The relationships and time course of exercise-induced muscle damage, estimated by beta-glucuronidase activity and microscopy, to muscle swelling, estimated by muscle water content and microscopy, and to the serum activity of creatine kinase (CK) and the concentration of carbonic anhydrase III were studied in rats 2, 12, 48, and 96 h after 90 min of intermittent running uphill (+13.5 degrees) or downhill (-13.5 degrees) at a speed of 17 m/min. The injury was more pronounced in soleus after uphill running and in the red parts of quadriceps femoris and in the white part of vastus lateralis after downhill running, whereas triceps brachii was not damaged. Increase in muscle water content preceded the increase of beta-glucuronidase activity. Both running protocols similarly increased serum CK 2 h postexercise. After downhill running a second peak in serum CK was observed 48 h later. The CK changes were not in concert with the changes in muscle water content or beta-glucuronidase activity, suggesting that these responses may not be mechanistically (or causally) related.

Paroxetine, like other SSRIs, is reported not to increase the number of malformations in infants exposed to these drugs in utero. However, late pregnancy exposure to SSRIs sometimes leads to perinatal complications resembling the symptoms seen in serotonergic overstimulation. We report here a case of third trimester paroxetine exposure with adverse birth outcome in a newborn. The clinical symptoms in the infant included severe tremor and rigidity as well as loose stools during the first 4 days of life. Plasma paroxetine concentrations in infant plasma were quite low after birth, but she was genotyped to be a poor metabolizer of CYP2D6, the enzyme catalyzing the metabolism of paroxetine. In accordance with an earlier report, we suggest that even low plasma concentrations of paroxetine may be related to perinatal complications in infants exposed to paroxetine during late pregnancy and that the poor metabolizer genotype of CYP2D6 may be a risk factor for these complications.

To study the impact of meconium aspiration on the biosynthesis of prostaglandins and nitric oxide, we investigated the effects of intratracheal meconium instillation on the expression of cyclooxygenase-1 (COX-1) and -2 (COX-2) and endothelial (NOS-3) and inducible (NOS-2) nitric oxide synthase in rat lungs. Anesthetized, tracheotomized, and ventilated rats received 3 mL/kg human meconium suspension intratracheally (n ϭ 19), and 14 control rats received an equal volume of saline. Ten rats were pretreated with indomethacin, and 13 rats were pretreated with dexamethasone. The lungs were ventilated with 70% oxygen for 3 h after the insult, and the level of COX-1, COX-2, NOS-2, and NOS-3 mRNA in lung tissue was analyzed by Northern blot hybridization. Furthermore, the expression and localization of the enzyme proteins was analyzed by immunohistochemistry. COX-1 and NOS-3 were clearly expressed in the lungs of control rats, whereas the level of COX-2 and NOS-2 expression was minimal. Meconium administration did not affect the expression of COX-1, but COX-2 expression was upregulated in the respiratory epithelium and alveolar macrophages. Meconium also induced up-regulation of NOS-2 in the pulmonary epithelium, vascular endothelium, and macrophages. Indomethacin pretreatment did not affect the enzyme expressions, whereas dexamethasone administration significantly inhibited the meconium-induced COX-2 and NOS-2 up-regulation. Our data thus indicate that intrapulmonary meconium upregulates lung COX-2 and NOS-2 gene expression, suggesting an important role for prostaglandins and nitric oxide in the meconium aspiration-induced pulmonary inflammation and hemodynamic changes. Aspiration of meconium frequently causes a severe neonatal disorder, characterized by initial airway obstruction with subsequent alveolocapillary injury and ventilation/perfusion mismatching in the lungs (1). In a few hours, the initial insult is followed by an inflammatory reaction in the lungs with neutrophil accumulation and concomitant increase in the pulmonary vascular resistance (1-4). The pathogenetic mechanisms of these alterations are still unclear, although the stimulation in the production of bioactive mediators in alveolar macrophages has been proposed (4 -6).Prostaglandins have been implicated as important modulators of various pathologic inflammatory and cardiovascular processes. The rate-limiting step in prostaglandin biosynthesis is the conversion of arachidonic acid to endoperoxides by cyclooxygenase enzymes, known to exist in two isoforms (7). The constitutive cyclooxygenase-1 (COX-1) is ubiquitously expressed and enrolled in physiologic processes, whereas the low basal activity of cyclooxygenase-2 (COX-2) can be stimulated by endogenous and exogenous mediators (7,8). Accordingly, COX-2 is activated in endotoxin and cytokinestimulated alveolar macrophages and pulmonary epithelial cells in vitro and this will result in the generation of large amounts of prostaglandin E 2 (8 -10). The activity of pulmonary prostaglandin synthesis after as...

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