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Biomedical subjects

M Halonen

Publications and source records attributed to M Halonen.

At least 91 records · Page 5Linked to original sources
PubMed1986

Bronchodilator activity of a nonxanthine phosphodiesterase inhibitor; 2,4-diamino-5-cyano-6-bromopyridine (compound I).

The ability of 2,4-diamino-5-cyano-6-bromopyridine (compound 1) to inhibit bronchiolar smooth muscle constriction was examined in isolated rings of rabbit primary bronchi and intrapulmonary bronchioles. After carbachol-induced constriction these tissue were significantly relaxed by either compound I or 1-methyl-3-isobutylxanthine (MIX) in a similar dose-dependent manner with 50 to 80% relaxation occurring at 100 microM of either compound. Compound I also attenuated the constrictor response of bronchial rings to histamine and significantly reduced the tension generated by horseradish peroxidase in sensitized tissues responding to this antigen. In addition, both compound I and MIX were found to inhibit the soluble cyclic AMP phosphodiesterase activity of rabbit bronchioles. Finally, both compound I and MIX caused a nearly 2-fold, time-dependent increase in cyclic AMP levels in isolated rabbit intrapulmonary bronchioles. The similarities of both the in vitro tissue responses to these compounds and the phosphodiesterase inhibitory properties suggest that the ability of compound I to reduce constrictor-induced tension generation in bronchial smooth muscle is related to the inhibition of cyclic nucleotide phosphodiesterases and the consequent elevation of cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Participation of platelets in the physiologic alterations of the AGEPC response and of IgE anaphylaxis in the rabbit. Effects of PGI2 inhibition of platelet function.

To further clarify the platelet dependence of acetyl glyceryl ether phosphorylcholine (AGEPC) physiologic activity and of IgE anaphylaxis in the rabbit, PGI2 was employed as an inhibitor of in vivo platelet function. Intravenous infusion of PGI2 (1 to 2 micrograms/kg/min) inhibited the AGEPC-induced decrease in dynamic compliance, increase in total pulmonary resistance, and transient decrease in tidal volume, but the right ventricular hypertension, bradycardia, and apnea were unaffected. Although PGI2 itself produced a marked systemic hypotension, AGEPC still induced a bimodal hypotensive response. Documentation that platelet function was inhibited by PGI2 included partial inhibition of AGEPC-induced thrombocytopenia, abrogation of platelet secretion (as assessed by plasma platelet factor 4 levels), and inhibition of ex vivo platelet aggregation. The AGEPC-induced leukopenia was not affected. In another group of rabbits, chlorpheniramine pretreatment inhibited the lung mechanical changes induced by AGEPC but did not affect the ventilatory or circulatory alterations, indicating that the lung mechanical alterations (but not any of the other alterations) are mediated by platelet-secreted histamine acting via H1 receptors. In IgE-producing rabbits intravenously challenged with antigen, PGI2 had no effect on any of the physiologic alterations, despite substantial inhibition of platelet secretion. From these results, together with previous platelet depletion studies, we conclude that AGEPC may be a significant mediator of the circulatory alterations and apnea of rabbit IgE anaphylaxis by platelet-independent mechanisms, but neither AGEPC nor platelets appear to be important in mediating the anaphylactic lung mechanical alterations.

Anaphylaxis↗
PubMed1985

Effect of specific IgG on IgE-induced systemic anaphylaxis in the rabbit.

Immunization of rabbits as neonates and periodically thereafter has been shown to induce the long-term preferential production of specific IgE antibodies. Specific IgG antibodies are not detected in the majority (greater than 70%) of rabbits when classical immunological detection techniques are used, including heterologous PCA in guinea-pig skin. Nevertheless, in this study we demonstrate that all rabbits neonatally immunized to the antigen horseradish peroxidase (HRP) do produce low levels of specific IgG antibody detectable by an ELISA technique. Serum levels of anti-HRP IgG were found to be log normally distributed, with a geometric mean for the heterologous PCA-negative sera of 31.6 X/divided by 2.69 micrograms/ml. Serum anti-HRP IgE levels (log2 homologous PCA titres) are bimodally distributed. Specific IgG and IgE levels in individual rabbits have a significant direct relationship. Six heterologous PCA-negative and seven heterologous PCA-positive rabbits were challenged intravenously with HRP. All of the respiratory and circulatory alterations typical of IgE anaphylaxis occurred in every challenged rabbit. Regression analysis of percentage changes in the physiological variables vs log specific IgE level indicated that none of the changes was either directly or inversely related to the specific IgG levels. Also the mean changes of the heterologous PCA-positive vs negative rabbits did not differ significantly. Thus, we could find no evidence for either a blocking or enhancing effect of the specific IgG antibodies (range 10-529 micrograms/ml serum) on the IgE-induced anaphylactic reaction.

Anaphylaxis↗
PubMed1984

The role of histamine in the physiologic alterations of IgE anaphylaxis in the rabbit.

The respiratory and circulatory alterations induced by intravenous histamine in the pentobarbital anesthetized rabbit were examined and compared to those alterations associated with IgE anaphylaxis following antigen challenge. Histamine induced several graded alterations including an increase in total pulmonary resistance, a decrease in dynamic compliance, an increase in breathing frequency, a decrease in tidal volume, a rise in right ventricular systolic pressure and systemic hypotension. Qualitatively similar alterations occurred during the anaphylactic response, but a quantitative comparison of the two responses revealed that the respiratory alterations in systemic anaphylaxis corresponded to relatively low equivalent histamine doses, whereas the anaphylactic circulatory alterations exceeded the maximum response obtainable with histamine. Pretreatment with H1 antihistamine competitively blocked all of the ventilatory and lung mechanical changes induced by histamine, but it inhibited only the increase in pulmonary resistance induced by antigen. The right ventricular hypertension induced by histamine was also inhibited by H1 antihistamine but the antigen-induced change in this variable was not significantly attenuated. Inhibition of the histamine-induced systemic hypotension required pretreatment with both H1 and H2 histamine antagonists. Such pretreatment, however, did not attenuate the fall in systemic arterial pressure induced by antigen. H1 antihistamine pretreatment prevented histamine- but not antigen-induced lethality. We conclude that histamine is an important mediator of the increase in pulmonary resistance but is not the major mediator of the other physiological alterations of IgE systemic anaphylaxis in the rabbit.

Airway Resistance↗
PubMed1984

Heightened cholinergic responsiveness in IgE-producing rabbits.

Atopic humans express an array of autonomic nervous system abnormalities. An animal model of IgE-mediated allergy was herein employed to determine if the induction of an IgE antibody response would affect autonomic responsiveness. Rabbits were immunized so as to selectively produce IgE antibodies, and their pupillary miotic and mydriatic responses to cholinergic and alpha adrenergic stimuli, respectively, were determined. IgE-producing rabbits exhibited hyperresponsiveness to cholinergic but not alpha adrenergic stimulation, a pattern resembling that seen in nonasthmatic atopic humans. Repeated sublethal anaphylactic episodes induced in three IgE-producing rabbits did not affect the pattern of autonomic responsiveness when compared to controls challenged with saline, despite clear evidence of increased plasma histamine levels immediately after antigen challenges in the IgE group. This study indicates that elicitation of an IgE antibody response is associated with the concomitant development of cholinergic hyper-responsiveness.

Animals↗
PubMed1983

Detection of beta-adrenergic receptors on rabbit mononuclear cells isolated free of significant contamination by other cell types.

In order to study rabbit mononuclear cell surface receptors, it was necessary to develop a procedure to isolate mononuclear cell preparations that are free of significant contamination by other cell types, especially platelets. Centrifugation of dextran-sedimented, anti-coagulated whole blood through Hypaque (density 1.060) at 600 X g for 5 min at 22 degrees C eliminated greater than 93% of starting platelets. A second 5-min Hypaque centrifugation of Hypaque-Ficoll-isolated mononuclear cells (MNC) (approximately 80% lymphocytes) at 450 X g for 5 min at 22 degrees C reduced platelet contamination to less than one platelet per three MNC, and resulted in the overall removal of greater than 99.5% of starting platelets. These relatively pure MNC which were isolated in less than 2 hr were identified as having beta-adrenergic receptors by radioligand binding techniques using [125I]iodohydroxybenzylpindolol [( 125I]IHYP). Binding of [125I]IHYP to intact rabbit MNC was a saturable, stereospecific, and rapid process with a dissociation constant (KD) of 0.53 +/- 0.18 nM and a binding capacity of 3,461 +/- 235 sites/cell.

Animals↗
PubMed1983

Interactions of smoking and immunologic factors in relation to airways obstruction.

The relationships of smoking, allergy skin test reactivity, and serum IgE to ventilatory function have been analyzed in 1,182 subjects from a general population sample. The study group consisted of subjects aged 35 or more who deny previous lung surgery, old tuberculosis, or a current diagnosis of heart disease in the absence of chronic bronchitis or emphysema. Impairment of the forced expiratory volume in one second (FEV1) shows a definite relationship to total serum IgE. However, this relationship is significant only for a low FEV1 which is accompanied by symptoms suggesting asthmatic or a chronic bronchitis type disease. Allergy skin test reactivity to a battery of common aeroallergens shows no overall relationship to FEV1. However, after accounting for total serum IgE, positive allergy skin tests tend to be associated with high rather than low FEV1 values. The findings suggest that some type of IgE which is not specific for aeroallergens but which is associated with smoking, may be important in the pathogenesis of the "chronic asthmatic bronchitis" syndrome.

Adult↗
PubMed1982

The relationship of serum immunoglobulin E, allergy skin tests, and smoking to respiratory disorders.

In this study of a general population sample in Tucson, Ariz., smokers showed higher levels of serum IgE despite having a lower rate of allergy skin-test reactivity to common aeroallergens than nonsmokers. The prevalence of rhinitis was closely related to the level of serum IgE in atopic subjects regardless of smoking habits. In nonatopic smokers, elevated IgE levels were not associated with high rhinitis rates. However, high IgE levels in nonatopic smokers were related to increased rates of diagnosed asthma, wheeze, and chronic cough and/or sputum (C/S). These relationships were especially striking in subjects over the age of 54. In older nonatopic smokers, reported prevalences of "chronic bronchitis" and of functional impairment also increased in relation to the level of serum IgE. Reduced ventilatory function showed this relationship to IgE only when accompanied by C/S. It is suggested that the excess IgE related to smoking is qualitatively different than that found in subjects reacting to aeroallergens, is not important in the pathogenesis of upper respiratory tract disease, but may play a role in the development of some lower respiratory tract disorders.

Adolescent↗
PubMed1981

Allergen skin-test reactivity in a community population sample: correlation with age, histamine skin reactions and total serum immunoglobulin E.

Allergen skin reactivity to 14 common local antigens was studied in a community population sample. Differences in the prevalence of positive reactions were related to both the specific antigen itself and the age of the subjects. For most allergens, peak prevalence occurred in the 20- to 34-yr age group, falling thereafter with increasing age. The frequency distribution of reactions revealed a bimodal curve, peaks occurring among nonreactors and those with eight positive reactions out of the 14 tests that were applied. The major contributor to this age--skin test relationship was the level of total serum IgE that was highest in young people and decreased progressively with age. Histamine skin reactions, which were smallest in younger subjects compared with all three older age groups, also contributed to the age-related prevalence of allergen skin-test reactions.

Adolescent↗
PubMed1981

Distribution of IgE in a community population sample: correlations with age, sex, and allergen skin test reactivity.

The distribution of total serum IgE determined by the paper radioimmunosorbent test (PRIST) is examined in a large random stratified community population. Prior to logarithmic conversion the distribution of this immunoglobulin is not normal, with almost 40% of values below 20 IU/ml. A normal distribution occurs following such conversion, with a geometric mean value of 32.1 IU/ml. Both age and sex, in addition to atopic status, relate to IgE level. In both sexes highest levels occur among 6- to 14-year-olds, and males have higher levels than females at any given age. Women over age 75 yr have the lowest levels (geometric mean 9.2 IU/ml). Subjects with positive skin test results have several times the concentration of IgE as their nonatopic counterparts.

Adolescent↗
PubMed1981

Differential effects of platelet depletion on the physiologic alterations of IgE anaphylaxis and acetyl glyceryl ether phosphorylcholine infusion in the rabbit.

Intravenously administered acetyl glyceryl ether phosphorylcholine (AGEPC) induced all of the respiratory and circulatory alterations observed during IgE anaphylaxis in the rabbit. Prior platelet depletion, however, had differential effects on these two physiologic responses. The AGEPC-induced increase in total pulmonary resistance and decrease in dynamic compliance were abrogated by prior platelet depletion, whereas these lung mechanical changes occurring as part of an IgE anaphylactic response after intravenous antigen challenge were unaffected by platelet depletion. The apneic episode observed in both the AGEPC and antigen-induced response was unaffected by platelet depletion, and the brief period of rapid shallow breathing of the AGEPC response was diminished to that characteristically seen in the anaphylactic response of both platelet-intact and platelet-depleted rabbits. Prior platelet depletion had little effect on right ventricular hypertension, bradycardia, and systemic hypotension of either the AGEPC or the anaphylactic responses. Thus, AGEPC induced lung mechanical alterations via platelet-dependent mechanisms and ventilatory and circulatory alterations by mechanisms largely independent of circulating platelets. These findings were consistent with the possibility that AGEPC released into the blood stream during IgE anaphylaxis may mediate the circulatory and ventilatory alterations but not the lung mechanical alterations of the anaphylactic response.

Anaphylaxis↗
PubMed1981

The relationship of serum immunoglobulin E to cigarette smoking.

Data from adults enrolled in a general population study in Tucson, Arizona, indicated that smokers have higher serum IgE concentrations than nonsmokers, despite a lower rate of allergy skin test reactivity, at least after 35 yr of age. After 15 yr of age there was a significant decline in serum IgE with age in both allergy skin test positive and skin test negative nonsmokers but no significant age decline was noted in similar groups of smokers. Ex-smokers showed a decline in serum IgE concentrations since quitting cigarettes. Also, the marked increase in geometric mean IgE that was seen in nonsmokers during the spring was not observed in smokers. The data suggested that smoking leads, directly or indirectly, to an increase in serum IgE and that this excess IgE may be qualitatively different from that seen in nonsmokers. Possible mechanisms for the effect are discussed. The observations raised the possibility that some of the adverse health effects of smoking might be immunologically mediated.

Adolescent↗
PubMed1980

Epidemiologic observations on eosinophilia and its relation to respiratory disorders.

The percentage of eosinophils (%EOS), determined from a differential blood smear, was measured in 2,311 subjects enrolled in a general population study in Tucson, Arizona. A subgroup of 290 subjects was tested in more detail during a later evaluation in which absolute eosinophil counts, leukocyte counts, and nasal smears for eosinophils were obtained. In men, but not in women, there was a significant tendency for the %EOS to decrease with age. The highest %EOS was noted during the months of February through May, the time when most plants in this region are in bloom. Blood eosinophils were significantly related to allergy skin test reactivity, circulating IgE concentrations, several respiratory symptoms and disease diagnoses, as well as to reduced ventilatory function. Among subjects younger than 55 yr of age, however, ventilatory function was significantly low, and symptom rates increased only when there was allergy skin test reactivity in addition to eosinophilia. Neither allergy skin test reactivity nor eosinophilia alone was related to ventilatory function in this age group. Among older subjects, blood eosinophilia was associated with definite impairment of ventilatory function, regardless of skin test reactivity and independent of smoking habits. The presence of eosinophilia identified a predominantly female group of elderly nonsmokers with markedly impaired ventilatory function. These subjects appeared to fall into the clinical category of "asthmatic bronchitis".

Adolescent↗
PubMed1980

Respiratory and circulatory alterations induced by acetyl glyceryl ether phosphorylcholine, a mediator of IgE anaphylaxis in the rabbit.

We examined the physiologic alterations induced in the rabbit by an acetyl glyceryl ether phosphorylcholine (AGEPC), a synthetic compound identical to rabbit basophil-derived platelet-activating factor. Intravenous administration of AGEPC led to a brief period of rapid, shallow breathing, a transient apnea, a decrease in dynamic compliance, and an increase in total pulmonary resistance. Circulatory alterations included brief bradycardia, increase in right ventricular pressure, and systemic hypotension. At a dose of 0.6 microgram/kg, AGEPC produced physiologic alterations both qualitatively and quantitatively indistinguishable from those which characterize IgE anaphylaxis in the rabbit. Mortality was also similar. After recovery to prechallenge baseline values, subsequent doses of AGEPC resulted in attenuated responses with respect to many of the physiologic alterations. Thrombocytopenia, leukopenia, and platelet secretion (as assessed by release of platelet factor 4 into the plasma) were also part of the response to AGEPC, further extending the similarity of this response to IgE anaphylaxis. Because AGEPC has been shown previously to be released into the circulation during IgE anaphylaxis, our results provide strong evidence that AGEPC is an important mediator of this acute allergic reaction in the rabbit.

Anaphylaxis↗
PubMed1977

Intravascular aggregation and pulmonary sequestration of platelets during IgE-induced systemic anaphylaxis in the rabbit: abrogation of lethal anaphylactic shock by platelet depletion.

Significant alterations in the circulatory properties of platelets have been documented during IgE-induced systemic anaphylactic shock in the rabbit. Within 30 to 60 sec after i.v. antigen challenge, platelet aggregation occurs in both the venous and arterial circulations. The platelet aggregates then sequester in small blood vessels of various organs, particularly in the lung. The organ sequestration results in the development of a profound thrombocytopenia within 3 to 5 min after antigen challenge. Fifteen min later deaggregation of platelets occurs and the platelets return to the peripheral circulation within normal, prechallenge levels by 60 min. Additional experiments demonstrated that platelet depletion before antigen challenge abrogates the lethal effects and significantly reduces the pathophysiologic manifestations of IgE-induced systemic anaphylaxis. We conclude that the IgE-induced platelet alterations, probably induced by the intravascular release of basophil and perhaps mast cell-derived platelet-activating factor (PAF), play a major role in the pathogenesis of systemic anaphylaxis in the rabbit.

Anaphylaxis↗