Background: Periodic breathing, an abnormal pattern of respiration consisting of alternating hyperpnea and hypopnea, has been recognized in patients with heart failure. Although fluctuations in pulmonary blood flow have been considered as a possible cause of this type of breathing, its patho-physiological mechanisms are not fully understood. In this study, we sought to determine whether inhaled nitric oxide (NO), a selective pulmonary vasodilator, attenuates periodic breathing. Methods: Eight cardiac patients who exhibited clear oscillatory ventilation while awake (age: 62 ± 16 years, left ventricular ejection fraction: 48 ± 20%) were enrolled in the study. After breathing room air (RA) for 15 min, the subjects inhaled air containing 30 ppm of NO for 15 min. Respiratory gas variables including minute ventilation (V˙E) were measured on a breath-by-breath basis throughout the test. Results: There were no differences in V˙E (10.7 ± 1.5 vs. 11.0 ± 1.7 l/min) or among any of the other hemodynamic or respiratory gas variables studied in the control and NO tests, with the exception of the end-tidal CO₂ partial pressure (5.0 ± 0.4 vs. 4.8 ± 0.5%; p = 0.018). The % magnitude of oscillation (i.e., the difference between the peak and nadir of oscillating V˙E, divided by the mean V˙E) was 40.0 ± 22.4% in RA and not influenced by inhaled NO (43.9 ± 20.8%, p = 0.57). Conclusion: Inhaled NO at a concentration of 30 ppm did not attenuate periodic breathing in awake patients with mild heart failure.

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To elucidate the mechanism of water flux across heart cell membranes, osmotically induced volume changes and sarcolemmal water permeability were evaluated in isolated guinea pig ventricular myocytes by videomicroscopic measurements of cell surface dimensions. Superfusion with anisosmotic solution (0.5–4 times normal osmolality) caused a rapid (lt;3 min to new steady state) and reversible cell swelling or shrinkage mainly because of proportional changes in cell width and thickness. The van't Hoff relationship between relative cell volume and the reciprocal of relative osmolality was linear and predicted an apparent osmotically dead space of ~35% cell volume. The osmotic water permeability coefficient (P_f) measured from the time course of cell swelling/shrinkage was ~22 μm·s⁻¹ at 35°C. Arrhenius activation energy (E_a), a measure of the energy barrier to water flux, was ~3.8 kcal·mol⁻¹ between 11 and 35°C; this value is equivalent to E_a for free-water diffusion in bulk solution (~4 kcal·mol⁻¹). Treatment with 0.1 mM Hg²⁺, a sulfhydryl-oxidizing reagent, reduced P_f by ~90%, and the sulfhydryl-reducing reagent dithiothreitol (10 mM) antagonized the inhibitory action of Hg²⁺. E_a measured from Hg²⁺-treated myocytes (12.3 kcal·mol⁻¹) was in the range of that for diffusional water movement through the lipid bilayers (>10 kcal·mol⁻¹). Although the observed P_f is small in magnitude, both the low E_a and the sulfhydryl-related modifications of P_f are characteristic of channel-mediated water transport. These data suggest that water channels form a major conduit for water crossing the sarcolemma of guinea-pig heart cells.

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A possible role of nitric oxide (NO) on adipocyte lipolysis was studied in exercise-trained (9 weeks of running) rats. Lipolysis in adipose tissue tended to be greater in trained rats than in control rats. A treatment of adipose tissue with 5 mM N^G-nitro-L-arginine methyl ester (L-NAME) showed that basal and isoproterenol-stimulated lipolysis were both significantly greater in trained rats than in control rats. In contrast, in isolated adipocytes L-NAME had no effect on lipolysis in either group of rats, though the lipolysis of isolated adipocytes was significantly greater in trained rats than in control rats. Training significantly reduced nitrite/nitrate production in adipocytes, but not in tissue. On the other hand, training increased the protein expression of endothelial nitric oxide synthase (eNOS), but not that of inducible NOS (iNOS) in the extracts of tissue homogenates. In tissue homogenates, eNOS activity but not iNOS activity was significantly greater in trained rats than in control rats. In cellular extracts, training significantly reduced the activities of both NOS's, but the mRNA expressions of both NOS's were not different between groups. The NO donors, S-nitroso-N-acetyl-penicillamine (SNAP) and 1-propamine, 3-(2-hydroxy-2-nitroso-1-propyl-hydrazine) (PAPA-NONOate), significantly inhibited adipocyte lipolysis in response to isoproterenol in both groups. This inhibitory effect of SNAP, but not that of PAPA-NONOate, was greater in the adipocytes of trained rats than in those of the control rats. Thus it is possible that NO is involved in the regulation of lipolysis and that exercise training enhances the responsiveness of adipocytes to extracellular NO with the reduced production of nitrite/nitrate in adipocytes because of decreased activities of NOS's. On the other hand, it is also possible that exercise increases either the activity or the protein expression of eNOS in adipose tissue.

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Several lines of studies have reported that olfactory perception is influenced by physical and hormonal conditions. In the present study, we investigated changes of olfactory perception during the menstrual cycle of the human. Cyclopentadecanolide vapor was used and its perception intensity was measured by 6-point category scale methods. We especially focused on a novel concept termed "olfactory contrast" that has been just very recently derived from the patch clamp experiment that uses the solitary olfactory receptor cell. The results obtained from 18 trials (15 subjects) showed that olfactory contrast was significantly enhanced at the ovulatory and/or menstrual phases. It is suggested that olfactory contrast, which we defined as a new parameter, provides a useful tool in many kinds of studies exploring the olfactory perceived ability.

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A simulation of some basic features of Ca²⁺ release from the sarcoplasmic reticulum (SR) in cardiac muscle was made with a model based on the mechanism of Ca²⁺-induced Ca²⁺-release. The half-sarcomere modeled as a circular cylinder was divided into 20 annular elements in the radial, 50 slices in the axial, and 125 slices in the azimuthal direction. The cylindrical surface of the sarcomere was covered by a layer of the SR. The rate of Ca²⁺ release from the terminal sac (TS) is proportional to the product of the open probability of the Ca²⁺ release channel and the difference of [Ca²⁺] between the TS and an element facing the TS. Ca²⁺ moves from element to element by simple diffusion and is taken up by the tubular SR via Ca²⁺-ATPase. Ca²⁺ influx (I_ca) to trigger the TS Ca²⁺ release was introduced to either a single element facing the TS (local I_ca) or to 20 elements aligned at the level of the Z-line (uniform I_ca). The simulation showed that with both types of I_ca, TS Ca²⁺ release is smoothly graded over a wide range of I_ca with the TS moderately loaded with Ca²⁺. The gain determined by dividing the total amount of TS Ca²⁺ release by I_ca was greater with local than with uniform I_ca. Mechanical alternans was simulated with both the local and uniform I_ca with an appropriate rate of Ca²⁺ replenishment to the TS. A Ca²⁺ wave was simulated with a model consisting of 8 longitudinally consecutive sarcomeres with TS heavily loaded with Ca²⁺. Thus the present model accounted for graded TS Ca²⁺ release, mechanical alternans, and Ca²⁺ wave in cardiac muscle at the same time.

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By projecting the image of a single ventricular myocyte upon a linear image sensor, the striation pattern was analyzed during resting and contracting states. During rest, the individual cycle length (ICL) of the striation pattern varied from 1.8 to 2.0 μm within a given cell. ICL measured every 2 ms fluctuated ≈0.05 μm around the mean. The variance of temporal fluctuations was decreased by chelating the extracellular Ca²⁺ and increased by the Ca²⁺ overload. Blocking the Ca²⁺ release channels with 10 μmol/l ryanodine reversed this increase. In the power spectral density, an increase in the power occurred in the frequency range below 10 Hz. This increase should reflect overall kinetics of both intracellular Ca²⁺ handling and responses of contractile filaments, because the same pattern was observed when spontaneous contractions occurred as well as when contractions were evoked by activating the L-type Ca²⁺ channels. It is suggested that the temporal fluctuations of ICL in the resting state are caused by spontaneous Ca²⁺ release from ryanodine receptors on the sarcoplasmic reticulum. Furthermore, under evoked contractions the shortenings of ICL were spatially inhomogeneous. These findings of nonuniform sarcomere shortenings are consistent with the temporal and spatial inhomogeneity of Ca²⁺ transients.

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An increase in cortical cerebral blood flow (CBF), independent of metabolic vasodilation, via the activation of cholinergic neurons originating in the nucleus basalis of Meynert (NBM) in the basal forebrain and projecting to the widespread cortices was recently demonstrated. In the present study, we aimed to clarify whether the increase in CBF following a stimulation of the NBM can improve delayed death of the cortical neurons following transient ischemia in rats. CBF was measured with a laser Doppler flowmeter, and the delayed neuronal death of the cerebral cortex produced by intermittent (every 5 s) occlusions of the unilateral common carotid artery for 60 min was measured histologically in the cortical hemisphere at 3 different coronal levels (6 μm thickness). In control rats without occlusion there were 6,000–8,000 intact neurons and 9–19 damaged neurons in the cortical hemisphere at each coronal level. During the occlusions, CBF ipsilateral to the occluded artery decreased by 13–32% of the preocclusion level. Five days after the occlusions, the numbers of damaged neurons were increased to 75–181. Repetitive electrical stimulation was delivered to the NBM, ipsilateral to the occluded artery, starting 5 min before the occlusions and finishing around the end of them. The increase in CBF induced by NBM stimulation prevented the occlusion-induced decrease in CBF in all 3 of the cortices. The delayed death of the cortical neurons previously observed after the occlusions was scarcely observable in all the cortices when NBM was stimulated. The present results suggest that NBM-originating vasodilative activation can protect the ischemia-induced delayed death of cortical neurons by preventing a blood flow decrease in widespread cortices.

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A low-affinity and high-capacity Na⁺-dependent glucose transporter (SGLT2) was inserted into the expression vector tagging of green fluorescent protein (EGFP). The protein expression and glucose transport activity were examined in Xenopus oocytes and Chinese hamster ovary (CHO) cells. In Western blotting analysis, EGFP-tagged SGLT2 protein expressed in both Xenopus oocytes and CHO cells. We also observed the EGFP fluorescence in both cells with a confocal laser microscope. To determine the function of EGFP-tagged SGLT2, we measured the uptake of [¹⁴C]-α-methyl glucopyranoside (AMG), a specific substrate for SGLT. The AMG uptake was time-dependently increased and inhibited by phloridzin in the EGFP-tagged SGLT2-expressing cells. The K_m value of 1.7 mM for AMG and the IC₅₀ of 2 μM for phloridzin consist with the renal low affinity Na⁺-dependent glucose transporter. These results indicate that EGFP-tagged SGLT2 protein functionally expressed both in Xenopus oocytes and CHO cells, and these models are useful for studying the regulatory mechanisms of glucose reabsorption.

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Effective communication distance and characteristic time are discussed in relation to the temporal nonuniformity of the secretion rate in intercellular signaling. We demonstrated that these characteristics significantly depend on secretion time and the strength of the enhanced secretion rate for human cytokines.

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