In vitro and ex vivo antioxidant activities of labetalol on rabbit neutrophil respiratory burst.

The beta-adrenoreceptor blocker labetalol has demonstrated important antioxidant properties in vitro that inhibit superoxide anion production during normal leukocyte oxidative metabolism. This study investigated the in vitro and ex vivo effects of labetalol on respiratory burst in rabbit neutrophils. The production of superoxide anions was examined in activated purified rabbit neutrophils after intravenous administration of labetalol (4.0 mg/kg of body weight). At a concentration up to 200 mg/L, labetalol did not demonstrate any cytotoxic effects on neutrophils, as determined by enzyme lactate dehydrogenase activity. In the cell-free system, labetalol demonstrated no significant activity, but in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rabbit neutrophils, labetalol demonstrated concentration-dependent antioxidant activity. The in vitro 50% inhibitory concentration (IC50) with the fMLP stimulus was 16.5+/-0.21 mg/L in the rabbit neutrophils and 13.2+/-0.16 mg/L in the human neutrophils. In the fMLP-stimulated rabbit polymorphonuclear leukocytes, labetalol demonstrated its peak inhibitory activity (47%) 3 hours after administration. The mechanism by which labetalol acts in the treatment of hypertension may occur from an interaction in the signaling pathway of protein kinase C activation. The antioxidant properties demonstrated in this mechanism contribute to the drug's antihypertensive action and thus, may reduce the risk of injuries inflicted by reactive oxygen species involved in the pathogenesis of hypertension.

Hyperlactataemia during antiretroviral therapy: incidences, clinical data and treatment.

Lactic acidosis is a serious complication of antiretroviral therapy. Symptomatic hyperlactataemia is a milder form of this syndrome, but its incidence is unclear. In this prospective ongoing observational study of a large cohort of HIV-infected adults, hyperlactataemia was diagnosed in 64 patients. Incidences were 18.3/1000 person-years with antiretroviral therapy, and 35.8/1000 person-years for stavudine (d4T) regimens. Ten of the 64 patients developed lactic acidosis during the first 13 months of treatment (incidence 2.9/1000 treated person-years). In four of ten patients, symptoms were absent or mild. More patients on d4T first-line therapy developed lactic acidosis than patients previously treated with other drugs (p = 0.008). Despite the occurrence of one death, the subsequent outcome for the remaining patients was favourable after antiretroviral therapy was stopped and supportive treatment with vitamins and antioxidants initiated. The early diagnosis of cases was the result of great vigilance and, combined with routine measurements of the anion gap, might be the most crucial factor explaining the low mortality rate observed here.

Antioxidant effects and anti-elastase activity of the calcium antagonist nicardipine on activated human and rabbit neutrophils--a potential antiatherosclerotic property of calcium antagonists?

Activated neutrophils which produce certain proteases, such as elastase and reactive oxygen species (ROS) are involved in oxidative stress and inflammation. In the present study, we have shown that nicardipine, a calcium channel blocker, affects the release of elastase and superoxide anion radicals (O(2-)) in vitro during human and rabbit neutrophil respiratory bursts. The drug inhibited the release of elastase and O(2-) by fMLP (N-formyl-methionylleucin-phenylalaninin), calcium ionophore (A23187) and PMA (phorbol-myristate-acetate)-stimulated human and rabbit neutrophils. Besides the release of elastase, strongly inhibited in the fMLP and A23187 stimulated systems, nicardipine affected elastase and O(2-) in a dose-dependent manner. The corresponding 50% inhibitory concentration (IC(50)) of nicardipine for elastase, released in PMA-stimulated human and rabbit neutrophils, was 15.95 +/- 0.17 microM and 18.06 +/- 0.08 microM, respectively, whereas for O(2-), the IC(50) of nicardipine in PMA, fMLP and A23187-stimulated human and rabbit neutrophils was 55.41 +/- 0.09 microM and 58.43 +/- 0.03 microM, 45.21 +/- 0.13 microM and 37.19 +/- 0.53 microM, 33.54 +/- 0.09 microM and 30.54 +/- 0.29, respectively. The mechanisms underlying the inhibition of elastase and superoxide anion radicals by nicardipine appear related to an inhibiting effect on the mobilisation of cytosolic calcium and on activation of protein kinase C (PKC). These antioxidant and anti-elastasic activities contribute to the properties of nicardipine, as positive side effects of its antihypertensive activity and may be useful to prevent inflammatory disorders (tissue damage, oxidative injury) involved in the pathogenesis of hypertension.