupo Control (C) (n = 24). Luego de tres semanas de control de PA, a 17 de ellas se les administró aMD per os a la dosis de 100 mg/kg/día durante 21 días (C alta). b) Grupo clip (K) (n = 19), a los que se les colocó un clip de plata en la arteria renal izquierda. Luego de tres semanas de hipertensión a (n = 9) (K alfa) se les administró aMD en forma similar a C Alfa. La respuesta al I se evaluó a los 21 a C y K y a los 42 días a C alfa y K alfa. A tal fin, previa anestesia se canularon la carótida, la arteria y vena femorales y se registró la frecuencia cardíaca (FC), la presión arterial media (PAM), la presión sistólica y diastólica de ventrículo izquierdo y la DP/DT + MAX en condiciones basales, y luego de dosis unicas crecientes de I. Al finalizar la experiencia se determinó el peso biventricular (PC) y se normalizó por el peso corporal (pc). La PA aumentó en K (p < 0,05): 179 ñ 2,3 vs C 125 ñ 2,9 y con aMD descendió: C alfa 111 + 2,5 y K alfa 151,7 ñ 6 (p < 0,05). EIPC (g) con aMD fue menor en C alfa (p < 0,05) 0,69 ñ 0,04 vs 0,78 ñ 0,05 y en K alfa...