PAF-induced bronchial hyperresponsiveness in the rabbit: contribution of platelets and airway smooth muscle.

1. Aerosol administration of platelet activating factor (PAF) to normal rabbits induced an enhanced airway responsiveness to inhaled histamine, 6 and 24 h after exposure. Following exposure to bovine serum albumin (BSA) as the carrier molecule for PAF, there was an increase in airway responsiveness to histamine 6 h after challenge, although by 24 h this was not significantly different from the responsiveness of airways to histamine before BSA. 2. PAF-induced bronchial hyperresponsiveness at 24 h was associated with a substantial increase in the number of neutrophils and mononuclear cells and a small, but significant increase in the number of eosinophils in the lungs as assessed by bronchoalveolar lavage. BSA exposure failed to alter the total number of cells in the lungs, although there was a significant increase in the number of neutrophils in the bronchoalveolar lavage fluid. 3. Selective platelet depletion with a guinea-pig anti-rabbit platelet serum inhibited PAF-induced bronchial hyperresponsiveness. In addition, there was an attenuation of PAF-induced airway inflammation in animals rendered thrombocytopenic. 4. The contractile potency to histamine, methacholine and carbachol was similar in intrapulmonary bronchi taken from rabbits exposed to an aerosol of BSA or PAF. Furthermore, the relaxant potency to the non-selective beta-adrenoceptor agonist isoprenaline, was unaltered in PAF-treated rabbits. In contrast, there was a 2.58 fold reduction in the relaxant potency to theophylline in rabbits exposed to PAF compared with rabbits exposed to BSA. 5. These results suggest that in the rabbit, PAF-induced bronchial hyperresponsiveness at 24 h is associated with airways inflammation and is dependent upon platelet activation, but is not related to changes in airway smooth muscle function.     

Endothelin-1 and bronchial hyperresponsiveness in the rabbit

Endothelins (ETs) are a family of peptide mediators that have a number of biological properties, including the ability to act as potent bronchoconstrictors of isolated human airways. Moreover, elevated concentrations of ET-1 in the bronchoalveolar lavage fluid from patients with symptomatic asthma have also been detected. We investigated the possible contribution of ET-1 in the development of bronchial hyperresponsiveness and the role of inflammatory cell accumulation in rabbit lungs. Our data show that ET-1 challenge to rabbits does not modify basal lung function but results in an increased airway responsiveness to inhaled histamine. Endothelin-treated rabbits were 3-fold (P<0.01) more responsive to inhaled histamine when compared with vehicle-treated rabbits. This hyperresponsiveness was not associated with an alteration in either total or differential inflammatory cell numbers as assessed by bronchoalveolar lavage (BAL). Pre-treatment with capsaicin (80 mg/kg s.c.) did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by endothelin-1, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine, achieved 24 h following endothelin-1 challenge. These results indicate that ET-1 may play a role in the development of bronchial hyperresponsiveness to inhaled histamine and that the maintenance of this state is unrelated to a detectable alteration in cellular infiltration within the airway lumen, but probably via the involvement of capsaicin-sensitive nerves.     

Effect of erythromycin on bronchial hyperresponsiveness in patients with bronchial asthma.

The effects of erythromycin (erythromycin stearate, Erythromycin; CAS 643-22-1) on the bronchial hyperresponsiveness and the functions of lymphocytes and neutrophils were evaluated. Administration of erythromycin to asthmatic patients in a dosage of 600 mg/d for 10 weeks reduced the bronchial hyperresponsiveness measured by histamine inhalation test. Furthermore, incubation with erythromycin for 96 h inhibited the mixed lymphocyte reaction at the concentration of more than 10 mumol/l in a dose-dependent manner, and the value of IC50 was about 30 mumol/l. 2-h incubation with erythromycin showed a weak inhibition to n-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced superoxide production of polymorphonuclear neutrophils (PMNs) at the concentration of more than 30 mumol/l in a dose-dependent manner. 1-h incubation with 1 mumol/l and 100 mumol/l of erythromycin inhibited FMLP-induced chemotaxis of PMNs. The rates of inhibition at the concentration of 1 mumol/l and 100 mumol/l were 29.7% and 41.7%, respectively. Erythromycin thus showed a beneficial effect on bronchial hyperresponsiveness. This effect might be due to the regulation of the inflammatory cells.     

Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol.

The effects of theophylline on allergen-induced airway obstruction and bronchial hyperresponsiveness were investigated in allergic rabbits. This allergic rabbit model was developed in our laboratory and stimulates the human model of allergic asthma in several aspects. Four allergic rabbits with hyperreactive airways were challenged with ragweed to elicit early- and late-phase asthmatic responses and subsequent increased airway responsiveness. Two to three weeks later, the rabbits received theophylline (5 mg/ml, nebulized for 3 min) prior to a second allergen challenge. Theophylline significantly inhibited the allergen-induced early- and late-phase asthmatic responses by 38% (P < 0.05) and 49% (P < 0.05), respectively. Further theophylline inhibited the allergen-induced increase in lung resistance by 42% (P < 0.05) during the late-phase responses. Theophylline also inhibited the allergen-induced bronchial hyperresponsiveness by 39% (P < 0.05) at 24 h. These data suggest a potential anti-inflammatory effect of theophylline in preventing allergen-induced asthmatic responses and bronchial hyperresponsiveness.     

Inhibition of PAF-induced eosinophil accumulation in pulmonary airways of guinea pigs by anti-asthma drugs

Intraperitoneal (i.p.) injection of platelet activating factor (PAF) in guinea pigs caused a dose-related increase in the number of eosinophils recovered from bronchoalveolar lavage fluid (BALF). The prevalence of eosinophils in BALF had significantly increased within 1 hr of i.p. injection of PAF (10 micrograms/animal) and was maximal after 24 hr. Subcutaneous osmotic mini-pumps were used to administer drugs for 5 days prior to i.p. injection of PAF (10 micrograms/animal) and for the subsequent 24 hr. The percentage increase of eosinophils in BALF, due to PAF, was inhibited in animals treated with dexamethasone, aminophylline, cromoglycate, tranilast or ketotifen, but not in animals treated with oxatomide, azelastine, amlexanox, ibudilast or AA-861. These results suggest that inhibition of pulmonary eosinophilia may be a necessary property of prophylactic anti-asthma drugs and provide indirect evidence favoring a role for PAF in eosinophilia of asthma.     

Endothelin-1 induced bronchial hyperresponsiveness in the rabbit: an ETA receptor-mediated phenomenon

Endothelin-1 (ET-1) is a potent and efficacious spasmogen of airway smooth muscle. Recent observations suggest that an increased intrapulmonary production of ET-1 may occur in asthma. Our previous study showed that endothelin-1 induced bronchial hyperresponsiveness to inhaled histamine in the rabbit. The aim of this study was to investigate whether the ET(A) and ET(B) receptors mediate the bronchial hyperresponsiveness induced by endothelin-1 in the rabbit. Our data showed that bronchial hyperresponsiveness induced by ET-1 was significantly inhibited (P<0.01) by the ET(A) receptor-selective antagonist, FR 139317 (from 2.5 to 10 mg kg(-1)). Moreover, bosentan (from 2.5 mg kg(-1) to 10 mg kg(-1)), an ET(A)/ET(B) receptor antagonist, also inhibited the bronchial hyperresponsiveness achieved 24 h following endothelin-1 challenge (P<0.01), but with no difference from FR 139317. The ET(B) receptor agonist, sarafotoxin S6c (from 25 microg to 2.5 mg kg(-1)) did not modify airway responsiveness to inhaled histamine in the rabbit. These results indicate that bronchial hyperresponsiveness induced by ET-1 may be mediated by ET(A) receptor activation.     

PAF-induced muscarinic cholinoceptor hyperresponsiveness of ferret tracheal smooth muscle and gland secretion in vitro.

1. The effects of exposure of the ferret trachea in vitro to platelet activating factor (PAF) were examined on methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs, and albumin transport across the tracheal epithelium. 2. Methacholine (0.1-30 microM) produced concentration-dependent increases in tracheal smooth muscle tone and mucus volume, lysozyme and albumin outputs from the trachea. 3. The concentration-response curves for methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs were all shifted upwards after exposure of the trachea to PAF (1 microM) with a significant increase in maximum response for each variable. The EC50 values for methacholine-induced smooth muscle contraction and mucus volume output were significantly reduced after PAF exposure suggesting an increase in the potency of methacholine. The concentration-response curve for methacholine-induced albumin output was shifted downwards after PAF exposure with a greatly reduced maximum but no change in the EC50 for methacholine. 4. PAF-induced hyperresponsiveness of methacholine-induced smooth muscle contraction, mucus volume and lysozyme outputs was not affected by indomethacin, FPL55712, or mepyramine and cimetidine, but was prevented by catalase and superoxide dismutase (SOD), and by WEB2086. Similarly, PAF-induced inhibition of methacholine-stimulated albumin output was prevented by catalase and SOD, and by WEB2086. 5. We conclude that PAF induces hyperresponsiveness of ferret tracheal smooth muscle and submucosal gland secretion (including lysozyme secretion from serous cells) to methacholine. This hyperresponsiveness is probably produced by receptor-mediated release of oxygen free-radicals. The inhibition of methacholine-induced albumin flux suggests a loss of epithelial function which is also probably mediated by release of free-radicals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of transdermal scopolamine on pulmonary function, symptoms and bronchial hyperresponsiveness to methacholine

This study is a result of two consecutive double-blind, placebo-controlled, cross-over studies. In the first study, we evaluated therapeutic effects of a single transdermal scopolamine patch (Scopoderm® TTS, size 2.5 cm², Ciba Geigy) on forced expiratory volume in one second (FEV₁), reversibility, peak expiratory flow (PEF) and symptoms in ten patients with reversible airways disease (ΔFEV₁9% predicted). During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels. The drug was adequately taken up from the patch into the systemic circulation. However, no significant clinical effects, nor correlations between the scopolamine levels and the outcome parameters were observed. Because of the possibility of sub-therapeutic doses in the first study, a second study with two transdermal scopolamine patches was performed in ten patients with bronchial hyperresponsiveness to methacholine. The blood and urine concentrations of free scopolamine were doubled compared to the first study. There were still no statistically significant effects on FEV₁, PEF, symptoms, and bronchial hyperresponsiveness, yet most of the patients now reported adverse side effects. We conclude that transdermal administration of scopolamine is not clinically useful in asthma and chronic obstructive pulmonary disease. Even application of two patches does not result in therapeutically effective levels at the muscarinic receptors in the lung, yet causes several side effects.     

Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats

We examined the effects of different immunomodulators administered topically on asthmatic responses in a rat model of asthma. Sensitised Brown-Norway rats were administered rapamycin, SAR943 (32-deoxorapamycin), IMM125 (a hydroxyethyl derivative of D-serine(8)-cyclosporine), and budesonide by intratracheal instillation 1 h prior to allergen challenge. Allergen exposure induced bronchial hyperresponsiveness, accumulation of inflammatory cells in bronchoalveolar lavage fluid, and also an increase in eosinophils and CD2+, CD4+ and CD8+ T cells in the airways. Interleukin-2, interleukin-4, interleukin-5, interleukin-10, and interferon-gamma mRNA expression was upregulated by allergen exposure. Budesonide abolished airway inflammation, suppressed the mRNA expression for interleukin-2, interleukin-4, and interleukin-5 (P<0.03), and bronchial hyperresponsiveness (P<0.05). IMM125 suppressed airway infiltration of eosinophils, and CD8+ T cells (P<0.02), and prevented the upregulated mRNA expression for interleukin-4, interleukin-5, and interferon-gamma (P<0.02). Rapamycin suppressed CD8+ T cell infiltration in airway submucosa (P<0.03), and mRNA expression for interleukin-2 (p<0.002), while SAR943 suppressed interleukin-2, interleukin-4, and interferon-gamma mRNA (P<0.05). IMM125, rapamycin and SAR943 did not alter airway submucosal CD2+ and CD4+ T cell infiltration, and bronchial hyperresponsiveness. CD8+ T cells, in contrast to CD4+ T cells, are more susceptible to the inhibition by IMM125 and rapamycin, which also caused greater suppression of Th1 compared to Th2 cytokine mRNA expression. In this acute model of allergic inflammation, differential modulation of Th1 and Th2 cytokines may determine the effects of various immunomodulators on airway inflammation and bronchial hyperresponsiveness.     

Effect of ageing on response to nicotine in rabbit bronchial preparation.

1. Effect of ageing on the response to nicotine was tested in the bronchial muscle preparations from 5, 13, 100 and 125 week-old rabbits. The pD2 value (potency) of nicotine significantly increased in the preparation from the 125 week-old rabbits. No age-related change was found in the pD2 value of carbamylcholine or pA2 value of atropine. 2. No age-related change in characteristics of nicotine receptors. Choline acetyltransferase activity, the amount of acetylcholine released by nicotine and acetylcholineesterase activity decreased in the preparations from the 125 week-old rabbits. 3. Decrease in the pD2 value of nicotine in the preparation from the older rabbit is due to a decline in choline acetyltransferase activity followed by a reduction in the acetylcholine released, and not to a change in characteristics of nicotine receptors. 4. These results also suggest that enzymes may be influenced more easily with age than drug receptors.     

Effect of resiniferatoxin on the isolated rabbit iris sphincter muscle: comparison with capsaicin and bradykinin.

The effect of resiniferatoxin on the isolated iris sphincter muscle of the rabbit was compared with the effects of capsaicin and bradykinin. The three compounds all contracted the sphincter muscle in a concentration-dependent manner. The contractions were inhibited by spantide II, a tachykinin antagonist. The concentration-response curve of resiniferatoxin was biphasic, yielding two EC50 values, one about 10,000 times lower than the other, the latter value being similar to that for capsaicin. The responses to resiniferatoxin, capsaicin or bradykinin were progressively reduced upon repeated application. The contraction evoked by either of the three compounds was not affected by thiorphan (an enkephalinase inhibitor) or captopril (an angiotensin-converting enzyme inhibitor). Pretreatment with capsaicin concentration dependently reduced the contractile response to a subsequent application of resiniferatoxin and vice versa. Bradykinin pretreatment reduced the resiniferatoxin response by about 50%; resiniferatoxin pretreatment completely abolished the response to bradykinin. Also, the contractile response to electrical stimulation was reduced concentration dependently by resiniferatoxin, capsaicin and bradykinin pretreatment. The response to electrical stimulation could be completely abolished by pretreatment with large doses of resiniferatoxin or capsaicin; pretreatment with large doses of bradykinin reduced the response by about 50%. Pretreatment with high concentrations of resiniferatoxin, or capsaicin, but not bradykinin, reduced the contractile response to the NK1 receptor agonist, [Sar9, Met(O2)11]SP (10(-8) M). The results suggest that the three compounds produce tachyphylaxis, mainly through partial (bradykinin) or complete (capsaicin, resiniferatoxin) exhaustion of the neuronal pool of releasable tachykinins although desensitization of tachykinin receptors may also contribute.     

Effect of pirenzepine and gallamine on cardiac and pulmonary muscarinic receptors in the rabbit.

1. The effect of muscarinic antagonists considered to be selective for M1 receptors (pirenzepine) and for M2 receptors (gallamine) were studied on bronchoconstriction and bradycardia elicited by stimulation of the vagal nerves and by i.v. acetylcholine (ACh) in anaesthetized rabbits. 2. Pirenzepine was equipotent as an antagonist of ACh-induced responses at postjunctional muscarinic receptors in the heart, lung and blood vessels, whereas gallamine was at least ten times less potent at pulmonary and vascular muscarinic receptors. Thus, gallamine never caused complete inhibition of bronchoconstrictor or hypotensive responses to i.v. ACh, whereas doses of pirenzepine in excess of 1 mumol kg-1 abolished all muscarinic responses. 3. In the lung, both antagonists inhibited bronchoconstriction caused by vagal stimulation and ACh-induced bronchoconstriction to the same extent (pirenzepine, mean ED50 65 +/- 22 and, 130 +/- 28 nmol kg-1 respectively; gallamine, ED50 greater than 10,000 nmol kg-1 for both responses). Enhancement of vagally-induced bronchoconstriction was never observed. 4. In the heart, however, both pirenzepine and gallamine were ten times less potent as antagonists of vagally-induced bradycardia than of ACh-induced bradycardia. This differential blockade was unaltered by propranolol (1 mg kg-1) pretreatment. 5. It is concluded that there is no evidence for M1 or M2 muscarinic receptors in the pulmonary innervation of the rabbit and the potency of the antagonists in abolishing in abolishing vagally-induced bronchoconstriction was consistent with blockade of M3 muscarinic receptors on airway smooth muscle. 6. The results suggest that M2 muscarinic receptors may exert an inhibitory effect on transmission in the parasympathetic nerves innervating the heart in the rabbit.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determinants of bronchial hyperresponsiveness in subjects with rhinitis

Subjects with rhinitis but without asthma may have coexisting bronchial hyperresponsiveness, although the reasons for this are uncertain. To evaluate the factors that determine BHR in rhinitis we examined 410 patients with symptomatic rhinitis with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC)>or=80% of the predicted value. In all subjects a skin prick test (SPT) was performed, a determination of total serum IgE and an eosinophils count in the blood. Of the 410 subjects we found that 161 (39.3%) exhibited a methacholine PD20 of 800 mg or less (Group A), whereas 249 (60.7%) had a methacholine PD20 more of 800 mg (Group B). Despite the matched mean values for FEV1 and FVC, compared with Group B, Group A had a lower predicted forced expiratory flow between 25% and 75%(FEF25%-75%) (86.7 +/- 12.0 vs. 93.7 +/- 7.3, P < 0.0001). A great portion of the subjects of the Group Ain respect to subjects of the Group B were exposed to passive smoke (37.8% vs. 22.0%, P = 0.0008), reported having mothers with asthma (34.1% vs. 6.0%, P < 0.0001), presented a positive skin prick test (93.7% vs. 67.0%, P < 0.0001), had higher levels of total serum IgE (geometric mean of Log10 2.46 +/- 0.27 kU/L vs. 2.06 +/- 0.38 kU/L, P < 0.0001) and higher blood eosinophil counts (geometric mean of Log10 2.67 +/- 0.07 x 10(-3) mL vs. 2.57 +/- 0.09 x 10(-3) mL, P < 0.0001), and reported increased nasal obstruction (2.0 (95% CI 1.8 to 2.2) vs. 0.6 (95% CI 0.5 to 0.7), P < 0.0001). Logistic regression demonstrates that nasal obstruction (OR 2.19, 95% CI 1.72 to 2.80) and the presence of positive SPT (OR 6.15, 95% CI 2.42 to 15.61) were the most available predictors to discriminate between subjects with BHR and subjects without BHR. In addition, BHR was positively related to blood eosinophil counts (OR= 2.80, 95% CI 1.54 to 5.07), FEF25%-75% values (OR= 2.72, 95% CI 1.23 to 5.99) and familiarity (mother) for asthma (OR = 2.45, 95% CI 1.10 to 5.46). Whereas passive smoke and total serum IgE were not positively related to BHR. Increased nasal obstruction and the presence of positive SPT were the most available predictors to discriminate between subjects with and without BHR. Finally, BHR was positively related to blood eosinophil counts, FEF25%-75% values and to familiarity (mother) for asthma.     

Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness

The role of nitric oxide (NO) in allergic inflammation and bronchial hyperresponsiveness is unclear. We studied a selective prodrug nitric oxide synthase (NOS)-2 inhibitor, L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (SC-51). In ovalbumin-sensitized and challenged rats, exhaled NO levels increased by 3 h following challenge (3.73 +/- 0.74 ppb; P < 0.05), peaking at 9 h (11.0 +/- 2.75; P < 0.01) compared to saline controls (1.87 +/- 0.26; P < 0.05 and 2.81 +/- 0.18; P < 0.01). Immunoreactive lung NOS2 expression was increased in ovalbumin-challenged rats compared with ovalbumin-sensitized, saline-challenged rats at 8 h post-challenge. SC-51 (10 mg/kg; p.o.) inhibited allergen-induced increase in exhaled NO levels to 1.3 +/- 0.17 ppb. SC-51 inhibited bronchial hyperresponsiveness in ovalbumin-sensitized and challenged rats (P < 0.05). In sensitized non-exposed rats, SC-51 increased bronchial responsiveness (P < 0.05). SC-51 reduced the allergen-induced increase in bronchoalveolar lavage neutrophils, but caused a nonsignificant reduction in bronchial mucosal eosinophil numbers. NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed.     

Effect of PF 10040 on PAF-induced airway responses in neonatally immunized rabbits.

1. The effect of adenosine on membrane voltage and ion currents was studied in rat mesangial cells in primary culture. Membrane voltage was measured with the patch clamp technique in the slow- or fast whole cell configuration. The resting membrane voltage of mesangial cells was -48 +/- 0.5 mV. Adenosine (10(-8)-10(-3) M) induced a sustained and concentration-dependent hyperpolarization of membrane voltage (ED50 approximately 6 x 10(-7) M). Adenosine (10(-5) M) hyperpolarized the membrane voltage by 14 +/- 0.5 mV. During the hyperpolarization ion currents were monitored simultaneously. An increase of the outward current by 51 +/- 11% was observed. 2. An increase of the extracellular K+ concentration (from 3.6 to 18.6 M) caused a depolarization of membrane voltage to -34 +/- 2 mV. In the presence of increased K+ the hyperpolarization of membrane voltage induced by adenosine was significantly attenuated by 61 +/- 5%. The K(+)-channel blocker, Ba2+ (5 x 10(-3) M) depolarized membrane voltage to -24 +/- 2 mV. In the presence of Ba2+ the adenosine-induced hyperpolarization was significantly inhibited by 72 +/- 8%. 3. Preincubation of the adenosine antagonist, 8-phenyltheophylline (10(-4) M) significantly inhibited the adenosine (10(-5) M) mediated membrane voltage response by 67 +/- 8%. The adenosine agonists 5-N-ethylcarboxamidoadenosine (NECA), R-(-)N6-(2-phenylisopropyl)adenosine (R-(-)-PIA), S-(+)-N6-(2-phenylisopropyl)adenosine (S-(+)-PIA), N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA), and 2-chloroadenosine (2-CA) also hyperpolarized membrane voltage of mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway hyperresponsiveness: using bronchial challenge tests in research and management of asthma.

Bronchial challenge tests have been standardized in detail during the past two decades. They are providing relevant pathophysiological and clinical information about patients with asthma or chronic obstructive pulmonary disease (COPD), by allowing the measurement of the degree of airway hyperresponsiveness, which includes an increased sensitivity as well as increased maximal response to bronchoconstrictor stimuli. There are various types of challenges, to which the responses are not interchangeable. Responses to so-called "indirect" challenges are largely dependent on the state of activation of inflammatory or resident cells within the airways, and the state of activation can vary rapidly, either spontaneously or through intervention. Responses to "direct" challenges are dependent on less variable, rather chronic features of airways inflammation or remodeling. Bronchoprovocation tests provide integrated information about multiple pathophysiological pathways within the airway. This is in contrast to the measurements of cells, mediators, or cytokines in biological fluids, which provide only very specific information on selected inflammatory pathways. It has recently been shown that the outcome of asthma can substantially be improved when long-term treatment is not only guided by symptoms and lung function, but also by the degree of airway hyperresponsiveness to direct stimuli. Taken together, current data warrant a broader usage of bronchoprovocation tests in the research as well as clinical management of asthma and COPD. In asthma, it allows selective, individually targeted therapy of the patient as opposed to the currently recommended regimens that are (increasingly) unselective in their approach. The potential benefits of monitoring other phenotypic disease markers is currently under investigation.     

Effect of chlorpromazine on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta.

1. The effects of chlorpromazine on sympathetic neuroeffector transmission have been studied in the rabbit isolated pulmonary artery and aorta. 2. Chlorpromazine (10(-8)-10(-5) M), prazosin (10(-9)-10(-7) M) and phentolamine (3 x 10(-8)-3 x 10(-5) M) decreased the contractions of pulmonary artery evoked by electrical field stimulation (150 pulses; 3 Hz). The rank order of inhibitory potency (ID50) was prazosin greater than chlorpromazine greater than phentolamine. 3. Rauwolscine (3 x 10(-9) M-4 x 10(-6) M) enhanced the neurogenic response by up to 201%. However, higher concentrations (6 x 10(-6)-3 x 10(-5) M) reduced the contractions evoked by transmural stimulation. 4. The inhibitory effect of prazosin (10(-6) M) was reversible, while that of chlorpromazine (10(-8) M) was not. 5. Chlorpromazine (10(-8)-10(-4) M), desmethylimipramine (3 x 10(-9)-10(-5) M), cocaine (10(-7)-3 x 10(-4) M) and phentolamine (10(-5)-3 x 10(-4) M) reduced the accumulation of [3H]-noradrenaline ([3H]-NA, 10(-8) M) by aorta. The rank order of inhibitory potency (ID50) was: desmethylimipramine greater than chlorpromazine greater than cocaine greater than phentolamine. Prazosin (10(-7)-10(-5) M) and rauwolscine (10(-8)-10(-4) M) did not reduce [3H]-NA accumulation. 6. Chlorpromazine (10(-8)-10(-6) M) and prazosin (3 x 10(-9)-10(-7) M) antagonized the contractions of aorta evoked by exogenous noradrenaline (10(-9)-3 x 10(-4) M) and phenylephrine (10(-9)-3 x 10(-3) M). The pA2 values for chlorpromazine on the alpha 1-adrenoceptors were 8.24 (noradrenaline) and 8.27 (phenylephrine). The corresponding values for prazosin were 8.64 and 8.57, respectively. 7. It is concluded that chlorpromazine and prazosin are potent inhibitors of postsynaptic alpha 1-adrenoceptors. Chlorpromazine and phentolamine, unlike prazosin and rauwolscine, are also inhibitors of Uptake.     

Effect of phenobarbital on cephaloridine toxicity and accumulation in rabbit and rat kidneys

Cephaloridine causes necrosis of renal proximal tubules in humans and laboratory animals. This antibiotic nephrotoxicity in rats has been shown to be reduced by mixed-function oxidase (MFO) inhibitors such as piperonyl butoxide and cobaltous chloride. The purpose of this study was to determine the effect of phenobarbital, a MFO inducer, on cephaloridine nephrotoxicity in rats and rabbits. Phenobarbital induced rabbit renal MFO activities and also potentiated cephaloridine toxicity in rabbit kidneys. In contrast, a similar treatment with phenobarbital produced little effect on rat renal MFO activities and did not alter cephaloridine nephrotoxicity in rats. These results suggested that cephaloridine may have to be bioactivated within the kidney prior to producing toxicity. However, a higher renal cortical concentration of cephaloridine was detected in phenobarbital-treated rabbits. This higher concentration appeared to be due to a greater ability of renal cortical cells to accumulate cephaloridine. Therefore, rather than as a result of enzyme induction, the potentiating effect of phenobarbital on cephaloridine nephrotoxicity might be due to the increased renal cortical accumulation of the parent drug, cephaloridine.     

The effect of prophylactic anti-asthma drugs on PAF-induced platelet accumulation in the thorax of the guinea pig

Intravenous infusion of platelet activating factor (PAF) causes an accumulation of platelets within the thorax of the guinea pig that is accompanied by increased sensitivity of the airways to spasmogens. A crystal scintillation detector has been used for measurement of intrathoracic accumulation of 111Indium-labeled platelets during responses to PAF. PAF-antagonists inhibit development of airway hyperreactivity, do not diminish platelet accumulation in response to an intravenous infusion of PAF. It is therefore concluded that intrathoracic platelet accumulation per se is not the determinant of increased airway reactivity.