Food restriction-mediated adrenal influences on antigen-induced bronchoconstriction and airway eosinophil influx in the guinea pig.

The aim of this study was to measure the effects of food restriction on antigen-induced bronchoconstriction and inflammatory cell influx in guinea pigs and to determine the role of plasma cortisol and catecholamine concentrations. Ovalbumin (OA; 0.3 mg/kg, i.v.) was administered to OA-sensitized, anesthetized guinea pigs which had been allowed free access to food or had been food restricted for 18 h prior to OA challenge. In addition to higher plasma levels of epinephrine (30% increase) and cortisol (33% increase), fasted guinea pigs had significantly lower (60% decreased) maximal bronchoconstrictor responses to OA than nonfasted, sensitized litter mates. Additionally, groups of fasted or fed animals were subdivided into two additional treatment groups: (1) saline-pretreated or (2) polyethylene glycol 400 (PEG)-pretreated (1 ml/kg, p.o., 1 h prior to antigen challenge). In saline-treated, fasted animals, bronchoconstrictor responses to antigen were significantly diminished (67% decreased) and epinephrine and cortisol levels were increased (64 and 34%, respectively) compared to the corresponding fed group. In both fasted and fed groups, the PEG-treated guinea pigs had higher plasma epinephrine and cortisol levels than animals which received saline, but no significant differences were detected within the PEG-treated group. Plasma norepinephrine concentrations were lower in all fasted groups. In a separate model in conscious guinea pigs, there were no differences in aerosol OA-induced bronchoconstriction and eosinophil influx between fasted and fed groups. However, compared to the saline pretreatment group, PEG administration reduced the antigen-induced bronchoconstriction and eosinophilia in both fed and fasted guinea pigs. We speculate that the reduced responsiveness to antigen in fasted versus fed animals may result from food-restriction-induced, stress-related release of epinephrine and cortisol from the adrenal glands, thereby suppressing mast cell degranulation or reducing responsiveness to spasmogenic and chemotactic mediators. In addition, the results suggest that oral dosing with 100% PEG may enhance this phenomenon.

The influence of endogenous catecholamines on the inhibitory effects of rolipram against early- and late-phase response to antigen in the guinea pig.

Selective inhibitors of the low-Km cAMP-specific phosphodiesterase (PDE4) inhibit inflammatory cell function and relax airway smooth muscle. Thus PDE4 inhibitors may be useful in the therapy of asthma. The present study was conducted to determine whether the in vivo activity of rolipram, a prototypical PDE4 inhibitor, is due to its ability to potentiate the anti-inflammatory effects of prostaglandins or catecholamines, endogenous activators of adenylyl cyclase, in models of the early- and late-phase response to antigen. Rolipram, administered i.v. to anesthetized, paralyzed and ventilated ovalbumin-sensitized guinea pigs, inhibited i.v. antigen-induced bronchoconstriction with an ID50 value of 0.2 mg/kg. Pretreatment with either of the beta adrenoceptor antagonists propranolol and nadolol (0.5 mg/kg i.v.), enhanced the bronchial reactivity to antigen and abolished the inhibitory activity of rolipram (0.1-10 mg/kg i.v.). In addition, the inhibitory activity of three structurally dissimilar PDE4 inhibitors was nearly abolished by propranolol. Cyclooxygenase inhibition by indomethacin slightly enhanced the reactivity to antigen but did not affect the inhibitory activity of rolipram. Plasma catecholamine concentrations were not altered by rolipram (0.3 or 1 mg/kg i.v.), which indicates that there was no stimulation of catecholamine release. Bilateral adrenalectomy reduced plasma epinephrine concentrations (from 1700 pg/ml to 400 pg/ml), significantly enhanced airway reactivity to antigen and substantially reduced the inhibitory activity of rolipram (3 mg/kg i.v.). Pretreatment of conscious guinea pigs with the beta adrenoceptor antagonist nadolol, 2 mg/kg p.o., enhanced aerosol antigen-induced bronchoconstriction and pulmonary eosinophil influx measured by bronchoalveolar lavage. Nadolol reduced the inhibitory effect of rolipram against antigen-induced bronchoconstriction but not eosinophil influx. The inhibitory effect of rolipram was unaffected by indomethacin. The present data suggest that circulating catecholamines play an important protective role against antigen-induced broncho-constriction in the guinea pig. Moreover, the inhibitory activity of PDE4 inhibitors against antigen-induced bronchoconstriction, but not eosinophil influx, is reduced by beta adrenergic blockade or adrenalectomy. Thus the inhibitory activity of PDE4 inhibitors against antigen-induced bronchoconstriction may be related to their synergism with endogenous catecholamines to suppress mast cell degranulation.

Catecholamine and beta-adrenoceptor influences on airway reactivity to antigen in guinea pigs.

The aim of the present study was to analyze the increased airway reactivity to antigen induced by beta-adrenoceptor blockade, adrenalectomy or medullectomy and to assess the contribution of circulating catecholamines to the increased reactivity. In anesthetized guinea pigs sensitized to ovalbumin (OA), administration of OA produced a dose-related bronchoconstriction characterized by threshold increases in airway insufflation pressure at 0.1 mg/kg i.v. and a near-maximal increase by 0.3 mg/kg i.v. Pretreatment with R(+) propranolol (0.5 mg/kg i.v.) 5 min prior to antigen did not significantly alter airway responses to antigen when compared to vehicle-treated animals. However, pretreatment with 0.5 mg/kg i.v. S(-) propranolol, racemic propranolol or nadolol markedly enhanced (10- to 15-fold) the airway response to the low-dose antigen. In addition, in guinea pigs which had been adrenalectomized, the reactivity to low-dose antigen was enhanced to a similar extent as that of beta-antagonist-treated animals when compared to sham-operated animals. Baseline plasma concentrations of epinephrine were significantly higher in sham-operate guinea pigs (1,494 +/- 223 ng/ml) when compared to adrenalectomized animals (412 +/- 44 ng/ml). Upon antigen exposure, epinephrine levels rose 5-fold (6,859 +/- 1,308 ng/ml) from baseline in sham-operated guinea pigs and were not significantly changed in adrenalectomized animals (848 +/- 208 ng/ml). Specific airway conductance measurements in conscious guinea pigs revealed that animals which had been medullectomized 2 weeks previously responded to lower provocative concentrations of aerosol OA (0.05-0.5%) than corresponding sham-operated animals. Airway reactivity to inhaled acetylcholine (0.1-1%) was similar in medullectomized and sham guinea pigs. Plasma concentrations of epinephrine were significantly lower in medullectomized guinea pigs (327 +/- 88 ng/ml) when compared to sham-operated animals (832 +/- 162 ng/ml). The results of the present study indicate that beta-adrenoceptor antagonism or changes in circulating epinephrine levels markedly alter the response to antigen in sensitized guinea pigs.

Inhibition of antigen-induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic AMP-specific phosphodiesterase inhibitor, rolipram.

Selective inhibition of the low Km cyclic AMP-specific phosphodiesterase has been shown to inhibit inflammatory cell function and relax airway smooth muscle. These studies were conducted to characterize the bronchodilator and anti-inflammatory activity of rolipram, an archetypical cyclic AMP-specific phosphodiesterase inhibitor, in in vitro and in vivo guinea pig airway models. In isolated tracheal rings from ovalbumin (OA)-sensitive guinea pigs, both R- and S-enantiomers of rolipram (1 microM) significantly antagonized OA-induced contractions. In contrast, neither enantiomer at concentrations up to 1 microM significantly inhibited histamine- or LTD4-induced contractions. In superfusion and mediator release experiments, both enantiomers of rolipram significantly reduced antigen-induced prostaglandin D2 release, but had minimal effect on histamine release. In anesthetized, ventilated OA-sensitive guinea pigs, racemic rolipram or enantiomers reduced OA-induced bronchoconstriction with ID50 values of approximately 0.25 mg/kg i.v. Histamine- and leukotriene D4-induced bronchoconstriction were not affected by doses of rolipram which abolished the response to OA. Higher doses (3-10 mg/kg) reduced histamine-, but not the leukotriene D4-induced bronchoconstriction. In conscious OA-sensitive guinea pigs, intragastric pretreatment with rolipram dose-dependently reduced both the OA-induced decreases in specific conductance as well as the corresponding pulmonary eosinophil influx as assessed by both bronchoalveolar lavage and histological evaluation. Therefore, rolipram produces significant inhibition of antigen-induced bronchoconstrictor and inflammatory responses, thus providing strong evidence that this pharmacological approach may be of significant therapeutic value in allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)