6,963 publications from this institution
Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced Superoxide anion (O2−) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10−3 M) inhibited O2− release by 27.6 ± 9.4% (mean ± SEM, p < 0.05), whereas at clinically relevant concentrations (10−6 and 10−5 M), it significantly potentiated this by 26.8 ± 9.9% (p < 0.05) and 36.9 ± 6.3% (p < 0.01), respectively. 8-phenyltheophylline (10−7 to 10−3 M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2− release by 72.4 ± 15.2% (p < 0.01), whereas addition of adenosine (3 × 10−8 to 10−6 M) reversed the potentiation induced by theophylline (10−5 M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2− release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.
Exogenous and endogenous tachykinins facilitate cholinergic nerve‐induced bronchoconstriction in guinea‐pig. Using a vagally innervated guinea‐pig tracheal tube preparation we have investigated the involvement of endogenous capsaicin‐sensitive neuropeptides in both pre‐ and postganglionic cholinergic neurotransmission. The effects of the neutral endopeptidase inhibitor (NEP), phosphoramidon, were investigated in this preparation either alone or in conjunction with sensory neuropeptide depletion by capsaicin pretreatment. The subtype of neurokinin receptor mediating this facilitatory effect of tachykinins has also been examined, by the use of selective tachykinin receptor agonists and a selective NK 1 receptor antagonist. Cholinergic contractions of the sealed Krebs filled tracheal tube preparation were recorded as increases in intraluminal pressure and were induced either by (i) pre‐ganglionic vagus nerve stimulation (PGS), (ii) stimulation of postganglionic intramural nerves via transmural stimulating electrodes (TMS) in the presence of ganglion‐blocking concentrations of hexamethonium and (iii) application of exogenous acetylcholine (ACh). The effect of phosphoramidon, which inhibits the breakdown of tachykinins, was investigated on ACh‐, PGS‐ and TMS‐induced contractions. Phosphoramidon (1–10 μ m ) facilitated contractions of the trachea induced by PGS, in a concentration‐dependent manner, but had no effect on contractions of the trachea induced either by TMS or exogenous ACh. The facilitatory effect of phosphoramidon (10 μ m ) on PGS‐induced contractions was abolished by pretreating guinea‐pigs with capsaicin 7 ± 2 days before the in vitro experiments. Capsaicin pretreatment did not significantly alter responses to the spasmogens, ACh or substance P. Depletion of sensory neuropeptides, by capsaicin pretreatment was confirmed by the lack of response to capsaicin (1 μ m ) in vitro . The facilitatory effect of phosphoramidon (10 μ m ) on PGS‐induced contractions was inhibited by the selective NK 1 receptor antagonist, GR71251 (1 μ m ). When applied to the tissues during nerve stimulation, GR71251 caused a small, but significant, inhibition of PGS‐induced contractions during low frequency stimulation. No significant effect of GR71251 on TMS‐induced contractions was seen at any frequency. There was no significant effect of the NK 1 receptor antagonist on contractions of the trachea induced by exogenous ACh. The selective NK 1 receptor agonist, GR73632 facilitated contractions of the trachea induced by stimulation of both pre‐ and postganglionic cholinergic nerves, in a concentration‐dependent manner, at concentrations that had no significant effect on basal tone (0.01–0.3 n m ). The facilitatory effect of GR73632 on both PGS‐ and TMS‐induced contractions was antagonized by GR71251 (1 μ m ). In contrast, neurokinin A (1–10 n m ), which preferentially stimulates NK 2 receptors, facilitated contractions induced by both PGS and TMS, and caused a significant increase in basal tone of the trachea. The selective NK 3 receptor agonist, senktide (30–300 m m ), had no significant effect on nerve‐induced contractions or basal tone of the trachea. These results suggest that there is release of endogenous tachykinins during vagus nerve stimulation, which can be depleted by capsaicin pretreatment and, which facilitate cholinergic nerve‐induced contractions at the level of the parasympathetic ganglia. Facilitatory tachykinin receptors on the postganglionic nerve terminals can be demonstrated by exogenous agonists but do not appear to be activated by endogenous tachykinins under the stimulation conditions of these studies. These data suggest that NK 1 receptors may be involved in mediating this facilitatory response to tachykinins but do not exclude an involvement of NK 2 receptors. It appears unlikely, however, that NK 3 receptors are involved.
The critical buckling characteristics of hydrostatically pressurized complete spherical shells filled with an elastic medium are presented. A model based on small deflection thin shell theory, the equations of which are solved using exact methods in conjunction with variational principles, is presented. In the current formulation, axisymmetric and inextensional assumptions are not used initially and the elastic medium is modelled as a Winkler foundation, i.e.using uncoupled radial springs with a constant foundation modulus that is independent of wave numbers of shell buckling modes. Critical buckling pressures and characteristic modal shapes are demonstrated for a wide range of material and geometric parameters. A phase diagram is established to obtain the requisite thickness to radius, and stiffness ratios for a desired mode profile. The present formulation can be readily extended to apply to more general cases of non-axisymmetric buckling problems.
A fiberoptic pressure sensor mounted on an 0.018-inch guidewire (Pressure Guide) was used to measure the transstenotic pressure gradient in 30 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with lesions considered suitable for quantitative coronary angiographic (QCA) assessment. The aim of the study was to correlate pressure gradients with parameters obtained with QCA. After intracoronary injection of 125 μg of nitroglycerin, multiple angiographic views were taken of the lesion. The Pressure Guide fiberoptic sensor was then positioned distal to the stenosis and the pressure gradients were recorded before and after PTCA. There was a significant correlation between mean pressure gradients (ΔP) and percent diameter stenosis (r = 0.73; p < 0.001) and absolute stenosis diameter (r = − 0.67; p < 0.001) and with percent area stenosis (r = 0.69; p < 0.001) and absolute stenosis area (r = −0.63; p < 0.001). The closest relationship, though, was found with stenotic flow reserve (SFR), which is an integrated parameter calculated from QCA. This relationship can be described by the equation: ΔP = 65.2 – 12.6·SFR (r = −0.79; p < 0.001). With a measured gradient of >15 mm Hg, the sensitivity was 94% and the specificity 96% to predict an SFR <3.5. In conclusion, a statistically significant relationship could be found between stenosis pressure gradients and angiographic parameters in this study with lesions without complicated morphology. The independent information obtained by pressure gradient measurement may be of particular value in intermediately severe lesions or in stenoses where the angiographic assessment otherwise is difficult.
Many neuropeptides have recently been identified in human and animal airways. These peptides, which may coexist with classical transmitters, have potent effects on airway calibre, blood vessels and secretions, raising the possibility that they may be involved in airway diseases such as asthma. Vasoactive intestinal peptide and peptide histidine methionine have potent relaxant effects on both vascular and bronchial smooth muscle, and may be neurotransmitters of non-cholinergic vasodilatation and non-adrenergic bronchodilation. Several neuropeptides which are found in sensory nerves, such as substance P, neurokinin A and calcitonin gene-related peptide, have both direct inflammatory effects and influence inflammatory cells, and might also contribute to the pathology of asthma if released from sensory nerve endings by an axon reflex.
