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Labetalol is one of the most used drugs for the treatment of hypertension. This molecule is able to bind to both alpha-1 (α1) and beta (ß) adrenergic receptors present in vascular smooth muscle among other tissues. It has been determined that human erythrocytes possess both alpha receptors and beta-adrenergic receptors expressed on their surface. The objective of this work was to study the effect of labetalol on the morphology of human erythrocytes. To accomplish this goal, human erythrocytes and model membranes built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. These lipid species are present in the outer and inner monolayers of the red blood cell membrane, respectively. Our findings obtained by X-ray diffraction and differential scanning calorimetry (DSC) indicate that labetalol interacted with both lipids in a process dependent on concentration. In fact, at low concentrations labetalol preferentially interacted with DMPE. On the other hand, results obtained by scanning electron microscopy (SEM) showed that labetalol alters the normal biconcave form of erythrocytes to stomatocytes and knizocytes (cells with one or more cavities, respectively). According to the bilayers couple hypothesis, this result implied that the drug inserted in the inner monolayer of the human erythrocyte membrane.

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Glutamic acid decarboxylase (GAD) activity was measured in the oviduct of normal rats in diestrous and in rats ovariectomized (OVX) seven days before. OVX induced a significant decrease of GAD activity in the Fallopian tube. This effect was completely reversed by coadministration of estradiol benzoate + progesterone (E + P). Simultaneous injection of atropine, but not of alpha-methyl-para-tyrosine or labetalol, completely prevented the activation of GAD induced by ovarian sterois. Moreover, prostigmin significantly potentiated the action of E + P on GAD activity in the rat oviduct. These data clearly suggest the participation of acetylcholine in the mechanisms whereby ovarian steroids regulate GAD activity in the rat Fallopian tube.

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The effects of the novel antihypertensive agent, carvedilol, on renal hemodynamics and excretory function have been investigated and compared with the effects of labetalol in conscious, spontaneously hypertensive rats. Sustained intravenous infusion of carvedilol or labetalol at a rate of 10 micrograms/kg/min resulted in a significant decrease in blood pressure which was equivalent in magnitude for both drugs. Carvedilol had no effect on renal hemodynamic parameters; glomerular filtration rate, renal blood flow, and filtration fraction were unchanged. In contrast, labetalol decreased the glomerular filtration rate by 13% (p less than 0.01) and the filtration fraction was reduced from 28 to 24%. Inasmuch as renal blood flow was unchanged and perfusion pressure was reduced, both compounds decreased renal vascular resistance. Urine flow decreased and osmolality increased with both carvedilol and labetalol. However, excretion of electrolytes was affected differently with the two compounds. While sodium and potassium excretion were significantly decreased with labetalol, sodium and potassium excretion remained stable during carvedilol infusion, which represents an important beneficial effect for a potent systemic vasodilator. We conclude, therefore, that carvedilol does not compromise the renal autoregulatory integrity in hypertensive rats, and that the antihypertensive activity of the compound is associated with an apparent 'renal sparing' effect, in that the decrease in blood pressure does not compromise the urinary excretion of sodium.

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The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

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En el presente estudio de diseño simple-ciego, placebo-control, cruzado y randomizado, evaluamos la respuesta tensional y las modificaciones hemodinámicas causadas por el tratamiento oral y durante dos semanas con un agente bloqueador beta-adrenérgico selectivo con efecto simpático-mimético intríseco (Acebutolol, 400 mg/día) o con un agente bloqueador alfa y beta-adrenérgico (Labetalol, 400 mg/día). A tal efecto, 25 pacientes hipertensos leves fueron sometidos a ejercicio isométrico al 30% de su capacidad máxima y a ejercicio dinámico hasta un máximo de 75W, bajo monitoreo con electrograma de impedancia y durante ciclos de tratamiento con placebo, Acebutolol o Labetalol en forma cruzada, La efectividad terapéutica de ambas drogas fue similar en reposo, pero el Labetalol indujo una menor respuesta hipertensiva al ejercicio isométrico que el Acebutolol, la cual parece deberse a un menor incremento de las resistencias periféricas. Durante el ejercicio dinámico se observó una atención de la respuesta hipertensiva similar con ambos medicamentos; el labetalol, sin embargo, permitió un incremento del gasto cardíaco mayor que el tratamiento con Acebutolol. Estos efectos diferenciales del Labetalol se atribuyen a su efecto bloqueador alfa-adrenérgico, y lo hacen particularmente útil en pacientes hipertensos con actividad física moderada o intensa

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1. Using conventional microelectrode techniques for the intracellular recordings of the membrane potential, the effects of labetalol were studied on cardiac Purkinje, atrial and ventricular muscle fibres of the dog. 2. Labetalol (1-10 microM) reduced, in a concentration-dependent manner, the action potential amplitude (APA) and the maximum rate of rise of the action potential (Vmax) in Purkinje fibres. 3. The action potential duration (APD) was decreased in Purkinje fibres but significantly increased in ventricular fibres after small concentrations of labetalol (1-3 microM). The atrial fibres were not very sensitive to labetalol. 4. Depolarization of the cardiac Purkinje fibres by increasing the external potassium concentration (8-12 mM), potentiated the labetalol effects on APA and Vmax but blocked its effects on the APD. 5. The effects of labetalol on Vmax of Purkinje fibres were dependent on the frequency of stimulation. 6. The ratio of the effective refractory period to the APD was increased both in normally polarized and depolarized Purkinje fibres after treatment with labetalol (10 microM). 7. Labetalol (10 microM) shifted the membrane responsiveness curve of Purkinje fibres by about 10 mV in the hyperpolarizing direction. 8. The slow response obtained in K-depolarized, Ba-treated Purkinje fibres was not significantly affected by labetalol (10-100 microM). 9. It is suggested that labetalol can exert Class I and Class III antiarrhythmic actions in cardiac muscle of the dog in vitro.

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The effect of labetalol, a new alpha and beta adrenergic blocker, on blood pressure, heart rate, plasma renin activity (PRA), and urinary aldosterone excretion was assessed in 23 essential hypertensive patients, divided in 2 subgroups: 11 with normal electrocardiogram and 12 with left ventricular hypertrophy (LVH). In the first subgroup significant differences were found in the arithmethyc mean for sistolic blood pressure in sitting position (control: 166.1 +/- 17.2 mm of Hg treatment: 153.9 +/- 13.8, p less than or equal to 0.005) and in standing position (control: 165.3 +/- 17.3, treatment: 152.8 +/- 13.8, p less than or equal to 0.005) and for diastolic blood pressure (control: 102.7 +/- 12.6 to 89.9 +/- 10.1, p less than or equal to 0.001 and 103.2 +/- 11.8 to 91.2 +/- 10.8, p less than or equal to 0.001; in sitting and orthostatic positions, respectively.). No significant differences were found in the group with LVH. Heart rate decreased in the total population during treatment (- 6.0 +/- 7.5, p less than or equal to 0.05 and - 5.4 +/- 7.5 beats per minute, p less than or equal to 0.05 in sitting and orthostatic positions, respectively. PRA diminished in 12 of 15 cases studied (- 2.5 +/- 4.65 ng/ml/hr., p greater than 0.5). Correlation coefficient between decrements of diastolic blood pressure (sitting position) and ARP was 0.637. Aldosterone decreased in a non significant way during treatment. These data support the thesis of an important role of the adrenergic system in the pathogenesis of non complicated essential hypertension and, therefore, simultaneous alpha and beta receptor blockade in these cases has a better therapeutic effect. The good correlation between the decrements of ARP and blood pressure suggests an intervention of the inhibition of renin angiotensine system, brought about by the blocker property of labetalol, in the antihypertensive mechanism of the drug.

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1 Hypertension in West Indians and Africans is common and has an unacceptably high mortality in the younger patients. 2 Fifty-three patients received labetalol (a combined alpha- and beta-adrenoreceptor antagonist) as part of an open evaluation of its anti-hypertensive effect. Ten non-caucasian patients were included. 3 Significant reductions in systolic and diastolic pressures were obtained in the caucasian patients, the African and West Indian patients remaining refractory to therapy.

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