b-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate b-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with b-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 mM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C b enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C b activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate b-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with b-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.Keywords: asthma; adrenergic receptor; myosin light chain; lung; bronchodilation Clinical RelevanceNatural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist-induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

SummaryIn a prospective, blind, randomised study, we examined the effects of midazolam-propofol co-induction on haemodynamic (blood pressure, heart rate and stroke volume) and heart rate variability. The latter was measured by spectral analysis using the maximum-entropy method to calculate the following: the low frequency component (LF), which reflects both the cardiac sympathetic and parasympathetic activity, the high frequency component (HF) and entropy, which reflects the cardiac parasympathetic activity, the total power (TP), calculated by the addition of LF and HF, and the LF ⁄ HF ratio, which reflects the balance between the cardiac sympathetic and parasympathetic nervous activity. Forty patients were randomly allocated to the propofol group and the midazolam-propofol group, and the parameters described above were calculated at baseline (T1), post induction (T2), after tracheal intubation (T3), and 3 min (T4) and 5 min after intubation (T5). Propofol was administered at 2.5 mg.kg )1 in the propofol group and midazolam at 0.1 mg.kg )1 followed by propofol at 1.5 mg.kg )1 in the midazolam-propofol group for anaesthesia induction. Then, propofol was administered at 4-6 mg.kg )1 propofol for maintenance in both groups. The midazolam-propofol group showed compensated haemodynamic changes, which were related to significant increases in the LF ⁄ HF ratio at T2, T4 and T5 (p = 0.011, 0.038 and 0.034). These results suggest that the midazolam-propofol combination yielded compensated modulatory effects on the cardiovascular system, including preserved baroreflex activity. Combined induction (co-induction) refers to the administration of a small dose of a sedative or anaesthetic agent prior to the induction of anaesthesia, with the aim of achieving more specific 'target' responses, while minimising side-effects. Co-induction with midazolam and propofol has been mainly studied in relation to the drugs' synergistic hypnotic actions of the drugs and haemodynamic changes [1-4] during induction of anaesthesia, but there are no reports to date of the haemodynamic changes occurring during tracheal intubation. Propofol decreases the arterial blood pressure, associated with a decrease of the cardiac output ⁄ index, stroke volume index, and systemic vascular resistance [5]; on the other hand, the cardiac output ⁄ index and ventricular filling pressures are maintained after the administration of midazolam [5,6]. The autonomic nervous system exerts important neural control on the heart for maintaining cardiovascular stability. Previous studies have evaluated the effects of propofol [7][8][9][10] and midazolam [11][12][13] on the cardiac autonomic nervous system by means of heart rate variability (HRV) analysis, a non-invasive technique [14][15][16]. There are, however, no reports on simultaneous analysis of the changes of the stroke volume and HRV during midazolam-propofol co-induction. The aim of this study was to investigate the haemodynamic changes and heart rate variability during midazolam co-induction with propofol as comp...

Dexmedetomidine (DEX) has a minimal respiratory depressive effect, which is beneficial for dentistry; however, it has the disadvantage of permitting an intraoperative arousal response such that the patient appears to be suddenly no longer sedated, and it has a variable amnestic effect. Since midazolam (MDZ) in an appropriate dose has a profound amnesic effect, we investigated whether additional MDZ compensates for the disadvantage of DEX and enables a better quality of sedation. Forty-three subjects were randomly divided into 4 groups. In group 1, MDZ (0.02 mg/kg) was administered intravenously, followed by a dose of 0.01 mg/kg every 45 minutes. After the first dose of MDZ, preloading with DEX (2 µg/kg/h for 10 minutes) was started and maintained with a dosage of 0.5 µg/kg/h. In group 2, MDZ was infused in the same manner as in group 1, followed by preloading with DEX (1 µg/kg/h for 10 minutes) and maintenance (0.3 µg/kg/h). In group 3, MDZ was infused 0.03 mg/kg, and a dose of 0.01 mg/kg was given every 30 minutes; DEX was administered at the same as in group 2. In group 4, DEX was infused using the same method as in group 1 without MDZ. The sedation levels, amnesia, and patient satisfaction were also investigated. Group 2 had a lower sedation level and a poor evaluation during the first half of the operation. Group 4 did not exhibit an amnesic effect at the beginning of the operation. An evaluation of the degree of patient satisfaction did not reveal any differences among the groups. Optimal sedation was achieved through the combined use of MDZ (0.02 mg/kg with the addition of 0.01 mg/kg every 45 minutes) and DEX (2 µg/kg/h for 10 minutes followed by 0.5 µg/kg/h).

Norepinephrine modulates synaptic plasticity in various brain regions and is implicated in memory formation, consolidation and retrieval. The cerebellum is involved in motor learning, and adaptations of the vestibulo-ocular reflex (VOR) and optokinetic response (OKR) have been studied as models of cerebellum-dependent motor learning. Previous studies showed the involvement of adrenergic systems in the regulation of VOR, OKR and cerebellar synaptic functions. Here, we show differential contributions of β- and α2-adrenergic receptors in the mouse cerebellar flocculus to VOR and OKR control. Effects of application of β- or α2-adrenergic agonist or antagonist into the flocculus suggest that the β-adrenergic receptor activity maintains the VOR gain at high levels and contributes to adaptation of OKR, and that α2-adrenergic receptor counteracts the β-receptor activity in VOR and OKR control. We also examined effects of norepinephrine application, and the results suggest that norepinephrine regulates VOR and OKR through β-adrenergic receptor at low concentrations and through α2-receptor at high concentrations.