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Biomedical subjects

D K Agrawal

Publications and source records attributed to D K Agrawal.

At least 19 recordsLinked to original sources
PubMed2006

A comparison of stent-induced stenosis in coronary and peripheral arteries.

BACKGROUND AND OBJECTIVES: Restenosis is a complication of interventional procedures such as angioplasty and stenting, often limiting the success of these procedures. Knowledge regarding the relative behaviour of different arteries after these procedures is limited, despite the extensive use of different vascular models. Although the results from studies using different vessels are analysed to predict the behaviour of coronary arteries and other vasculature, direct controlled comparisons between different arteries are necessary for a better understanding of the differential response to restenosis. METHODS: This study examines the response to stenting in coronary and internal iliac arteries as characterised by intimal hyperplasia and restenosis. In a swine model of in-stent stenosis, coronary arteries exhibited higher levels of intimal hyperplasia and per cent stenosis than internal iliac arteries. RESULTS: After normalisation for injury score, coronary arteries were found to undergo 47% more intimal hyperplasia (p<0.05), whereas per cent stenosis normalised for injury score tended to be higher (p = 0.01). Other measurements reflecting post-stenting intimal hyperplasia (maximal intimal thickness, medial area) did not exhibit significant differences between the artery groups. CONCLUSIONS: These results show that coronary vessels are more prone to develop significant intimal hyperplasia and subsequent restenosis than internal iliac vessels. A better insight into how different arteries and arterial components behave is important in understanding and developing newer and better therapeutic measures for restenosis.

Animals↗
PubMed2006

In stent restenosis: bane of the stent era.

The long term outcome of stent implantation is affected by a process called in stent restenosis (ISR). Multiple contributory factors have been identified, but clear understanding of the overall underlying mechanism remains an enigma. ISR progresses through several different phases and involves numerous cellular and molecular constituents. Platelets and macrophages play a central role via vascular smooth muscle cell migration and proliferation in the intima to produce neointimal hyperplasia, which is pathognomic of ISR. Increased extracellular matrix formation appears to form the bulk of the neointimal hyperplasia tissue. Emerging evidence of the role of inflammatory cytokines and suppressors of cytokine signalling make this an exciting and novel field of antirestenosis research. Activation of Akt pathway triggered by mechanical stretch may also be a contributory factor to ISR formation. Prevention of ISR appears to be a multipronged attack as no therapeutic "magic bullet" exists to block all the processes in one go.

Apoptosis↗
PubMed2005

Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells.

Characteristics of hVSMC apoptosis and its inhibition by insulin-like growth factor-1 (IGF-1) remain unclear. Also unclear is whether a balance in hVSMCs exists whereby c-Jun N-terminal stress kinases (JNK) promote apoptosis while extracellular signal-regulated (ERK1/2) MAP kinases inhibit cell death. In this study, we examined the involvement of Akt/PKB and its upstream kinase, PDK1 and whether JNK activation correlated with human and rat VSMC apoptosis induced by staurosporine and by c-myc, respectively. We observed a strong, sustained JNK activation (and c-Jun phosphorylation), which correlated with VSMC apoptosis. IGF-1 (13.3 nM), during apoptosis inhibition, transiently inhibited JNK activity at 1 h in a phosphatidylinositol 3-kinase (PI3-K)- and MEK-ERK-dependent manner, as wortmannin (100 nM) or PD98059 (30 muM) partially attenuated the IGF-1 effect. PKC down-regulation had no effect on JNK inhibition by IGF-1. While IGF-1 alone produced a strong phosphorylation of Akt/PKB in hVSMCs up to 6 h, it was notably stronger and more sustained during ratmyc and hVSMCs apoptosis inhibition. Further, whereas transient expression of phosphorylated Akt protected VSMCs from apoptosis by nearly 50%, expression of dominant interfering alleles of Akt or PDK1 strongly inhibited IGF-1-mediated VSMC survival. These results demonstrate for the first time that transient inhibition of a pro-apoptotic stimulus in VSMCs may be sufficient to inhibit a programmed cell death and that sustained anti-apoptotic signals (Akt) elicited by IGF-1 are augmented during a death stimulus. Furthermore, PI3-K and ERK-MAPK pathways may cooperate to protect VSMCs from cell death.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2004

Anti-inflammatory properties of desloratadine.

BACKGROUND: Allergic rhinitis (AR) is associated with robust infiltration of immune cells and mediators that may contribute to clinical manifestations of the disease. OBJECTIVE: To review the complex immune effector mechanisms involved in the allergic response and discuss their effects on the pathophysiological and clinical manifestations of AR. Desloratadine, a novel antihistamine, was used as a probe with the goal of attaining a better understanding of the inflammatory processes underlying the allergic response. METHODS: Data were obtained from abstracts and peer-reviewed journals. The pathophysiology of the allergic response has been extensively studied. This paper presents only data from studies that used desloratadine at physiologically relevant concentrations. RESULTS: Key mediators involved in the allergic response and in pathophysiological and clinical manifestations of the immune response were reviewed. Desloratadine was used as a probe to further elucidate the mechanisms involved during an allergic response. CONCLUSIONS: Some have proposed a link between the pathophysiology of AR and the clinical manifestation of symptoms. Desloratadine, a new-generation antihistamine, has demonstrated anti-inflammatory effects in vitro; indeed, desloratadine is capable of intervening at various points in the immune cascade. Although in vitro results do not necessarily correlate with clinical efficacy, the anti-inflammatory properties of desloratadine may contribute to its efficacy in patients with AR, allergy-induced asthma, and other related allergic conditions. Antihistamines that modulate in the immune system at various stages may optimize treatment of allergic disease.

Cell Adhesion↗
PubMed2004

Cl- channels are expressed in human normal monocytes: a functional role in migration, adhesion and volume change.

Increased adhesion and diapedesis of monocytes appear to be primary initiating factors in the pathophysiology of occlusive vascular diseases, including atherosclerosis and restenosis. However, the underlying mechanisms of transendothelial migration and invasion of monocytes into the blood vessels are not known. Alterations in ion channels on the cell membrane are generally involved in induced changes in shape and volume. In the present study, we investigated the expression and functional role of chloride channels in freshly isolated human blood monocytes. The Cl- currents in whole-cells were measured by the patch-clamp technique. We observed whole cell Cl- currents, which were time-independent and outwardly rectifying. The chloride channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy]acetic acid 94 (IAA94) attenuated the Cl- currents. NPPB and IAA94 also inhibited chemotaxis of monocytes, as measured in Boyden chemotactic chambers, with the same sensitivity. NPPB but not IAA94, increased the cell volume as measured by shape change, and decreased tumour necrosis factor (TNF)-alpha-induced monocyte adhesion to endothelial cells. These results suggest that monocytes contain Cl- channels which regulate transendothelial migration of monocytes, due presumably to an alteration in cell volume.

Adult↗
PubMed2001

Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma.

Allergens, in combination with genetic predisposition, drive undifferentiated T cells towards the type 2 T cells. Some childhood infections may activate the production of a type 1 T cell profile. It is reasonable to speculate that a decrease in childhood infections may increase the incidence of allergy by allowing the immune balance to shift towards the type 2 T cells. We hypothesized that pre-exposure of mycobacterial antigens in sensitized mice would prevent the development of asthma-like conditions. Specifically, we examined the effect of mycobacterial antigens, Bacillus Calmette-Guerin (BCG) vaccine and Mycobacterium vaccae, on antigen-induced bronchoconstriction, airway hyperresponsiveness to methacholine, bronchoalveolar lavage eosinophilia, and plasma IL-4 and IL-12 levels in ovalbumin (OVA)-sensitized and challenged Balb/c mice. Challenge with OVA produced a 2-3-fold increase in bronchoconstriction within 3-5 min, followed by a delayed response after 60 min, the latter of which was significantly attenuated by both BCG and M. vaccae. Airway hyperresponsiveness to methacholine 24 h after OVA challenge was prevented by BCG and M. vaccae. Airway eosinophilia was also prevented by BCG and M. vaccae. The plasma IL-12 levels were significantly increased and plasma IL-4 levels were significantly decreased following BCG or M. vaccae administration in OVA-sensitized and challenged mice. Interestingly, a significant increase in plasma IL-12 was observed with BCG as compared to M. vaccae administration, suggesting a stronger type 1 response to BCG. These data support our hypothesis and suggest that BCG and M. vaccae may prevent the underlying pathophysiological changes in asthma.

Algorithms↗
PubMed2001

Flt3 ligand: a novel cytokine prevents allergic asthma in a mouse model.

Flt-3 ligand (FL), a recently described growth factor affecting early hematopoietic progenitor cells, can also support the expansion of dendritic cells secreting IL-12. Since type 2 T cells predominate in asthma and IL-12 prevents the differentiation of naive T lymphocytes to a type 2 phenotype, we hypothesized that FL could prevent the development of asthma-like conditions in the ovalbumin mouse model. We found that co-administration of FL during ovalbumin sensitization abrogated late allergic responses, but had no effect on early allergic responses. Airway hyperresponsiveness to methacholine was also blocked by FL treatment. Analysis of bronchoalveolar lavage (BAL) fluid demonstrated a significant reduction in eosinophils, with concomitant decreases in IL-5 and increases in IFN-gamma levels. However, there was no change in BAL fluid IL-4 and serum IgE levels. These data suggest that FL treatment prevents ovalbumin-induced asthma in the mouse and may provide a useful adjuvant in the treatment of human asthma.

Airway Resistance↗
PubMed2001

Modification of eosinophil function by suplatast tosilate (IPD), a novel anti-allergic drug.

Suplatast tosilate (IPD), a new dimethylsulfonium agent, is used therapeutically in allergic diseases. Suplatast has been reported to attenuate airway hyperresponsiveness in guinea pigs, human IgE synthesis, and murine peritoneal eosinophilia. However, the effect of suplatast on human eosinophils is not known. In this study, we examined the effects of suplatast in human eosinophils on platelet activating factor (PAF, 1 microM)-induced chemotaxis by the blind well chamber technique, eosinophil adhesion to TNF-alpha (10 ng/ml) or IL-4 (10 ng/ml)-stimulated human umbilical vein endothelial cells (HUVECs), and expression of very late antigen-4 (VLA-4) on eosinophils and vascular cell adhesion molecule-1 (VCAM-1) on HUVECs by flow cytometry. Suplatast suppressed IL-4-induced eosinophil adhesion to HUVECs in a dose-dependent manner. Eosinophils from the normal subjects did not express VLA-4. However, there was a significant increase (P < 0.01) in the basal expression of VLA-4 in allergic patients. PAF or IL-4 did not enhance VLA-4 expression on eosinophils, and there was no significant effect of suplatast on VLA-4 expression in allergic patients. Suplatast did not affect TNF-alpha-induced VCAM-1 expression. Interestingly, suplatast significantly suppressed IL-4 induced VCAM-1 expression on HUVECs and PAF-induced eosinophil chemotaxis. These data suggest that suplatast may modify eosinophil participation in airway inflammation by attenuating inflammatory mediators-induced chemotaxis and adhesion to endothelial cells, and thus might be useful in the treatment of bronchial asthma.

Anti-Allergic Agents↗
PubMed2001

Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug.

Desloratadine is a biologically active metabolite of the second-generation antihistamine loratadine. Desloratadine is a highly selective peripheral H1 receptor antagonist that is significantly more potent than loratadine. Results of in vitro and in vivo studies have suggested that desloratadine has anti-allergic effects that are unrelated to its ability to antagonise the effects of histamine. Desloratadine inhibits the expression of cell adhesion molecules, inhibits the generation and release of inflammatory mediators and cytokines, attenuates eosinophil chemotaxis, adhesion and superoxide generation. Studies in animals indicate that desloratadine does not cross the blood-brain barrier and therefore does not cause sedation and does not impair cognition or psychomotor performance. Desloratadine has an excellent overall safety profile. It has no effect on QRS and QTc intervals and does not cause arrhythmias. Desloratadine is not associated with any significant changes in gastrointestinal function. In clinical studies, oral desloratadine is rapidly absorbed and bioavailability is not affected by ingestion with food or grapefruit juice. The half-life of desloratadine in humans is 27 h; the linear kinetic profile is unaltered by race or gender. Desloratadine is not a substrate for P-glycoprotein or organic anion transport polypeptide and the drug does not appear to be metabolised to a significant extent by the cytochrome P450 CYP3A4 pathway. It therefore may be safely administered with ketoconazole, erythromycin, fluoxetine, or azithromycin. Clinically, desloratadine effectively controls both nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR), including nasal congestion. Desloratadine also provides significant relief of SAR symptoms in patients with co-existing asthma and is effective in the treatment of chronic idiopathic urticaria. Desloratadine improves quality of life and is well-tolerated.

Animals↗
PubMed2000

Bioreactivity of glutathionyl hydroquinone with implications to benzene toxicity.

Glutathionyl hydroquinone (GHQ), a highly reactive metabolite of benzene, has been implicated as a causative intermediate of benzene toxicity. To substantiate, the bioreactivity of GHQ was investigated under in vitro and in vivo conditions using end points, characteristic of benzene toxicity. Under in vitro conditions, the presence of GHQ: (a) linearly increased the release of aldehydic products from L-glutamate or deoxyuridine at GHQ concentrations of 5-25 microM and from rat liver homogenates at GHQ concentrations of 50-250 microM; (b) cleaved plasmid pUC 18 supercoiled DNA through a single strand nick to yield open circular relaxed DNA, and through a double strand cut to give out linear DNA at GHQ concentrations of 25-200 microM, with evidence of protection by catalase and superoxide dismutase; and (c) induced cross-linking and polymerization of lymphocyte nuclear DNA through in situ generation of GHQ, which was protected by pretreatment of lymphocytes with N-ethylmaleimide. In vivo exposure of Swiss albino mice to GHQ (100 mg/kg, intraperitoneally once daily for 30 days) resulted in significant increase of liver weight and inhibition of mitotic index in the bone marrow. The other test parameters, namely spleen weight, hematological indices, hepatic sulphahydryl content and nonenzymatic lipid peroxidation, and chromosomal aberrations in the bone marrow were, however, unaffected by GHQ treatment. The observations indicate pro-oxidant and cytotoxic potential of GHQ, mediated by the reactive oxygen species generated during the course of its auto-oxidation. Bioreactivity of GHQ with cellular macromolecules in vitro and inhibition of mitotic index of bone marrow on in vivo exposure have relevance to benzene toxicity, although in situ generation of GHQ at the site of action appears critical in bringing about hematological and chromosomal effects that were probably spared due to rapid metabolic disposition and, consequently, poor bioavailability of intraperitoneally administered GHQ.

Animals↗
PubMed1999

Insulin like growth factor-1 activates nuclear factor-kappaB and increases transcription of the intercellular adhesion molecule-1 gene in endothelial cells.

A critical early event in the pathogenesis of occlusive vascular disease is the adhesion of monocytes to endothelial cells. The authors have previously reported that insulin-like growth factor-1 increases monocyte-endothelial cell adhesion and increases the expression of intercellular adhesion molecule-1. In this study, it is hypothesized that the upregulation of intercellular adhesion molecule-1 expression after treatment with insulin-like growth factor-1 is caused by an increase in the transcription of intercellular adhesion molecule-1 in endothelial cells, and that this transcription is regulated, at least in part, by activation of nuclear factor-kappaB. Adherence cell assays were performed using insulin-like growth factor-1 treated human umbilical vein endothelial cells and human monocytes. To determine the role of nuclear factor-kappaB, Western blotting using the anti-p65 (activated portion of nuclear factor-kappaB) was performed on cell lysate of human umbilical vein endothelial cells treated with insulin-like growth factor-1. RT-PCR was performed on RNA extracted from insulin-like growth factor-1-treated human umbilical vein endothelial cells. Intercellular adhesion molecule-1 antibody attenuated the increase in monocyte-endothelial cell adhesion of endothelial cells exposed to insulin-like growth factor-1. We observed an increase in expression of the activated nuclear factor-kappaB p65 protein in response to insulin-like growth factor-1 treatment. Peak increase occurred at 30 min. This effect was sensitive to pretreatment of human umbilical vein endothelial cells with the insulin-like growth factor-1 receptor antibody. Human umbilical vein endothelial cells treated with insulin-like growth factor-1 for 2 and 4 h revealed a significant increase in intercellular adhesion molecule-1 mRNA as compared with untreated human umbilical vein endothelial cells. Tumor necrosis factor-alpha produced a larger increase in intercellular adhesion molecule-1 mRNA expression. These results suggest that insulin-like growth factor-1 enhances intercellular adhesion molecule-1 transcription and activates nuclear factor-kappaB in endothelial cells. The intracellular pathways that increase cell adhesion molecule expression may provide a common link to understanding the monocyte-endothelial cell adhesion that occurs in the early stages of atherosclerosis and restenosis.

Arteriosclerosis↗
PubMed1999

Performance of broiler chicks fed on diets containing urea ammoniated neem (Azadirachta indica) kernel cake.

1. The performance, nutrient utilisation, blood profile, carcase composition, gross pathology and sensory evaluation of meat from broiler chicks fed from 3 to 42 d on diets containing urea ammoniated neem (Azadirachta indica, A.juss) kernel cake (NKC) as a protein supplement to replace peanut meal (PNM), were evaluated. NKC was ammoniated with urea at 15 (UANKC 1) or 25 g (UANKC 2)/kg and incorporated into the test diets to replace either half (134.5 g/kg (L-UANKC 1) and 127.5 g/kg (L-UANKC 2), respectively) or all (269, g/kg (H-UANKC 1) and 255.0 g/kg (H-UANKC 2), respectively) of the nitrogen provided by the PNM. 2. The growth, food intake and efficiency of nutrient utilisation of the birds were comparable between the reference and L-UANKC 1 and 2 diets but were depressed on the other UANKC diets. 3. The retention of dry matter (DM), crude fibre (CF), nitrogen-free extract, total carbohydrate, gross energy, acid detergent fibre, calcium and phosphorus were similar among groups, except lower DM and higher CF and phosphorus retentions were noted in chicks fed on the H-UANKC 1, H-UANKC 2 and L-UANKC 2 diets. All the chicks were in positive nitrogen balance and percentage nitrogen retention did not differ between the reference and test diets. 4. Haemoglobin, total erythrocyte count and aspartate amino transferase activity were unaffected by diet, but total leucocyte count was higher in chicks fed on the H-UANKC 1 and 2 diets and alanine amino transferase activities were lower in chicks fed on the test diets. Blood urea increased as the amount of urea in the diets increased. 5. Most of the physico-chemical carcase characteristics from birds fed on the L-UANKC 2 were comparable to those from birds fed on the reference diet. No bitter taste was noticed in cooked meat from any diet by the sensory panel. 6. Incorporation of L-UANKC 2 was economical and responses were comparable to those observed on the reference diet. 7. It was concluded that NKC detoxified with 25 g urea/kg can economically and successfully replace half the nitrogen of PNM in broiler diets thereby mitigating the chronic shortage of costly oil cakes in developing countries.

Ammonia↗
PubMed1998

Morphologic and temporal analysis of vascular smooth muscle cell apoptosis induced by c-myc and E1A.

Apoptosis is a physiologic form of cell death present in many disease conditions. When the balance of mitosis versus apoptosis is altered, tumor-like growth or degeneration of tissues may ensue. This appears to occur in several diseases, including those of the cardiovascular system, where apoptosis plays a key role in atherosclerosis and restenosis following angioplasty. Since c-myc is upregulated in the pathogenesis of these diseases, we chose to study the sequential morphologic features of programmed cell death in vascular smooth muscle cells induced by c-myc and by the adenovirus early gene E1A. Morphology and timed events in apoptotic cell cultures were analyzed by scanning electron microscopy, transmission electron microscopy, and time-lapse videomicroscopy. We observed that both c-myc- and E1A-induced apoptosis (in serum-free medium) resulted in numerous, tightly packed clusters of apoptotic blebs, as well as in one or two asymmetrically larger blebs. Transmission electron miscroscopy analysis revealed the larger blebs contained mostly nuclear chromatin, whereas the many smaller fragments often had little or no chromatin. Time-lapse studies showed that apoptosis was induced at a slower rate in cells stably transfected with c-myc versus those stably transfected with E1A. The early changes of apoptosis, including cell shrinkage and intense blebbing, occurred in under 5 min in both cells. Slight alterations such as cell size and further rounding occurred up to 8 h following the initial changes of apoptosis. Rather than being a part of the apoptotic response, release from the culture floor almost entirely resulted from movement of the culture flask. These studies provide a framework of timed morphologic events for future mechanistic investigation into the key aspects of myc- and E1A-induced apoptosis in vascular smooth muscle.

Adenovirus E1A Proteins↗
PubMed1998

Mechanisms controlling cellular suicide: role of Bcl-2 and caspases.

Apoptosis is an essential and highly conserved mode of cell death that is important for normal development, host defense and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in degenerative conditions, vascular diseases, AIDS and cancer. Among the numerous proteins and genes involved, members of the Bcl-2 family play a central role to inhibit or promote apoptosis. In this article, we present up-to-date information and recent discoveries regarding biochemical functions of Bcl-2 family proteins, positive and negative interactions between these proteins, and their modification and regulation by either proteolytic cleavage or by cytosolic kinases, such as Raf-1 and stress-activated protein kinases. We have critically reviewed the functional role of caspases and the consequences of cleaving key substrates, including lamins, poly(ADP ribose) polymerase and the Rb protein. In addition, we have presented the latest Fas-induced signalling mechanism as a model for receptor-linked caspase regulation. Finally, the structural and functional interactions of Ced-4 and its partial mammalian homologue, apoptosis protease activating factor-1 (Apaf-1), are presented in a model which includes other Apafs. This model culminates in a caspase/Apaf regulatory cascade to activate the executioners of programmed cell death following cytochrome c release from the mitochondria of mammalian cells. The importance of these pathways in the treatment of disease is highly dependent on further characterization of genes and other regulatory molecules in mammals.

Animals↗
PubMed1998

Chlamydia pneumoniae and occlusive vascular disease: identification and characterization.

Chlamydia pneumoniae, a respiratory pathogen, has been associated with occlusive vascular disease, including atherosclerosis and intimal hyperplasia, through seroepidemiologic studies. Furthermore, using immunohistochemistry (IHC), polymerase chain reaction (PCR), transmission electron microscopy (TEM), and in situ hybridization, this association has been reconfirmed by detecting this organism in atherosclerotic vascular tissue. This review summarizes and critically analyzes these findings and also discusses various mechanisms of how Chlamydia pneumoniae could be involved in the pathogenesis of occlusive vascular disease. Although more studies are needed to reproduce these results and, possibly, uncover a mechanism, the current literature fails to include detailed methodologies for studying Chlamydia pneumoniae. Therefore, to provide a general standard, we have also outlined specific protocols for IHC, PCR, and TEM. These protocols incorporate essential components from various studies and are presented in a concise and easily adaptable format.

Arterial Occlusive Diseases↗
PubMed1998

Measurement of bronchoconstriction using whole-body plethysmograph: comparison of freely moving versus restrained guinea pigs.

We have previously measured pulmonary function in guinea pigs using a double-chambered plethysmograph, however, the question remains regarding the accuracy of the double-chamber to gauge the long-term pulmonary function of late asthmatic response. This may be affected by confounding factors, such as stress on the animal and differences in size of the collar around the neck. Therefore, in this study we compared histamine-induced bronchoconstriction in the same guinea pigs using a single- versus a double-chambered body box. In the double-chambered body box, the specific airway resistance is proportional to time delay between thoracic and nasal flows and measured in cmH2O x s. Whereas, in the single-chambered body box, PenH units (Enhanced Pause) reflect "effort of breathing." This is measured as the pause between inspiration and expiration. Doubling concentrations of histamine (12.5-200 microg/ml dissolved in normal saline) were administered by DeVilbiss nebulizer for 1 min, followed by 1 min suction of residual drug in the chamber, and then the airway resistance was recorded by the computer for the following 3 min. There was a 15-min wash-out period between two doses of histamine. There was no statistically significant difference (p > 0.05) in the PC100 values for histamine between the two methods, however, it was much easier to work with the single-chambered body box in terms of handling the animal and eliminating the possible influence of collar placement on the bronchoconstriction. In conclusion, the data suggests histamine challenges produce equivalent PC100 data in both the double-chambered plethysmograph with sRAW units and single-chambered plethysmograph using the PenH units.

Aerosols↗
PubMed1998

An in vivo model of beta-adrenoceptor desensitization.

Chronic use of beta2-agonists and increased production of inflammatory mediators during the late allergic reaction after antigen challenge results in the desensitization of beta-adrenoceptors in the airways and the accompanying rise in nonspecific airway hyperresponsiveness. In this study, we established an in vivo model of beta2-adrenoceptor desensitization in guinea pig airways by administration of IL-1beta intratracheally or chronic albuterol by inhalation. In the establishment of beta-adrenoceptor desensitization in response to both beta-agonist or inflammatory mediator, baseline pulmonary function responses were established to methacholine and isoproterenol-induced relaxation of methacholine bronchoconstriction. This was followed by the administration of IL-1beta (500 IU/d intratracheally for 2 days) or chronic albuterol (0.1 g/L by aerosol for 1 min three times a day for 10 days). After administration, the methacholine and isoproterenol-methacholine response was once again evaluated. Intratracheal administration of IL-1beta or chronic administration of albuterol significantly decreased (p < 0.05) the protective effect of isoproterenol on methacholine-induced bronchoconstriction, eliciting beta-adrenoceptor desensitization in vivo. The in vivo model will be very useful in monitoring the effect of other potential drugs on beta-adrenoceptor function in the airways.

Administration, Inhalation↗