1 Inotropic responses to x-adrenoceptor stimulation and the effects of antagonists were examined in isolated ventricular preparations from neonatal and adult mice. 2 Phenylephrine, in the presence of propranolol, produced positive inotropic responses in neonates up to 1 week after birth, while it produced negative inotropic responses in mice older than 3 weeks. 3 Both positive and negative responses to phenylephrine in neonates and adults, respectively, were antagonized by prazosin, WB4101 (2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane) and 5-methylurapidil, but not by atropine, yohimbine or chlorethylclonidine. 4 Noradrenaline (NA) produced positive inotropic responses both in the neonate and adult; the responses were observed in a lower concentration-range in the neonate than in the adult. WB4101 produced a significant leftward shift of the concentration-response curve for noradrenaline in adult preparations while only a slight rightward shift was observed in the neonate. 5 Our results demonstrate the presence of x-adrenoceptor-mediated inotropic responses in the mouse ventricular myocardia. The response to phenylephrine changes from a positive to a negative effect during postnatal development. The responses are mediated by a,-adrenoceptors, and modulate the overall inotropic response to NA in the adult.

This study was performed to investigate the intrapulmonary penetration of lascufloxacin in humans. Thirty healthy adult male Japanese subjects, allocated into five groups, received lascufloxacin in a single oral dose of 75 mg. Bronchoalveolar lavage and blood sampling were performed simultaneously in each subject at 1, 2, 4, 6, or 24 h after administration, and lascufloxacin concentrations in plasma, epithelial lining fluid, and alveolar macrophages were determined. Lascufloxacin was rapidly distributed to the epithelial lining fluid with a time to maximum drug concentration () of 1 h, which was identical to that in plasma. The maximum concentration of drug () values in plasma, epithelial lining fluid, and alveolar macrophages were 0.576, 12.3, and 21.8 μg/ml, respectively. The corresponding area under the concentration-time curve from 0 to 24 h (AUC) values were 7.67, 123, and 325 μg · h/ml. The mean drug concentrations in the epithelial lining fluid and alveolar macrophages were much higher than those in plasma at all time points examined, and the average site-to-free plasma concentration ratios fell within the ranges of 57.5 to 86.4 and 71.0 to 217, respectively. Drug levels in epithelial lining fluid and alveolar macrophages exceeded the MIC values for common respiratory pathogens. (This study was registered at JAPIC under registration number JapicCTI-142547.).

Chronotropic and inotropic responses to noradrenaline and acetylcholine were examined in isolated right atrial and ventricular preparations from neonatal and adult mice. Noradrenaline and acetylcholine produced positive and negative chronotropic responses, respectively, in the atria from both ages. Noradrenaline produced positive inotropic responses in ventricular preparations from both ages. In all cases, the sensitivity, expressed in terms of pD2 values, was higher in neonatal preparations. In the ventricle, desipramine produced a leftward shift of the concentration-response curve for noradrenaline in the adult, but no such shift was observed in the neonate. The sensitivity to isoprenaline of ventricular preparations was higher in the neonate than in the adult. Our results demonstrated developmental decreases in sensitivities to autonomic transmitters in mouse myocardia. As for the inotropic response to noradrenaline of ventricular muscle, both pre- and postjunctional mechanisms were responsible for the developmental decrease in sensitivity.

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