Neurotrophins [e.g., brain-derived neurotrophic factor (BDNF), neurotrophin 4 (NT4)], known to affect neuronal structure and function, are expressed in nonneuronal tissues including the airway. However, their function is unclear. We examined the effect of acute vs. prolonged neurotrophin exposure on regulation of airway smooth muscle (ASM) intracellular Ca(2+) concentration ([Ca(2+)](i)): sarcoplasmic reticulum (SR) Ca(2+) release and Ca(2+) influx (specifically store-operated Ca(2+) entry, SOCE). Human ASM cells were incubated for 30 min in medium (control) or 1 or 10 nM BDNF, NT3, or NT4 (acute exposure) or overnight in 1 nM BDNF, NT3, or NT4 (prolonged exposure) and imaged after loading with the Ca(2+) indicator fura-2 AM. [Ca(2+)](i) responses to ACh, histamine, bradykinin, and caffeine and SOCE following SR Ca(2+) depletion were compared across cell groups. Force measurements were performed in human bronchial strips exposed to neurotrophins. Basal [Ca(2+)](i), peak responses to all agonists, SOCE, and force responses to ACh and histamine were all significantly enhanced by both acute and prolonged BDNF exposure (smaller effect of NT4) but decreased by NT3. Inhibition of the BDNF/NT4 receptor trkB by K252a prevented enhancement of [Ca(2+)](i) responses. ASM cells showed positive immunostaining for BDNF, NT3, NT4, trkB, and trkC (NT3 receptor). These novel data demonstrate that neurotrophins influence ASM [Ca(2+)](i) and force regulation and suggest a potential role for neurotrophins in airway diseases.

([Ca 2ϩ ]o), nifedipine, and KCl (preventing Ca 2ϩ influx through L-type and SOCC channels). SOCC was then activated by reintroduction of [Ca 2ϩ ]o and characterized by several techniques. We examined cAMP effects on SOCC by activating SOCC in the presence of 1 M isoproterenol or 100 M dibutryl cAMP (cell-permeant cAMP analog), whereas we examined cGMP effects using 1,2-diolate (DETA-NO nitric oxide donor) or 100 M 8-bromoguanosine 3',5'-cyclic monophosphate (cell-permeant cGMP analog). The role of protein kinases A and G was examined by preexposure to 100 nM KT-5720 and 500 nM KT-5823, respectively. SOCC-mediated Ca 2ϩ influx was dependent on the extent of SR Ca 2ϩ depletion, sensitive to Ni 2ϩ and La 3ϩ , but not inhibitors of voltage-gated influx channels. cAMP as well as cGMP potently inhibited Ca 2ϩ influx, predominantly via their respective protein kinases. Additionally, cAMP cross-activation of protein kinase G contributed to SOCC inhibition. These data demonstrate that a Ni 2ϩ /La 3ϩ -sensitive Ca 2ϩ influx in ASM triggered by SR Ca 2ϩ depletion is inhibited by cAMP and cGMP via a protein kinase mechanism. Such inhibition may play a role in the bronchodilatory response of ASM to clinically relevant drugs (e.g., ␤-agonists vs. nitric oxide).capacitative calcium entry; trachea; adenosine 3Ј,5Ј-cyclic monophosphate; guanosine 3Ј,5Ј-cyclic monophosphate; nitric oxide; isoproterenol AIRWAY SMOOTH MUSCLE (ASM) tone represents a balance between bronchoconstriction and bronchodilation. The goal of clinical therapy for pathophysiological states such as asthma, allergy, and inflammation is to prevent excessive bronchoconstriction, both in the acute and chronic setting, and to restore a balance by producing bronchodilation. Cytosolic (intracellular) Ca 2ϩ concentration ([Ca 2ϩ ] i ) is a key determinant of ASM tone (12,23,33 The cyclic nucleotides cyclic adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) and cyclic guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) mediate the effects of a variety of endogenous substances as well as clinically relevant drugs, e.g., ␤ 2 -agonists and nitric oxide (NO), used to produce relaxation of ASM (13,25,28). Cyclic nucleotide effects are mediated in part by downregulation of mechanisms that would normally elevate [Ca 2ϩ ] i in ASM. Previously, we demonstrated that salbutamol, a ␤ 2 -agonist (28), as well as NO donors (26) inhibit ACh-induced [Ca 2ϩ ] i oscillations in ASM that occur via repetitive SR Ca 2ϩ release and reuptake. Both cAMP and cGMP also influence the plasma membrane via membrane hyperpolarization (9, 15) and inhibition of Ca 2ϩ influx via L-type Ca 2ϩ channels (16,17). Given the relative novelty but somewhat ubiquitous expression of SOCC, there is currently limited and sometimes inconsistent data on cyclic nucleotide modulation of Ca 2ϩ influx via this mechanism in tissues other than ASM. In rat aorta, cAMP inhibits SOCC (34) but enhances it in astrocytes (37). We hypothesize that cyclic nucleotides inhibit SOCC, preventing [Ca 2ϩ ] i elevation as well as S...

These data indicate that volatile anesthetics prevent sarcoplasmic reticulum refilling by inhibiting SOCE and enhancing cyclic nucleotide blunting of Ca influx in ASM. Such interactions likely result in substantial airway relaxation in the presence of both anesthetics and bronchodilatory agents such as beta agonists or nitric oxide.

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There was no significant gender difference in the proportion of DES implantation versus BMS for AMI in contemporary years. Women treated with either BMS or DES for AMI had higher in-hospital death than men.