The hyperpolarization-activated cation current (IH) is expressed differentially in various subpopulations of rat sensory neurons. For example, IH is infrequently expressed by C-and Aä-type dorsal root ganglion (DRG) neurons but is prominent in most Aá-and Aâ-type DRG neurons (Harper & Lawson, 1985a,b;Scroggs et al. 1994; Valiere & McLachlan, 1996). Since C-and Aä-type DRG neurons are typically involved in the transmission of different types of information than Aâ-and Aá-type DRG neurons, it is likely that agents which modulate IH may selectively affect certain types of sensory information. Serotonin (5_HT) has previously been shown to increase IH in rat nucleus prepositus hypoglossi neurons and in guinea-pig thalamic neurons through an increase in cAMP. However, the possibility that 5_HT may modulate IH in DRG neurons, as well as the potential mechanisms involved, have not previously been explored.In an earlier study we developed a set of criteria which appeared useful in categorizing small-and medium-diameter DRG cell bodies into four groups, types 1, 2, 3 and 4, based on capsaicin sensitivity, expression of IH, IA (a transient, 4_aminopyridine-sensitive outward K¤ current) and T_type Ca¥ current amplitude (Cardenas et al. 1995). The likelihood that these categories have some functional significance is supported by subsequent findings that 5_HT1A receptor activation selectively inhibited high-threshold Ca¥ currents in type 1 DRG cells and 5_HTÚ receptor activation selectively increased TTX-insensitive Na¤ currents in type 2 DRG cells (Cardenas et al. 1995(Cardenas et al. , 1997a. In the present study we observed that 5_HT increased IH in type 4 DRG cells and a subpopulation of large-diameter DRG cells, but not in type 1, 2, or 3 DRG cells. The 5_HT receptor involved responded to several selective 5_HT Journal of Physiology (1999) 1. The effect of serotonin (5_HT) on the hyperpolarization-activated cation current (IH) was studied in small-, medium-and large-diameter acutely isolated rat dorsal root ganglion (DRG) cells, including cells categorized as type 1, 2, 3 and 4 based on membrane properties. 5_HT increased IH in 91% of medium-diameter DRG cells (including type 4) and in 67% of large-diameter DRG cells, but not other DRG cell types. 2. The increase of IH by 5_HT was antagonized by spiperone but not cyanopindolol, and was mimicked by 5-carboxyamidotryptamine, but not (+)_8-hydroxydipropylaminotetralin (8_OH_DPAT) or cyanopindolol. These data suggested the involvement of 5_HTÝ receptors, which were shown to be expressed by medium-diameter DRG cells using RT-PCR analysis. 3. 5_HT shifted the conductance-voltage relationship of IH by +6 mV without changing peak conductance. The effects of 5_HT on IH were mimicked and occluded by forskolin, but not by inactive 1,9-dideoxy forskolin. 4. At holding potentials negative to −50 mV, 5_HT increased steady-state inward current and instantaneous membrane conductance (fast current). The 5_HT-induced inward current and fast current were blocked by Cs¤ but not Ba¥ and re...

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Methylprednisolone (MP) disposition was evaluated in 20 individuals who participated in an ongoing randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of MP in the treatment of acute respiratory distress syndrome (ARDS). MP (1 mg/kg) was given as a loading infusion over 30 minutes followed by a 1 mg/kg/day continuous i.v. infusion. Patients were switched to oral MP upon restoration of oral intake. MP plasma concentrations (n = 110) were determined using a specific HPLC method. Population pharmacokinetic analysis was performed using nonlinear mixed-effects models, implemented in NONMEM, version V. MP plasma concentration data were described by a one-compartment open model with a time-dependent, non-linear increase in the clearance (CL) of MP during the course of therapy. Initial clearance of MP (CLo) in ARDS patients at the start of therapy increased to a maximal value (CLmax) after approximately 7 days. The estimate of CLmax was similar to the CL of MP in healthy individuals reported previously. Population mean estimates (+/- SE) of parameters in the model were as follows: CLo = 13.2 +/- 2.4 L/h, CLmax = 25.0 +/- 3.6 L/h, time of half-maximal increase in CL (T50) = 41.1 +/- 8.2 h, gamma (Hill coefficient) = 3.8 +/- 0.6, and volume of distribution (Vd) = 137 +/- 30.2 L. Disease progression indices and patient demographics were evaluated as covariates, and no significant correlation was found. Means (+/- SD) of plasma protein binding differed between healthy individuals (72% +/- 4%) and ARDS patients (46% +/- 11%) (p < 0.001). The pharmacokinetics of MP in ARDS patients has not been described previously.