Kinetics and mechanisms of cholesterol esterase inhibition by cardiovascular drugs in vitro.

Cardiovascular drugs such as lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride inhibit cholesterol esterase (CEase) in vitro. In the present paper, an attempt was made to determine kinetically the reaction mechanism for CEase inhibition by these drugs. The inhibition constant, Ki, for the mixed-type inhibition of CEase by these drugs in the presence of triton-X-100 or taurochloate were measured. Moreover, the pKi values were correlated with the molecular weights of these drugs. In conclusion, the fact that these drugs lower cholesterol levels in the plasma low-density lipoprotein may be partially due to the CEase inhibition by these drugs.

Gene expression in uremic left ventricular hypertrophy: effects of hypertension andanemia

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P<0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P<0.01). Compared with U, UH has lower HW/BW and LV/BW (P <0.05) and UE has normal HW/BW but lower LV/BW than U (P<0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal alpha-actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure- overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.

Modification of radio-thermo-chemotherapy by AK-2123 and hydralazine in tumor bearing mice.

The effects of chemical modifiers of hypoxic radiosensitizer, a 3-nitrotriazole derivative AK-2123 (200 mg/kg) before treatment, and vasodilator of hydralazine (HDZ; 5.0 mg/kg) after treatment on tumor growth of SCCVII of mice were investigated in the radio-thermotherapy combined with mitomycin C (MMC; 2.0 mg/kg) or adriamycin (ADM; 3 mg/kg). The tumor treated by 10 Gy alone (tumor doubling time = 7.5 days), MMC alone (6.9 days), and hyperthermia (43 degrees C, 30 min; HT) alone (8.0 days) showed a slight growth delay (control: 5.6 days). Prolonged growth delay (23.2 days) was observed by MMC-radio-thermotherapy (MMC-10Gy/HT) than that (12.4 days) by 10 Gy/HT. The modification of MMC-radio-thermotherapy by HDZ administered between 10 Gy and HT (MMC-10 Gy/HDZ/HT) resulted in the significant prolongation of tumor growth delay (31.7 days). AK-2123 administration before this treatment, (MMC-AK-2123)-10 Gy/HDZ/HT), enhanced a further tumor growth delay (37.6 days) which is equal to that by 50 Gy alone and resulted in the highest dose modifying factor (DMF) of 5.2. While modification of ADM-radio-thermotherapy by AK-2123 and HDZ, (ADM-AK-2123)-10 Gy/HDZ/HT, gave the equal tumor growth delay to that by 30 Gy alone (DMF = 3.1). These high efficacies of radio-thermo-chemotherapy modified by AK-2123 and HDZ may be caused by tumor blood flow reduction.

Effect of chronic treatment with hydralazine on various in vitro preparations of rat.

Effect of chronic treatment with hydralazine (40 mg/kg/day) on isolated heart, anococcygeus muscle and myometrial preparations from rats has been studied. The treatment for 6 weeks caused a significant increase in isoprenaline induced positive inotropic response in rat heart. However, isoprenaline induced positive chronotropic effects were not altered significantly by chronic hydralazine treatment. Chronic hydralazine treatment also failed to alter noradrenaline induced contractile effects on rat anococcygeus muscle. However, on myometrial preparations from hydralazine treated rats showed an increase in adrenaline induced relaxations. The results of the present study can be explained on the basis of the effect of hydralazine on adenylate cyclase-cyclic adenosine monophosphate (cAMP).

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

Effect of antihypertensive drugs on ethanol induced gastric lesions: is there a correlation with mucosal blood flow?

We studied the effect of five antihypertensive drugs on ethanol-induced gastric haemorrhagic lesions in rats. While hydralazine aggravates these lesions, nifedipine and propranolol have a protective action. On the other hand, enalapril and prazosin have no effect. Thus the effects of antihypertensive drugs on ethanol-induced lesions do not always correlate with their reported actions on gastric mucosal blood flow.

Uso da hidralazina intravenosa para o tratamento da crise hipertensiva / Use of intravenous hydralazine in treatment of hypertensive crisis

Purpose­To evaluate the efficacy and safety of intravenous hidralazine in arterial hypertension. Patients and Methods­12 patients, meanage 45,33 15,82,8 men and 4 women all of them with systolic (S) arterialpressure (AP) 180 and or diastolic (D) 126 mmHg with symptoms like headache, incaracteristic toraxic pain and others but without an hypertensive emergency neither acute manifestation of hypertensive encephalopathy through fundi examination were studied. The AP was taked 10 minutes after rest (inicial) and 5, 15, 30 and 60 min (final) after intravenous administration of hidralazine-HCL (5mg) which was repeated when at least 20% AP reduction was not achieved. Results­ The inicial and final SAP, DAPand heart rate (HR) wre 208 ± 19,4 and 176 ± 17,2 (p < 0.0001), 133 ± 11,3 and 112 ± 11,5 (p< 0.001) and 72 ± 12,9 and 80 ± 15,5 (NS), respectively. Side effects related to the drug were observed in 3 (25%) patients. One had symptomatic ortostatic hypotension, the second had precordial pain with ST-T changes compatible with myocardial ischemia and the third presented a torax and abdominal cutaneous erithema, but all of them reversible. Conclusion­ Intravenous hydralazineHC1 is an alternative when rapid arterial pressurereduction is needed

Diez años de experiencia con el uso de vasodilatadores en el tratamiento de la hipertensión arterial pulmonar primaria (HAP-P), 1977-1987 / 10 years experience with the use of vasodilators in the treatment of primary pulmonary hypertension

En el presente estudio, se analiza la experiencia derivada del tratamiento de la hipertensión arterial pulmonar primaria (HAP-P) con vasodiilatadores, en nuestra Institución, a lo largo de 10 años. Son 40 pacientes (29 mujeres y 11 hombres). Todos tuvieron criterios uniformes de diagnóstico, evaluación hemodinámica, y enfoque terapéutico. Se analiza con énfasis, su evolución clínica y hemodinámica y la repercusión del tratamiento en la calidad de vida y sobrevida de los enfermos. La edad promedio fue de 21 ñ 1.6 años y el tiempo de seguimiento 50 ñ 8 meses. Las drogas vasodilatadores utilizadas fueron: isoproterenol (ISO), hidralazina (HDL) y nifedipina (NFD). Basados en su respuesta hemodinámica se conformaron dos grupos: 20 pacientes con respuesta (R) y 20 sin ella (NR). Los pacientes del grupo R tienen un perfil clínico y hemodinámico basal característico. Al comparar ambos grupos, el grupo R tuvo una menor Pp (49 vs 77 mmHf, p < 0.05), menor Rp (17 vs 29 U/m2, p < 0.05) y menor relación Rp/Rs (0.59 vs 1.05, p < 0.05). El grupo R ha continuado su medicación a largo plazo por vía oral con HDL (7 pac.) y NFD (13 pac.) y mantienen, la mayoría, una respuesta hemodinámica benéfica con mejoría de su calidad de vida; por el contrario, la mayoría del grupo NR han evolucionado hacia un mayor deterioro funcional. La mortalidad es mayor en el grupo NR (8 pac.) que en el grupo R (3 pac). La probabilidad de sobrevida en el grupo R es del 86% a los 5 años, mientras que disminuye al 45% en los NR en el mismo lapso de tiempo. En conclusión, en la HAP-P hay un subgrupo de pacientes con un perfil clínico-hemodinámico característico que los hace candidatos a terapia vasodilatadora; estos mejoraran significativamente su calidad de vida sin mostrar efecto clínico ni hemodinámico adverso. Es por ello, que el reto farmacológico a través del estudio hemodinámico es indispensable en la selección de dichos enfermos. Se establece además que el pronóstico en cuanto a sobrevida depende, de manera fundamental, del perfil clínico y hemodinámico del paciente con HAP-P al momento del diagnóstico, hecho que debe tomarse en cuenta al juzgar el efecto de cualquier intervención terapéutica

Historia natural de la atelectasia pulmonar experimental en perros a tórax cerrado / Natural history of experimental pulmonary atelectasis in dogs with closed thorax

Se estudió el comportamiento del cortocircuito venoarterial (Qs/Qt) en una preparaçäo canina de atelectasia lobar a tórax cerrado. A 10 perros se les ocluyó el bronquio del lóbulo inferior derecho através de broncoscopía rígida, utilizando el globo de una sonda de Foley. A los 15 minutos postatelectasia el QS/Qt llegó a su máximo incremento de 8.2 ñ 3.6% a 29.7 ñ 11.7% (p < 0.05) y la PaO2 a su mayor disminución de 357 ñ 49 mm Hg a 100 ñ 43 mmHg (p < 0.05). A partir de los 45 minutos el Qs/Qt disminuyó y la PaO2 aumentó paulatinamente. Este cambio fué significativo a los 135 minutos (p < 0.05). La estabilidad gasomética y hemodinámica se apreció hasta 3 horas postatelectasia. Dado que los cambios en Qs/Qt y la Pa O2 no fueron secundarios a las modificaciones que ocurreran en gasto cardíaco, se concluye que la historia natural observada de la preparación obedece a vasoconstricción pulmonar hipóxica

Estudio de bloqueadores del canal de calcio, como alternativa de tratamiento de la preenclampsia severa / Calcium channel blockers as alternative of treatment of severe preeclampsia

Se estudiaron 20 casos de pacientes con diagnóstico de preeclampsia severa, ingresados a la Maternidad del Hospital Clínico de la Universidad de Chile durante los años 1983 y 1984. Se trataron 10 casos con nifedipina y 10 con hidralazina, distribuidos al azar. Los resultados confirman que ambas drogas tienen buenos resultados, siendo un poco mejor los resultados con nifedipina, tanto en los porcentajes de baja de la presión arterial como la menor cantidad de reacciones adversas, pero sin diferencias significativas. No se encontraron efectos deletéreos sobre el feto o recién nacido. Se concluye que nifedipina puede ser una alternativa de tratamiento en los casos de preenclampsia severa