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PubMed1990

Occupational challenge studies with laboratory workers allergic to rats.

To relate airborne Rat N I concentrations to airway responses in allergic laboratory workers, we collected allergen on personal monitors while workers and control subjects were exposed in a rat vivarium for 1 hour. Allergen concentrations ranged from less than 1.5 to 310 ng/m3 and were significantly (p less than 0.001) higher during cage cleaning (19 to 310 ng/m3) than during quiet activity (less than 1.5 to 9.7 ng/m3). Among 12 rat-allergic volunteers, all had a nasal response during the exposure with an increase in nasal lavage histamine concentrations or TAME-esterase activity, but only five volunteers had a lower respiratory tract response (fall in FEV1 greater than 10%). Two of five allergic control subjects had a small change in nasal TAME-esterase activity, and none had a 10% fall in FEV1. A dose response was demonstrated between the allergen concentrations and the intensity of the nasal allergic response. This occupational challenge procedure thus was able to measure the nasal and lower respiratory tract response to airborne allergen exposure in a work environment. It can be used to define further the determinants of this response.

Adolescent↗
PubMed1987

Elevated mononuclear leukocyte phosphodiesterase in allergic dogs with and without airway hyperresponsiveness.

To investigate if mononuclear leukocyte beta-adrenergic hyporesponsiveness of Basenji greyhound (BG) dogs is associated with atopy or nonspecific airway hyperresponsiveness, we examined the relationship between mononuclear leukocyte cAMP phosphodiesterase levels, airway responsiveness to methacholine, and intradermal allergen responses in 17 BG dogs, five unrelated purebred Basenjis, and five greyhounds. BG dogs were hyperresponsive to aerosols of methacholine compared to Basenjis and greyhounds. Both BG dogs and Basenjis were allergic and had increased leukocyte cAMP phosphodiesterase activity compared to greyhounds. We concluded that the leukocyte abnormality is not associated with airway hyperresponsiveness. The leukocyte abnormality is either associated with the allergic state, with some hereditary trait that BG dogs acquired from the Basenji ancestry, or the leukocyte abnormality is necessary but not sufficient for the development of airway hyperresponsiveness.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma.

Airway inflammation is assumed to be an important determinant in increased bronchial responsiveness (BR). We tested the hypothesis that treatment with an inhaled anti-inflammatory drug (i.e., budesonide) but not with an inhaled beta-agonist (i.e., terbutaline) would reduce BR in children with asthma and with minimal or no bronchoconstriction. Twelve patients were treated with budesonide and seven with terbutaline for 6 months. BR decreased in 11 patients receiving budesonide and was significant in seven patients. BR decreased in none of the patients receiving terbutaline. FEV1 demonstrated a small increase with budesonide but remained unchanged with terbutaline. Except in one patient who received terbutaline, the clinical effect was good. We conclude that inhaled corticosteroids but not inhaled beta-agonists will decrease persistent BR in most children with asthma.

Administration, Inhalation↗
PubMed1987

Interpretation of the results of methacholine inhalation challenge tests.

Methacholine inhalation challenge studies are conventionally expressed as the provocative cumulative dose of methacholine that causes a 20% fall in FEV1 (PD20). This method is widely used and most suitable for expressing results for challenges in subjects with asthma. However, it is impossible to present results in this manner in other circumstances. Normal subjects and many subjects with allergic rhinitis do not have significant bronchial reactivity and will not reach a 20% fall during standard challenge protocols. This limitation precludes the use of this large population in the quantitative analysis necessary in epidemiologic, genetic, or drug studies. To compound this difficulty, a subset of patients with allergic rhinitis may demonstrate a 20% drop but have a subsequent plateau drop in FEV1. Expressing the results of their methacholine challenge with only a PD20 loses valuable information available in the test. We demonstrate that expressing results as the area beneath a dose-response curve provides useful parametric data on all studied subjects and distinguishes among subjects who might otherwise be classified as equivalent when results are expressed solely as a PD20.

Adolescent↗
PubMed1988

Iontophoretic study of skin vessel reactivity in atopic dermatitis and its correlation to serum IgE levels.

Skin vessel reactivity was studied by means of an iontophoretic technique in 19 adult patients with atopic dermatitis. Fifteen patients were available for reinvestigation some 6 months later in winter. Compared with a control group, we found a significantly increased sensitivity in summer of dermal skin vessels toward the alpha 1-agonist phenylephrine. Patients with elevated serum IgE levels seemed to be more sensitive to phenylephrine. However, the difference was not significant. Isoproterenol, the beta-adrenoceptor agonist, induced blanching (as opposed to erythema) in 7 of 19 (37%) atopic dermatitis patients in summer and in 9 of 15 (60%) in winter compared with 1 of 36 in the control groups. This blanching was antagonized by the alpha-blocker phentolamine. From the results we concluded that there may be an increased alpha-adrenoceptor reactivity and/or a decreased beta-adrenoceptor reactivity in atopic dermatitis patients, which might be a primary defect.

Adult↗
PubMed2004

Enhanced cutaneous vascular response in AD subjects under donepezil therapy.

OBJECTIVE: Abnormal cutaneous vasodilatory responses to the iontophoresis of vasodilators were previously observed in Alzheimer's disease (AD). We sought to replicate these observations and further identify peripheral vascular components of AD pathology. METHODS: Methacholine chloride (MCh), acetylcholine chloride (ACh), and sodium nitroprusside (SNP) were applied iontophoretically to forearm skin. Laser Doppler imaging of treated areas yielded total perfusion response values. RESULTS: Response to MCh was enhanced 78% ( P=0.003 ) in AD subjects under therapy with the acetylcholinesterase inhibitor (AChEI) donepezil ( N=9 ), relative to age- and sex-matched controls ( N=12 ). Significant increases in perfusion were also observed after application of ACh (68%, P=0.03 ) and SNP (46%, P=0.04 ). CONCLUSIONS: A previous study reported attenuated response to ACh in AD. Paradoxically, we observed a substantially enhanced response that is likely a consequence of donepezil therapy. The increased response to the endothelium-independent vasodilator SNP indicates improved general vasodilatory response, perhaps due to preservation of endogenous ACh by donepezil. Cerebral perfusion in response to functional activation may be improved in this way, suggesting a secondary therapeutic mode of donepezil.

Aged↗
PubMed1984

Clinical application of inhalation tests in patients with airway allergy.

Some patients with allergic rhinitis complain of lower airway symptoms, and the number of cases deemed to be related to lower airway hypersensitivity is considerable. We studied the clinical applications related to nasal allergy by the methacholine inhalation test using rhinograph to investigate upper and lower airway hypersensitivity. Fifty-three out of 58 patients (91.4%) with allergic rhinitis showed a reaction of Rr after the methacholine inhalation test. Elevation of RBN in 17 cases (85%) of allergic rhinitis was seen after methacholine nasal spray. This test can be done in a short time, and the burden on the patient is a light because the test can be performed while the patient is at rest. The methacholine inhalation test with rhinograph is thought to make it possible to detect the degree of hypersensitivity of the upper and lower airways.

Adolescent↗
PubMed1989

3-(aminoalkyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c] pyridin-5-ones as potential anticholinergic bronchodilators.

A series of 3-(aminoalkyl)benzopyrano[3,4-c]pyridin-5-ones was prepared and tested as potential orally active anticholinergic bronchodilators. Inhibition of methacholine-induced collapse in guinea pigs and inhibition of pilocarpine-induced bronchoconstriction in dogs served as in vivo models. Simultaneous measurement of salivary inhibition in the dog model allowed determination of a pulmonary selectivity ratio. The benzopyrano[3,4-c]pyridin-5-one parent ring system was prepared by Pechman condensation of phenols with a piperidine beta-keto ester. Alkylation with aminoalkyl halides, or with 1-chloro-2-propanone followed by reductive amination, yielded the 3-substituted target compounds. Bronchodilator potency was related to the extent of steric crowding surrounding the side-chain terminal amine function. Addition of a methyl substituent on the carbon alpha to the terminal amine often increased potency or pulmonary selectivity. After secondary pharmacological evaluation, compound 7a, designated CI-923, was selected for clinical trial as a bronchodilator.

Airway Resistance↗
PubMed1984

Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 2. Amides.

Thirty amides patterned after the antiarrhythmic drug changrolin were synthesized and their antiarrhythmic and parasympatholytic activities were assessed. There was no correlation between antiarrhythmic and parasympatholytic activities. Several of the amides were found to be potent antiarrhythmic agents that possessed low parasympatholytic activity. All of the compounds appear to act by a class I mechanism.

Amides↗
PubMed1989

Distribution of two distinct Ca2+-ATPase-like proteins and their relationships to the agonist-sensitive calcium store in adrenal chromaffin cells.

Many cellular functions are regulated by activation of cell-surface receptors that mobilize calcium from internal stores sensitive to inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). The nature of these internal calcium stores and their localization in cells is not clear and has been a subject of debate. It was originally suggested that the Ins(1,4,5)P3-sensitive store is the endoplasmic reticulum, but a new organelle, the calciosome, identified by its possession of the calcium-binding protein, calsequestrin, and a Ca2+-ATPase-like protein of relative molecular mass 100,000 (100K), has been described as a potential Ins(1,4,5)P3-sensitive calcium store. Direct evidence on whether the calciosome is the Ins(1,4,5)P3-sensitive store is lacking. Using monoclonal antibodies raised against the Ca2+-ATPase of skeletal muscle sarcoplasmic reticulum, we show that bovine adrenal chromaffin cells contain two Ca2+-ATPase-like proteins with distinct subcellular distributions. A 100K Ca2+-ATPase-like protein is diffusely distributed, whereas a 140K Ca2+-ATPase-like protein is restricted to a region in close proximity to the nucleus. In addition, Ins(1,4,5)P3-generating agonists result in a highly localized rise in cytosolic calcium concentration ([Ca2+]i) initiated in a region close to the nucleus, whereas caffeine results in a rise in [Ca2+]i throughout the cytoplasm. Our results indicate that chromaffin cells possess two calcium stores with distinct Ca2+-ATPases and that the organelle with the 100K Ca2+-ATPase is not the Ins(1,4,5)P3-sensitive store.

Adrenal Medulla↗
PubMed1988

Dose-response of inhaled diltiazem on airway reactivity to methacholine and exercise in subjects with mild asthma.

Methacholine challenges were performed by 10 asthmatic subjects, 2 hours before and 15 minutes after placebo (diluent alone) and 5, 10, 15, 30, and 60 mg inhaled diltiazem given in a single-blind crossover manner. There was no significant change from placebo in the dose of methacholine required to produce a 20% decrease in forced expiratory volume in the first second (FEV1) (PD20); the fold increase in PD20 from baseline was 1.1 +/- 0.1 after placebo, 1.4 +/- 0.2 after 5 mg, 1.8 +/- 0.3 after 10 mg, 1.4 +/- 0.2 after 15 mg, 1.6 +/- 0.2 after 30 mg, and 1.2 +/- 0.1 after 60 mg. There was a 1% chance that we missed a twofold difference between placebo and the 10 mg dose because of inadequate sample size. Fifteen minutes before a standardized exercise challenge, 10 subjects received placebo, 10 mg, and the highest dose tolerated during the methacholine study (20 to 45 mg) in a randomized double-blind crossover design. The mean +/- SE maximum postexercise decrease in FEV1 was 28.8% +/- 5.7% after placebo, 23.4% +/- 4.6% after 10 mg, and 20.8% +/- 3.0% after high-dose diltiazem (P greater than 0.05). There was a 12% chance that we missed a 15% difference between placebo and the high-dose regimen because of inadequate sample size. We conclude that diltiazem does not attenuate airway reactivity to methacholine or exercise even when high concentrations are delivered to the lungs.

Adult↗
PubMed1988

Ocular autonomic nerve function in proliferative diabetic retinopathy.

Ocular autonomic nerve function was assessed in 28 diabetic patients with proliferative retinopathy (PDR) and 61 age- and sex-matched control subjects, by measurement of the pupil cycle time and determination of autonomic denervation hypersensitivity of the iris. Sustained pupil cycle time was absent in 88.5 per cent of PDR compared with 9.8 per cent of control subjects (p less than 0.001). Pupil constriction in response to 2.5 per cent methacholine--indicative of parasympathetic denervation hypersensitivity--was significantly increased in PDR (p less than 0.001), whilst pupil dilation in response to 0.5 per cent phenylephrine--indicative of sympathetic denervation hypersensitivity--was also significantly higher in PDR (p less than 0.001). Pupil reflexes were abnormal in 88.5 per cent of diabetics with proliferative retinopathy, with established autonomic denervation hypersensitivity in 57 per cent of patients.

Adult↗
PubMed1981

The relationship of phosphatidylinositol turnover to receptors and calcium-ion channels in rat parotid acinar cells.

To help elucidate the possible role of phosphatidylinositol in the regulation of membrane permeability to Ca2+, the relationship in the rat parotid gland of phosphatidylinositol turnover to hormone receptor binding and to the hormone-mediated increase in K+ permeability (a Ca2+-dependent phenomenon) was investigated. The concentrations of adrenaline and substance P required to stimulate phosphatidylinositol turnover were found to be similar to those required for the Ca2+-mediated change in K+ permeability and for ligand binding. However, in the case of muscarinic (cholinergic) receptor stimulation, the phosphatidylinositol response was better correlated to the increase in membrane permeability to Ca2+, as determined by the change in K+ permeability, than to receptor occupation. Consistent with this relationship between the phosphatidylinositol response and Ca2+-channel activation were results obtained by simultaneous administration of maximal or submaximal concentrations of muscarinic and alpha-adrenergic agonists. The extent of 32P incorporation when stimulated by maximal concentrations of two agonists did not summate, but, rather, was intermediate between the response of either agonist alone. One interpretation for these observations is that the phosphatidylinositol response may not be related to receptor occupation or activation, but may be involved in the Ca2+-gating mechanism itself.

Animals↗
PubMed1982

Regulation of phosphatidate synthesis by secretagogues in parotid acinar cells.

The metabolism of phosphatidate in rat parotid acinar cells was investigated, particularly with regard to the actions of agonists known to act by mobilizing Ca2+. When cells were incubated in medium containing 10 microM-[32P]Pi, phosphatidate was rapidly labelled, approaching an apparent steady-state with a half-time of approx. 20 min. Methacholine provoked a more than doubling of phosphatidate radioactivity, which was reversed by the muscarinic antagonist atropine. These results suggest that phosphatidate labels to near steady-state rapidly and that in cells prelabelled for 60 min the increase in radioactivity induced by agonists probably reflects net synthesis rather than an increase in specific radioactivity. Phosphatidate synthesis in response to methacholine was rapid and occurred, within the resolution of a few seconds, with no measurable latency. Adrenaline and substance P also stimulated phosphatidate synthesis but both agonists were less efficacious than methacholine. A Ca2+ ionophore, ionomycin, did not provoke phosphatidate synthesis. By using a protocol that eliminates the receptor-regulated Ca2+ pool, it was demonstrated that methacholine-induced phosphatidate formation does not come about as a consequence of Ca2+ influx nor of Ca2+ release. These results indicate that the phosphatidate synthesis response has characteristics compatible with its previously suggested role as a primary mediator of membrane Ca2+-gating.

Animals↗
PubMed1982

Receptor-mediated net breakdown of phosphatidylinositol 4,5-bisphosphate in parotid acinar cells.

The metabolism of phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] in rat parotid acinar cells was investigated, particularly with regard to the effects of receptor-active agonists. Stimulation of cholinergic-muscarinic receptors with methacholine provoked a rapid disappearance of 40--50% of [32P]PtdIns(4,5)P2, but had no effect on PtdIns4P. Adrenaline, acting on alpha-adrenoceptors, and Substance P also stimulated net loss of PtdIns(4,5)P2. The beta-adrenoceptor agonist, isoprenaline, and the Ca2+ ionophore, ionomycin, failed to affect labelled PtdIns(4,5)P2 or PtdIns4P. By chelation of extracellular Ca2+ with excess EGTA, and by an experimental protocol that eliminates cellular Ca2+ release, it was demonstrated that the agonist-induced decrease in PtdIns(4,5)P2 is independent of both Ca2+ influx and Ca2+ release. These results may suggest that net PtdIns(4,5)P2 breakdown is an early event in the stimulus-response pathway of the parotid acinar cell and could be directly involved in the mechanism of agonist-induced Ca2+ release from the plasma membrane.

Animals↗
PubMed1984

Receptor-mediated metabolism of the phosphoinositides and phosphatidic acid in rat lacrimal acinar cells.

The metabolism of the inositol lipids and phosphatidic acid in rat lacrimal acinar cells was investigated. The muscarinic cholinergic agonist methacholine caused a rapid loss of 15% of [32P]phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and a rapid increase in [32P]phosphatidic acid (PtdA). Chemical measurements indicated that the changes in 32P labelling of these lipids closely resembled changes in their total cellular content. Chelation of extracellular Ca2+ with excess EGTA caused a significant decrease in the PtdA labelling and an apparent loss of PtdIns(4,5)P2 breakdown. The calcium ionophores A23187 and ionomycin provoked a substantial breakdown of [32P]PtdIns(4,5)P2 and phosphatidylinositol 4-phosphate (PtdIns4P); however, a decrease in [32P]PtdA was also observed. Increases in inositol phosphate, inositol bisphosphate and inositol trisphosphate were observed in methacholine-stimulated cells, and this increase was greatly amplified in the presence of 10 mM-LiCl; alpha-adrenergic stimulation also caused a substantial increase in inositol phosphates. A23187 provoked a much smaller increase in the formation of inositol phosphates than did either methacholine or adrenaline. Experiments with excess extracellular EGTA and with a protocol that eliminates intracellular Ca2+ release indicated that the labelling of inositol phosphates was partially dependent on the presence of extracellular Ca2+ and independent of intracellular Ca2+ mobilization. Thus, in the rat lacrimal gland, there appears to be a rapid phospholipase C-mediated breakdown of PtdIns(4,5)P2 and a synthesis of PtdA, in response to activation of receptors that bring about an increase in intracellular Ca2+. The results are consistent with a role for these lipids early in the stimulus-response pathway of the lacrimal acinar cell.

Animals↗
PubMed1985

Properties of receptor-controlled inositol trisphosphate formation in parotid acinar cells.

Activation of muscarinic receptors in rat parotid cells results in breakdown of polyphosphoinositides liberating inositol phosphates, including inositol trisphosphate. Formation of inositol trisphosphate appears independent of agonist-induced Ca2+ mobilization, since neither formation nor degradation of inositol trisphosphate are appreciably altered in low-calcium media, and elevation of cytosolic Ca2+ with a calcium ionophore does not cause an increase in cellular inositol trisphosphate. Further, activation of substance P receptors and alpha 1-adrenoreceptors, but not beta-adrenoreceptors, increases inositol trisphosphate formation. The dose-response curve for methacholine activation of inositol trisphosphate formation more closely approximates the curve for receptor occupancy than for Ca2+-activated K+ release. These results are all consistent with the suggestion that inositol trisphosphate could function as a second messenger linking receptor occupation to cellular Ca2+ mobilization.

Animals↗
PubMed1987

Homologous desensitization of substance-P-induced inositol polyphosphate formation in rat parotid acinar cells.

Maximal concentrations of substance P and methacholine induced a rapid increase in [3H]inositol trisphosphate ([3H]IP3) formation. After about 1 min, the [3H]IP3 in the substance-P-treated cells ceased to increase further, whereas in the methacholine-treated cells [3H]IP3 continued to increase. Addition of methacholine to the substance-P-treated cells caused a rapid increase in [3H]IP3, whereas a second addition of a 10-fold excess of substance P had no effect. Pretreatment of cells with substance P, followed by removal of the substance P by washing, resulted in a decreased response to a second application of substance P. A similar protocol involving pretreatment with methacholine had no effect on subsequent responsiveness to substance P. Analysis of [3H]substance P binding to substance-P-treated cells indicated that the number of receptors for substance P was decreased, but the affinity of the receptors for substance P was unaffected. After substance P pretreatment, a prolonged incubation (2 h) restored responsiveness of the cells to substance P, measured as [3H]IP3 formation, and restored the number of binding sites to control values. These findings indicate that, in the rat parotid gland, substance P induces a homologous desensitization of its receptor, which involves a slowly reversible down-regulation or sequestration of substance-P-binding sites.

Animals↗