Biomedical subjects

G Danko

Publications and source records attributed to G Danko.

13 recordsLinked to original sources

PubMed1996

Augmentation of neurally evoked cholinergic bronchoconstrictor responses by prejunctional NK2 receptors in the guinea-pig.

1. We examined the effect of exogenously administered tachykinins, neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) on neurally mediated cholinergic bronchoconstrictor responses in guinea-pigs. 2. Electrical stimulation of regions in the dorsal medulla oblongata produced a cholinergic bronchospasm that was not affected by depletion of endogenous tachykinins with capsaicin pretreatment (50 mg kg-1, s.c., 1 week earlier) or by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon (3 mg kg-1, i.v.). 3. Infusion of NKA (0.03-0.1 microgram kg-1 min-1), SP (1 microgram kg-1 min-1) or NKB (1 microgram kg-1 min-1) potentiated the bronchoconstrictor response to electrical stimulation of the dorsal medulla. The doses of tachykinins tested were subthreshold for direct activation of airway smooth muscle, because they were devoid of direct bronchoconstrictor effects. The relative rank order potency for augmentation of centrally induced bronchospasm was NKA > NKB approximately SP, suggesting activation of the NK2 receptor subtype. 4. Infusion of NKA, SP and NKB had no effect on bronchoconstrictor responses to i.v. methacholine (1 microgram kg-1) indicating that a prejunctional neural mechanism of action was responsible for the effects on CNS stimulation-induced bronchospasm. 5. Potentiation of the bronchoconstrictor response to dorsal medullary stimulation produced by infusion of NKA was blocked by pretreatment with the NK2 antagonist SR 48968 (1 mg kg-1, i.v.) but not by the NK1 antagoinst CP 96,345 (1 mg kg-1, i.v.). 6. The potentiation of CNS-induced bronchospasm produced by infusion of SP was partially inhibited by CP 96,345 (1 mg kg-1, i.v.) but not by SR 48968 (1 mg kg-1, i.v.). Treatment with combined SR 48968 (1 mg kg-1, i.v.) and CP 96,345 (1 mg kg-1, i.v.) completely blocked the SP-induced potentiation of CNS-stimulated bronchospasm. 7. These results identify an important modulatory role for NK2 receptors, located at prejunctional sites on parasympathetic nerves, on cholinergic bronchoconstrictor responses in guinea-pigs. 8. It is proposed that substances that release tachykinins from airway sensory nerves, e.g. inflammatory mediators or irritants, may induce hyperresponsiveness of cholinergic bronchomotor responses by activation of NK2-receptors on parasympathetic airway nerves. Furthermore, these studies indicate that endogenous tachykinins are not involved in the maintenance of basal cholinergic bronchomotor tone in the intact guinea-pig.

Animals↗

PubMed1996

Pilot study of explicit grading criteria in the American Board of Psychiatry and Neurology. Part II. Examination.

OBJECTIVE: The purpose of this study was to identify specific competencies that differentiated passing from failing performance on the American Board of Psychiatry and Neurology Part II oral board certification examination. METHOD: A total of 363 candidates were rated in 18 areas of competence defined by behavioral criteria. Data were analyzed to determine which areas best discriminated between passing and failing candidates. RESULTS: In both parts of the examination, the ability to develop a comprehensive treatment plan was most influential. After that, specific interview and observational skills discriminated best. Failing candidates had most difficulty detecting and following informational and affective cues in their interview of a patient and presenting a biopsychosocial formulation and comprehensive treatment plan. CONCLUSIONS: Specific candidate competencies related to passing and failing performances can be identified and assessed by a rating scale of observable behaviors on the board certification examination in psychiatry.

Clinical Competence↗

PubMed1996

The rate and characteristics of suicide attempters in the native Hawaiian adolescent population.

Native Hawaiian high school students, N = 1779, were surveyed for symptoms of psychopathology and suicide attempts in the previous 6 months. Seventy-seven (4.3%) of the students reported making a suicide attempt. There were no significant differences in prevalence rates for males and females. Depression, anxiety, aggression, substance abuse symptoms, and low family support, but not peer support, were significantly correlated with suicide attempts. On logistic regression, depression, substance abuse, and family support independently predicted attempts. The lack of gender difference may indicate a cultural characteristic of the Hawaiian population that differentiates it from mainstream American populations but likens it to the Native American population.

Adolescent↗

PubMed1994

Histamine H3 receptors inhibit sympathetic modulation of airway microvascular leakage in allergic guinea pigs.

Histamine H3 receptor modulation of antigen-induced airway microvascular leakage (AML) during sympathetic nerve stimulation was studied in guinea pigs. Intravenous administration of ovalbumin (100 micrograms) to sensitized guinea pigs produced AML that was reduced by electrical stimulation of sympathetic sites in the dorsal medulla. The sympatho-inhibition of this AML was attenuated by the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 100 micrograms/kg). The effect of (R)-alpha-methylhistamine was blocked by i.v. administration of the histamine H3 antagonists, thioperamide (1 and 3 mg/kg), burimamide (1-10 mg/kg) and impromidine (1 and 3 mg/kg). Thioperamide (3 mg/kg) and impromidine (3 mg/kg), but not burimamide (10 mg/kg) blocked the reduction in blood pressure due to (R)-alpha-methylhistamine. These results show that histamine H3 receptors inhibit sympathetic nerves that control the airway vasculature.

Animals↗

PubMed1993

Further evidence for prejunctional GABA-B inhibition of cholinergic and peptidergic bronchoconstriction in guinea pigs: studies with new agonists and antagonists.

We examined the effect of the potent and selective GABA-B agonists, baclofen, 3-aminopropylphosphinic acid (3-APPi) and 3-aminopropyl (methyl) phosphinic acid (SKF 97541), and the GABA-B antagonists, 3-aminopropyl (diethoxymethyl) phosphinic acid (CGP 35348), 2-hydroxysaclofen and 3-aminopropylphosphonic acid (3-APPA) on cholinergic and peptidergic contractile responses in the airways of guinea pigs. Electrical field stimulation of the isolated guinea pig trachea produced cholinergic contractions that were inhibited by baclofen (EC50 = 5 mumol/l), 3-APPi (EC50 = 0.3 mumol/l) and SKF 97541 (EC50 = 0.4 mumol/l). The inhibition by baclofen (30 mumol/l) was reduced by CGP 35348 (IC50 = 65 mumol/l), 2-hydroxysaclofen (IC50 = 273 mumol/l) and 3-APPA (IC50 = 355 mumol/l). The in vivo cholinergic bronchoconstrictor response to vagal nerve stimulation (5 V, 20 Hz, 0.5 ms for 5 s) was attenuated by intravenous baclofen (ED50 = 1.7 mg/kg), 3-APPi (ED50 = 0.9 mg/kg) and SKF 97541 (ED50 = 0.2 mg/kg). The inhibition of vagally induced bronchoconstriction by baclofen was blocked by CGP 35348 (1-10 mg/kg, i.v.) and 2-hydroxysaclofen (10 mg/kg, i.v.). A cholinergic bronchoconstriction induced by CNS stimulation (400 microA, 2 ms, 32 Hz for 5 s) was inhibited by baclofen (ED50 = 5.1 mg/kg, i.v.) and 3-APPi (ED50 = 0.6 mg/kg, i.v.). The effect of baclofen was attenuated by 3-APPA (5 mg/kg, i.v.). A peptidergic bronchoconstriction was evoked by intravenous nicotine (1 mg/kg) in animals treated with ipratropium and phosphoramidon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs.

GABA is a known inhibitory neurotransmitter in the CNS. Recent studies have also demonstrated the presence of GABA in peripheral tissue, including lung. To delineate a role for GABA in lung, the effect of GABA and selective GABA agonists and antagonists on neuronally-induced airway contractions in guinea pigs were studied. In vitro, tracheal contractions induced by electrical field stimulation (EFS) were inhibited by tetrodotoxin and atropine indicating that the contractions were mediated by neuronal release of acetylcholine. The contractions caused by EFS, but not those by exogenous acetylcholine, were inhibited by GABA (EC50 = 4.5 microM) and the selective GABA-B agonist baclofen (EC50 = 9 microM), but not by the GABA-A agonist, muscimol. The inhibitory effect of baclofen was not affected by the GABA-A antagonist, bicuculline, but was significantly reversed with the GABA-B antagonists, 3-aminopropylphosphonic acid (3-APPA) (pA2 = 4.5) and 2-hydroxysaclofen (pA2 = 4.1). In vivo, vagal nerve stimulation (5 V, 20 Hz, 0.5 ms, 5 s) in anesthetized, mechanically ventilated guinea-pigs caused cholinergic-dependent bronchospasms that were inhibited by intravenous GABA (3 and 10 mg/kg) and baclofen (1-10 mg/kg), but not by muscimol. The inhibitory effects of GABA and baclofen against vagal bronchospasm were blocked by 3-APPA (5 mg/kg, i.v.), but not by bicuculline. Responses to the GABA-B agonists were unaltered after the treatment of animals with phentolamine or propranolol to block alpha-adrenergic and beta-adrenergic receptors, respectively. Bronchospasm due to intravenous methacholine was also unchanged by GABA and baclofen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Simple, noninvasive method to measure the antibronchoconstrictor activity of drugs in conscious guinea pigs.

A simple, noninvasive method is described for measurement of the oral antibronchoconstrictor activity of drugs in conscious guinea pigs. The guinea pigs were placed in a head-out plethysmograph for measurement of tidal volume (VT), and a head chamber was used to deliver a hypercapnic gas mixture (10% CO2, 69% N2, 21% O2) and histamine aerosol (0.05% for 30 s). Inhalation of CO2 caused an increase in VT that was reduced (61 +/- 3%) by exposure to histamine. The histamine-induced reduction of VT was significantly (p less than 0.05) reduced 1 hr after oral administration with the bronchodilators albuterol (1 and 10 mg/kg) and aminophylline (100 mg/kg), the calcium antagonist nifedipine (30 mg/kg), and the antihistamine chlorpheniramine (0.5 mg/kg). These results demonstrate the oral antibronchoconstrictor activity of drugs in this model. The major advantages of this technique are that it is simple to operate, is noninvasive, and does not require anesthesia.

Aerosols↗

PubMed1988

Effect of the PAF antagonists, CV-3988 and L-652,731 on the pulmonary and hematological responses to guinea pig anaphylaxis.

To define the role of PAF in the acute phase of guinea pig anaphylaxis, we have measured the pulmonary (bronchoconstrictor) and hematological (thrombocytopenia, leukopenia, hemoconcentration, plasma TxB2 increase) responses to PAF infusion and compared these responses to the effect of antigen exposure in actively and passively sensitized guinea pigs. We have also determined the effect of the structurally unrelated PAF antagonists, CV-3988 and L-652,731 on these responses. Intravenous administration of PAF (50-400 ng/kg) caused a dose-related bronchoconstriction, thrombocytopenia, leukopenia, hemoconcentration and increase in plasma TxB2. These PAF-induced responses were inhibited, to a variable degree, by pretreatment with CV-3988 (3 and 10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). Intravenous administration of ovalbumin to actively or passively sensitized guinea pigs caused bronchoconstriction, thrombocytopenia, leukopenia and hemoconcentration, but there was no increase in TxB2. Moreover, the anaphylactic bronchoconstriction, thrombocytopenia, leukopenia (actively sensitized) and hemoconcentration were not inhibited by CV-3988 (10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). The different profile of changes produced by PAF and allergic anaphylaxis and the failure to alter the responses to allergic anaphylaxis with PAF antagonists suggest that PAF is not an important mediator of the acute phase of guinea pig anaphylaxis.

Anaphylaxis↗

PubMed1985

Effect of propranolol on pulmonary function and bronchoconstrictor responsiveness in guinea pigs and rats.

The beta-blocker propranolol was studied for its effects on basal pulmonary functions and on bronchoconstrictor responses to methacholine and histamine in mechanically ventilated guinea pigs and rats. Using doses that blocked the antibronchoconstrictor (bronchodilator) effects of the beta 2-agonist salbutamol, propranolol had no measurable effect on basal airway resistance and dynamic lung compliance in both guinea pigs and rats. However, bronchoconstrictor responses to methacholine and histamine were augmented by propranolol in guinea pigs. In contrast, propranolol did not change bronchoconstrictor responses to methacholine in rats. These results are discussed in terms of the functional role of pulmonary beta-receptors in guinea pigs and rats.

Airway Resistance↗

PubMed1985

Hyperventilation-induced bronchoconstriction in guinea pigs.

The purpose of this study was to investigate the pulmonary effects of hyperventilation in anesthetized, mechanically ventilated guinea pigs. Airway resistance (Raw), dynamic lung compliance (CDyn), blood pressure (BP), heart rate (HR), arterial blood gases (PaO2, PaCO2), pH and arterial plasma HCO3- were measured before and after a 10-min period of hyperventilation produced by increasing the respiratory rate from 60 to 120 breaths/min while maintaining tidal volume at 4 ml. There was a significant increase in Raw and decrease in CDyn lasting up to 20 min after hyperventilation was stopped with no change in BP and HR. PaO2 was reduced from 109 +/- 3 mm Hg before to 53 +/- 7 mm Hg at 5 min after hyperventilation. The Raw and CDyn changes were prevented and reversed with the bronchodilators salbutamol and aminophylline indicating that reversible bronchospasms are induced in guinea pigs following a period of hyperventilation. Additional studies demonstrated that the pulmonary mechanical responses to hyperventilation were not changed by vagotomy, ventilation with high CO2 or by pretreatment with chlorpheniramine, methysergide, atropine, indomethacin, FPL 55712 or calcium-influx blockers. These results indicate that neither vagal reflexes, airway hypocapnia, receptors of histamine, serotonin, acetylcholine nor the products of arachidonic acid metabolism were involved in hyperventilation-induced bronchospasm in guinea pigs.

Airway Resistance↗

PubMed1984

Effect of extra- and intracellular calcium blockers on histamine and antigen-induced bronchospasms in guinea pigs and rats.

The extracellular calcium antagonists, nifedipine and verapamil, the mixed extra/intracellular calcium antagonist diazoxide and the intracellular calcium antagonist TMB-8 were studied for their effects on histamine-induced bronchospasm in guinea pigs and on antigen-induced bronchospasms in guinea pigs and rats when administered directly to the tracheobronchial tree. Nifedipine and verapamil inhibited histamine and antigen-induced bronchoconstriction in guinea pigs, and verapamil was effective in preventing antigen-induced bronchospasms in rats. However, using doses of the extracellular blockers which produce these pulmonary effects, significant reduction of blood pressure occurred in both guinea pigs and rats. Diazoxide was inactive against histamine and antigen-induced bronchoconstrictions in guinea pigs. TMB-8 was inactive against histamine and antigen-induced bronchospasm in guinea pigs and rats. These studies demonstrate the antibronchoconstrictor activity of extracellular Ca2+ antagonists in guinea pigs and rats, but indicate that intracellular Ca2+ antagonists are not antibronchospastic agents in these species in vivo.

Albuterol↗

PubMed1975

Benzopyranopyridine derivatives. 1. Aminoalkyl derivatives of the azaxanthenes as bronchodilating agents.

The preparation of the four isomeric azaxanthones 3 and a number of their aromatic ring substituted derivatives is described. These ketones were converted into the title compounds which were examined for their biological properties. The most interesting compound in this series, the 1-methyl-4-piperidylidene derivative of 1-azaxanthene, shows the profile of an orally effective potent bronchodilating agent as well as a moderate antihistamine. Biological properties of this compound were compared to a number of antihistamines as well as known bronchodilating agents. Structure-activity relationships are also discussed.

Airway Resistance↗

PubMedDate not supplied

Role of cholinergic, vagal reflexes on the bronchoconstrictor responses to histamine during carbon dioxide inhalation in conscious guinea-pigs.

Histamine-induced bronchoconstriction in conscious guinea-pigs involves a cholinergic, bronchoconstrictor reflex, but the role of this reflex during elevated levels of inspired carbon dioxide is unknown. In this study we examined the role of cholinergic, vagal reflexes on the bronchoconstrictor responses to histamine during CO2 inhalation. Guinea-pigs were placed inside a whole body plethysmograph for measurement of tidal volume (VT), respiratory rate (f) and minute volume (V) and a head chamber was used to deliver a hypercapnic gas mixture (10% CO2, 21% O2, 69% N2) and for inhalation of aerosolized drugs. Inhalation of CO2 caused an increase in VT, f and V and these effects were reduced by exposure to aerosolized histamine (0.01-0.05% for 30 s). The histamine-induced reduction of VT was significantly (P less than 0.05) attenuated following a 60 s exposure to inhaled atropine (0.03 and 0.1%) as was the reduction of VT due to inhaled methacholine. Intravenous atropine (1 mg/kg) also blocked the VT reduction due to aerosolized histamine. Intravenous administration of the ganglionic blockers hexamethonium (1 mg/kg) and mecamylamine (10 mg/kg) did not inhibit the histamine-induced reduction of VT at doses of these drugs that revealed systemic evidence of ganglionic blockade, i.e. inhibition of vagally stimulated bronchoconstriction and bradycardia. The results demonstrate that the bronchoconstrictor responses to histamine during CO2 inhalation in guinea-pigs involves stimulation of airway cholinergic receptors, but this response does not involve ganglionic neurotransmission. It is speculated that histamine's bronchoconstrictor effects during CO2 breathing involves stimulation of postganglionic, parasympathetic nerves innervating airway smooth muscle.

Aerosols↗