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Biomedical subjects

B J Undem

Publications and source records attributed to B J Undem.

At least 19 recordsLinked to original sources
PubMed1995

Prevention of the excitatory actions of bradykinin by inhibition of PGI2 formation in nodose neurones of the guinea-pig.

1. Intracellular recordings were made from neurones in intact guinea-pig nodose ganglia in vitro and from acutely isolated adult guinea-pig and rabbit nodose neurons to study a bradykinin (BK)-mediated block of a slow spike after-hyperpolarization (AHPslow) that is prominent in 30-40% of these neurones. 2. BK (100 nM) reversibly blocked the AHPslow, resulting in an ablation of the spike accommodative properties of these neurones. The B1 BK receptor agonist [des-Arg9]-BK did not mimic or prevent the actions of BK. In contrast, the B2 BK receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (HOE 140) prevented BK-induced block of the AHPslow and the effect of BK on spike frequency adaptation. 3. The BK block of the AHPslow in acutely dissociated neurones was prevented by indomethacin, indicating that this BK effect was dependent upon a cyclo-oxygenase metabolite intrinsic to these neurones. 4. One to twenty femtomoles of the prostanoids PGE2, PGD2, 9 alpha, 11 beta-PGF2 (a metabolite of PGD2), PGF2 alpha, TxB2 and PGI2 were released spontaneously from a nodose ganglion in 15 min. BK (100 nM) selectively increased PGI2 release 2.8-fold without affecting the release of the other prostanoids. Treatment with 10 microM tranylcypromine (TCP), a putative PGI2 synthase inhibitor, completely prevented the BK-induced release of PGI2. 5. In the presence of 10 microM TCP, BK no longer produced significant effects on the AHPslow. In contrast, 10 microM TCP did not prevent PGI2 from blocking the AHPslow. 6. These results suggest that vagal afferents that exhibit AHPslow also possess the B2 type of BK receptor. Activation of these BK receptors results in the production of PGI2, which in turn controls spike frequency adaptation by affecting the amplitude of the AHPslow.

Animals↗
PubMed1995

Cysteinyl leukotrienes in asthma: old mediators up to new tricks.

The cysteinyl leukotrienes have long been suspected to play a role in the pathogenesis of asthma. This speculation was based largely on their release in human lung following antigen challenge as well as their potent bronchoconstrictor activity. However, there is increasing evidence that the cysteinyl leukotrienes also produce several pro-inflammatory effects and alter the activity of neuronal pathways in the airways. Douglas Hay, Theodore Torphy and Bradley Undem review these recent data and discuss the therapeutic possibilities of cysteinyl leukotriene receptor antagonists and 5-lipoxygenase inhibitors.

Animals↗
PubMed1995

Antigen depolarizes guinea pig bronchial parasympathetic ganglion neurons by activation of histamine H1 receptors.

Studies were carried out to evaluate the mechanism by which neurotransmission through airway parasympathetic ganglia may be modulated during immediate hypersensitivity reactions. Guinea pigs were passively sensitized by injection of guinea pig serum containing high-titer anti-ovalbumin antibodies. Intracellular recordings were obtained from intrinsic parasympathetic ganglion neurons from the right mainstem bronchus in vitro. Ovalbumin (10 micrograms/ml) elicited a membrane potential depolarization and changes in membrane resistance in bronchial ganglion neurons from passively sensitized guinea pigs. Histamine mimicked the depolarizing effect of ovalbumin in a concentration-dependent manner (0.1-10 microM) and caused a transient increase and decrease in membrane resistance. Pyrilamine, a histamine H1-receptor antagonist, inhibited the histamine-induced membrane depolarization and decrease in resistance. By contrast, blocking histamine H2 and H3 receptors did not inhibit histamine-induced depolarization. Pyrilamine also reduced the antigen-induced depolarization of ganglion neurons, demonstrating a role for histamine H1 receptors in this response. The data provide evidence that the antigen-induced depolarization of airway ganglion neurons is secondary to an antigen-antibody interaction on intrinsic mast cells and the consequential effect of histamine on H1 receptors. These studies demonstrate that histamine released during an immediate hypersensitivity reaction has direct effects on airway parasympathetic nerves.

Animals↗
PubMed1995

Antigen-induced long-term potentiation of nicotinic synaptic transmission in the superior cervical ganglion of the guinea pig.

1. Recordings of evoked postganglionic compound action potentials (CAPs) evoked by preganglionic stimulation were obtained from guinea pig superior cervical ganglia (SCGs) in vitro to study the effects of specific antigen challenge on ganglionic synaptic transmission. SCGs were removed from guinea pigs actively sensitized to ovalbumin. 2. Exposing SCGs from sensitized animals to the sensitizing antigen (0.01-10 micrograms/ml) for 5 min produced a sustained increase in the magnitude of the evoked CAP unaccompanied by a change in the preganglionic volley. Nonsensitizing antigens were ineffective. Also ineffective were antigens applied to nonsensitized SCG. This persistent antigen-induced increase in synaptic transmission was designated antigen-induced long-term potentiation (LTP) (A-LTP) because its duration (> 30 min) greatly outlasted posttetanic potentiation (PTP) in this ganglion. 3. A-LTP and neurogenic LTP (N-LTP) were observed to coexist in the same ganglion; the presence of one form of synaptic plasticity did not preclude the development of the other. Both phenomena were influenced by presynaptic factors: prolonged (2 h, 40 Hz) repetitive presynaptic stimulation abolished A-LTP or N-LTP but did not affect PTP. 4. By contrast to N-LTP, which requires a brief presynaptic tetanus, A-LTP could be triggered over a wide range of presynaptic stimulation (0.016-3 Hz) or even in the absence of presynaptic stimulation. 5. The amplitude and duration of A-LTP were not significantly affected by 1) H1, H2, or H3 histamine receptor antagonists added before or after antigen challenge; 2) the presence of saturating concentrations of histamine (100-300 microM); 3) the presence of specific or nonspecific lipoxygenase inhibitors or a selective cyclooxygenase inhibitor; or 4) blockade of alpha- or beta-adrenergic receptors, 5-HT3 receptors, muscarinic receptors, or glutamate receptors, or inhibition of acetylcholinesterase or protein synthesis. 6. Our results indicate that specific antigen challenge of isolated sympathetic ganglia activates resident mast cells to release substances that initiate a novel form of synaptic plasticity, an activity-independent and long-lasting increase in synaptic efficacy.

Animals↗
PubMed1995

Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity.

We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.

Animals↗
PubMed1994

Evidence that antidromically stimulated vagal afferents activate inhibitory neurones innervating guinea-pig trachealis.

1. We recently described a capsaicin-sensitive vagal pathway mediating non-adrenergic, non-cholinergic (NANC) relaxations of an isolated, innervated rostral guinea-pig tracheal preparation. These afferent fibres are carried by the superior laryngeal nerves and relaxations elicited by their activation are insensitive to autonomic ganglion blockers such as hexamethonium. In the present study this vagal relaxant pathway was further characterized. 2. Relaxations of the trachealis elicited by electrical stimulation of capsaicin-sensitive vagal afferents were mimicked by bath application of capsaicin. Relaxations elicited by both methods were abolished when the tissue between the trachea and the adjacent oesophagus was disrupted. Indeed, separating the trachea from the oesophagus uncovered a contractile effect of capsaicin administration on the trachealis. 3. Capsaicin-induced, oesophagus-dependent relaxations of the trachealis were blocked by pretreatment with the fast sodium channel blocker tetrodotoxin (TTX). By contrast, capsaicin-induced contractions of the trachealis (obtained in the absence of the oesophagus) were unaffected by tetrodotoxin. 4. Substance P, neurokinin A (NKA) and neurokinin B (NKB) also elicited NANC relaxations of precontracted trachealis that were abolished by separating the trachea from the oesophagus or by TTX pretreatment. Like capsaicin, the tachykinins elicited only contractions of the trachealis following TTX pretreatment or separation of the trachea from the adjacent oesophagus. 5. Relaxations elicited by stimulation of the capsaicin-sensitive nerves were unaffected by a concentration of the tachykinin NK2 receptor-selective antagonist, SR 48968, that is selective for NK2 receptor blockade and were not mimicked by the NK2 receptor-selective agonist [beta-Ala8]-NKA(4-10). This suggests that NK2 receptors are not responsible for these relaxations. By contrast, the NK3 receptor-selective agonist, senktide analogue, and the NK1 receptor-selective agonist, acetyl-[Arg6, Sar9, Met (O2)11]-SP(6-11), elicited oesophagus-dependent relaxations of the trachealis that were abolished by oesophagus removal. Furthermore, pretreatment with the NK1-selective antagonists, CP 96345 and CP 99994, or pretreatment with a concentration of SR 48968 that also blocks NK3 receptors, markedly attenuated relaxations elicited by stimulation of the capsaicin-sensitive vagal pathways. 6. The data are consistent with the hypothesis that relaxations elicited by stimulation of capsaicin-sensitive vagal afferents involve tachykinin-mediated activation of peripheral NANC inhibitory neurones that are in some way associated with the oesophagus. The data also indicate that airway smooth muscle tone might be regulated by peripheral reflexes initiated by activation of capsaicin-sensitive afferent fibres.

Animals↗
PubMed1994

Modulation of antigen- and mitogen-induced proliferative responses of peripheral blood mononuclear cells by nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors.

Cyclic nucleotide phosphodiesterase (PDE) enzymes are felt to play a role in the regulation of inflammatory responses through their effects on cAMP. In this study, we investigated the effects of nonselective and isozyme selective PDE inhibitors on the proliferative responses of peripheral blood mononuclear cells (PBMCs) to ragweed (RW, a Th2 stimulus), tetanus toxoid (TT, a Th1 stimulus), and phytohemagglutinin in ragweed-allergic patients. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) produced nearly identical concentration-dependent inhibition for PBMCs cultured with either Ag (RW and TT) or mitogen (phytohemagglutinin). Neither the type V inhibitor, zaprinast, nor the type III inhibitor, siguazodan, was effective at inhibiting antigen- or mitogen-driven proliferative responses of human PBMCs. The type IV inhibitor, rolipram, was unique in its ability to inhibit the RW-driven proliferative response and, to a lesser extent, the TT-driven proliferative response. However, rolipram was ineffective at inhibiting the mitogen-driven proliferative response. Only with a combination of type III and type IV inhibitors could the efficacy on the TT response be made to approximate that of the type IV inhibitor alone in the RW-driven system. Although the efficacies of IBMX and rolipram were identical in the RW-driven system, the IC50 value of the latter was 10-fold lower, similar to the difference noted in the TT-driven system between IBMX alone and the combination of rolipram with siguazodan. Dose-response curves generated by using the D- or L-isomers of rolipram were not appreciably different from each other or from the curve generated with racemic rolipram. The addition of supraphysiologic doses of human rIL-2 and rIL-4 was unable to counteract the inhibitory effect of IBMX or rolipram. These data support the hypothesis that modulation of proliferation of PBMCs by selective PDE inhibitors varies in sensitivity with the type of stimulus used, and that the type IV PDE exerts the predominant cAMP-associated regulatory effect on allergen-driven proliferation. Finally, the inhibitory effect induced by rolipram is independent of its stereochemistry and cannot be exclusively attributed to deficits in IL-2 or IL-4.

Allergens↗
PubMed1994

Neural-immunologic interactions in asthma.

Recent investigations offer insights into the possible cause of asthma: Rather than being due to either neural or immunologic events, the fault may lie in concurrent malfunctioning of two interacting systems. Antigenic stimulation, for example, can affect neural depolarization and firing; by the same token, nerve stimulation can affect the growth and function of inflammatory cells.

Animals↗
PubMed1994

Differential release of prostaglandins and leukotrienes by sensitized guinea pig urinary bladder layers upon antigen challenge.

The relative contributions of mucosal/submucosal and detrusor layers to the release of inflammatory mediators were investigated in isolated, ovalbumin (OVA) sensitized guinea pig urinary bladders. Ovalbumin challenge of sensitized mucosa induced release of prostaglandins (PG): PGE2, PGD2 and PGF2 alpha, in that order of magnitude. The total release of PGs was significantly higher from the mucosa/submucosa than from the detrusor/serosa. Under the same conditions, net release of leukotriene (LT) was observed predominantly from the detrusor. The total amount of histamine released from the mucosa was greater than that from the muscle layer. These results indicate differential production and release of inflammatory mediators from the mucosal/submucosal and detrusor smooth muscle layers. These results may have serious implications in disorders, such as interstitial cystitis, involving bladder mucosal damage. The cytoprotective effect of PGE2 is likely to be lost when the mucosa is damaged, and LT release from deeper layers may contribute significantly to symptoms of bladder inflammation.

Animals↗
PubMed1994

Immunological aspects of allergic asthma.

Asthma is a chronic obstructive disease of the lower airways. It is characterized by episodic exacerbations of at least partially reversible airflow limitation, along with bronchial hyperreactivity and airway inflammation. This latter characteristic, airway inflammation, is now a major focus of investigation, in large part because of a growing body of evidence to support its critical role in the pathogenesis of this disorder. Investigations of the histopathologic, cytologic, and chemical events accompanying fatal and nonfatal asthma, as well as experimental allergen-induced allergic reactions of the lower airways, have confirmed that a wide variety of immunologic phenomena occur, including local release of preformed mediators, newly synthesized metabolites of arachidonic acid, and soluble pro-inflammatory proteins including kinins and cytokines; alterations in vascular permeability and the development of airways edema; leukocyte activation and accumulation; and immune-mediated neurogenic responses that affect airway smooth muscle and other local responses. This information has led to new pharmacologic approaches designed to antagonize each of these elements of the asthmatic diathesis, with varying degrees of success. Nevertheless, the development of novel antagonists of mediators, pro-inflammatory proteins, cells, adhesion molecules, neuropeptides, and their respective receptors have begun to yield additional insight into their relative importance in the immunologic basis of asthma.

Asthma↗
PubMed1994

Endogenous vasodilators modulate pulmonary vascular anaphylaxis.

We examined the role of endothelium-derived nitric oxide during antigen-induced contraction in pulmonary arteries isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml)-induced contraction was not sustained, and tension returned to baseline within 15 min. Pretreatment with methylene blue (10(-5) M) increased both the amplitude and the duration of the contractile response in these tissues. At 15 min, tension remained elevated and was > 70% of the peak amplitude. Removal of the endothelium with saponin (200 micrograms/ml) increased the magnitude of the contraction by > 125%; however, the duration of the response was unaffected. After pretreatment with saponin, methylene blue no longer increased the amplitude of antigen-induced contraction but its effect on the duration was unchanged. Pretreatment with nitro-L-arginine methyl ester significantly increased the magnitude of the contraction in each of the tissues. These results suggest that the response of guinea pig pulmonary arteries to antigen is modulated by two types of endogenous vasodilators, endothelium-derived nitric oxide that inhibits the initial phase of the response and an endothelium-independent relaxing factor that is guanosine 3',5'-cyclic monophosphate dependent and attenuates the duration of anaphylactic contraction.

Anaphylaxis↗
PubMed1994

Role of cysteinyl-leukotrienes and histamine in mediating intrinsic tone in isolated human bronchi.

The intrinsic isometric tone of human isolated intralobar bronchi was evaluated in vitro. Human bronchi (inner diameter, 3 to 12 mm) were obtained from patients undergoing lung resection and from organ donors. The organ donor tissue was studied approximately 24 h after resection, during which time it was shipped to the laboratory in RPMI 1640 medium at 4 degrees C. The bronchi obtained from patients with cancer was placed in the same medium and studied within 4 h of resection. All tissues were suspended in 10-ml organ baths containing oxygenated Krebs' solution at 37 degrees C, at an initial load of 2 g. Tissues were washed every 15 min until they exhibited a stable tension (usually 60 min). Under these conditions the amount of active tension in the bronchi studied on the day of resection averaged 65 +/- 9% of the maximal response to BaCl2 (30 mM), whereas after overnight incubation it averaged 31 +/- 6%. Neither indomethacin nor atropine influenced the intrinsic tone in these tissues. By contrast, the LTD4 antagonists SKF 104353 and ICI 198615 and the histamine H-1 antagonists pyrilamine and chlorpheniramine effectively relaxed the bronchi. The 5' lipoxygenase inhibitor zileuton also produced a small fall in tension. Studies in which pyrilamine was combined with the leukotriene receptor antagonists indicated an additive effect. These results indicate that human bronchial smooth muscle exhibits a high degree of intrinsic tone, averaging more than 50% of available tone in fresh tissues studied in vitro under isometric conditions. The results suggest that this tone is due to the continual production and release of histamine and cysteinyl-leukotrienes.

Bronchi↗
PubMed1994

Ragweed antigen E and anti-IgE in human central versus peripheral isolated bronchi.

The ability of antigen to contract passively sensitized tissues was examined in human central (5 to 12 mm) and peripheral (0.5 to 2 mm) bronchi. Both central and peripheral bronchi contracted to ragweed antigen E (RW AgE), and these contractions were virtually abolished by a combination of indomethacin, cysteinyl-leukotriene, and histamine antagonists. There were, however, quantitative differences in contractile responses and in mediator release to RW AgE between central and peripheral bronchi. RW AgE was approximately 20-fold more potent in contracting peripheral bronchi compared with central bronchi. On a per weight of tissue basis, RW AgE released six-fold more histamine, 15- to 20-fold more immunoreactive leukotriene D4 (i-LTD4) and two- to 10-fold more prostanoids in the peripheral bronchi compared with central bronchi. Anti-IgE mimicked the effect of RW AgE with respect to inflammatory mediator release and with respect to the magnitude of the contractile response in peripheral and central bronchi. Anti-IgE, however, was more potent in contracting central than peripheral bronchi. Moreover, in peripheral bronchi, contractile responses to anti-IgE were only partially inhibited by a combination of indomethacin, cysteinyl-leukotriene, and histamine antagonists. These results indicate that the qualitative characteristics of antigen-induced mediator release and muscle contraction are similar in central versus peripheral bronchi. However, RW AgE is much more potent in causing smooth muscle constriction, and is capable of releasing a greater quantity of inflammatory mediators in peripheral bronchi/bronchioles than in the more central bronchi.

Adult↗
PubMed1994

Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes.

Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.

Atropine↗
PubMed1994

Recombinant stem cell factor-induced mast cell activation and smooth muscle contraction in human bronchi.

The effect of human recombinant stem cell factor (SCF) on inflammatory mediator release and smooth muscle contraction was evaluated in human isolated intralobar bronchi. Bronchi from 21 of 26 donors contracted in response to SCF. The threshold concentration was approximately 0.01 micrograms/ml. At 1 micrograms/ml, the tissues contracted to about 60% of the carbamylcholine-induced maximum contraction. The responses to SCF mimicked those obtained with anti-IgE. Thus, the contractions to SCF and anti-IgE were inhibited to a similar extent by a combination of a cysteinyl-leukotriene receptor antagonist and a histamine H1 receptor antagonist. SCF also mimicked the effect of anti-IgE in releasing histamine, i-LTD4, and PGD2 from the bronchi. At a threshold concentration for contraction (0.01 micrograms/ml), SCF had no effect on subsequent responses to anti-IgE in the bronchi. The data suggest that human recombinant SCF contracts airway smooth muscle by stimulating the release of contractile mediators from bronchial mast cells. The data fail to support the hypothesis that SCF primes bronchial mast cells to subsequent immunologic stimuli.

Antibodies, Anti-Idiotypic↗
PubMed1994

Release of inflammatory mediators from guinea pig trachea by electrical field stimulation: lack of neuronal involvement.

Electrical field stimulation (EFS; 5-10 V, 1 ms, 20 Hz for 1 min) of isolated guinea pig trachea resulted in a rapid increase in tone that is blocked by either atropine or tetrodotoxin (TTX). EFS of tracheal spirals also caused large increases in the release of certain prostanoids with release of prostaglandin (PG)D2, PGE2 and PGF2 alpha (16.5-, 3.0- and 4.1-fold, respectively). In contrast to the smooth muscle response, however, EFS-induced release of prostanoids was not significantly altered in the presence of TTX. Removal of the epithelium reduced the amount of prostanoids released by EFS. Thus, EFS-induced production of PGD2, PGE2 and PGF2 alpha was significantly reduced by about 30%, 70% and 80% in epithelium-denuded tissues, respectively. Direct vagal stimulation caused a rapid contraction of the trachealis but failed to elicit increases in the release of histamine or arachidonic acid metabolites. Furthermore, the selective stimulant of C-type sensory fibers capsaicin (3 microM) or exogenously applied substance P (1 microM) or neurokinin A (1 microM) failed to induce histamine, leukotriene or prostanoid release from guinea pig tracheal rings. Although, the mechanism involved in stimulation of arachidonic acid metabolism by EFS is unclear, this effect in part involves the epithelium but apparently is not mediated by airway elements sensitive to TTX, direct vagal stimulation or tachykinins.

Animals↗
PubMed1994

Inhibition of neurally mediated nonadrenergic, noncholinergic contractions of guinea pig bronchus by isozyme-selective phosphodiesterase inhibitors.

We studied the effect of inhibiting phosphodiesterase (PDE) isozyme types III, IV and V on the cholinergic and noncholinergic (tachykinergic) contractile responses to electrical field stimulation (EFS) in the guinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a slight (approximately 30%) but significant inhibitory effect on the noncholinergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramatically inhibited the noncholinergic contractions by nearly 70%. The EC50 for rolipram was approximately 20 nM. Rolipram (1 microM) had no effect on contractions elicited by either capsaicin or neurokinin A. EFS, but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by rolipram. Rolipram had the same inhibitory effect on EFS- and vagus nerve stimulation-induced noncholinergic contractions. The effect of rolipram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition of PDE V with zaprinast (3 microM) had no effect on the tachykinergic contractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due to stimulation of tachykinergic fibers is significantly reduced by selective inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of the smooth muscle. It is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin release from capsaicin-sensitive fibers in the guinea pig bronchus.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗