Tachyphylaxis to beta-adrenoceptor agonists in human bronchial smooth muscle: studies in vitro.

In studies on human isolated peripheral airway smooth muscle; 1 A concentration dependent beta-adrenoceptor tachyphylaxis was observed to isoprenaline. 2 Cross desensitization to other beta-adrenoceptor agonists was demonstrated. 3 The desensitization was reversible with time. Hydrocortisone appeared to accelerate the recovery from the desensitized state. Low concentration isoprenaline (10(-9) mol l-1) prevented recovery whereas cyclohexamide 1.8 x 10(-4) mol l-1 had no noticeable effect on recovery. Continued occupancy of the receptor appears to prevent recovery. The recovery from the desensitized state does not apparently require synthesis of new proteins. 4 Bronchial wall cyclic AMP response to isoprenaline was attenuated after isoprenaline induced desensitization whereas total phosphodiesterase activity of bronchial wall was not altered by desensitization. Thus by exclusion the adenylate cyclase receptor complex may be altered in human peripheral airway smooth muscle beta-adrenoceptor tachyphylaxis.     

Characterization of beta-adrenoceptor subtype mediating the metabolic actions of salbutamol.

1. The following four intravenous treatments were administered in a balanced, randomized, Latin square design to four healthy volunteers: (1) saline injection (10 min); salbutamol infusion (0.15 microgram kg-1 min-1 for 60 min) (sS), (2) propranolol injection (0.3 mg kg-1 for 10 min); salbutamol infusion (pS), (3) practolol injection (2 mg kg-1 for 10 min); salbutamol infusion (PS) and (4) saline injection; saline infusion (ss). 2. Heart rate was recorded and venous blood taken for estimation of insulin, glucose and potassium before and after each injection (0 and 12-15 min) and at various times during the infusion (30,45,60 and 75 min). 3. The mean, peak % heart rate changes from baseline, control were +65.8%, +23.0%, -10.9% and -12.1%, the mean, peak % glucose changes, +61.0%, +7.1%, +3.6% and +6.9%, and the mean, peak % insulin changes, +298%, +28%, -28% and -43% during the infusions for sS, PS, ss and pS respectively. 4. The mean serum potassium levels before the injections and at the completion of the infusions were 3.98 and 3.08 4.03 and 3.63, 4.07 and 4.15, and 4.03 and 4.13 meq/l for sS, PS, ss and pS respectively. 5. Propanolol completely abolished the cardiac and metabolic responses of salbutamol. 6. Practolol produced only partial cardiac beta-adrenoceptor blockade, but completely inhibited the metabolic actions of salbutamol.     

Effects of beta-adrenoceptor agonists in human bronchial smooth muscle.

1. We have investigated the potency and duration of action of isoprenaline and a range of beta-adrenoceptor agonists as relaxants of inherent tone in human superfused, isolated bronchial smooth muscle, a tissue reported to contain a homogeneous population of beta 2-adrenoceptors. 2. All of the beta-adrenoceptor agonists caused concentration-related inhibition of inherent tone, with isoprenaline having an EC50 of 27 nM. The rank order of agonist potency was: formoterol > or = -salmeterol > or = clenbuterol > fenoterol = isoprenaline > terbutaline > or = salbutamol > quinprenaline. 3. Relaxant responses to salmeterol were fully reversed by the selective beta 2-adrenoceptor blocking drug, ICI 118551, demonstrating the involvement of beta 2-adrenoceptors. 4. Rt50, i.e. the time taken for 50% recovery from the effects of an EC50 concentration of agonist, differed considerably between the different beta 2-adrenoceptor agonists. Most agonists were short-acting, having Rt50 values less than 13 min. Quinprenaline was of moderate duration, with an Rt50 value of > or = 20 min. In contrast, salmeterol was extremely long-acting, with no sign of recovery within 4 h. 5. Estimates of relative potency and duration of action were similar to those previously determined for these agonists in the guinea-pig isolated trachea. These results suggest, therefore, that guinea-pig trachea is a suitable alternative to human bronchus for the evaluation of the actions of beta-adrenoceptor agonists on airways smooth muscle.     

Characterization of adenosine receptors mediating the vasodilator effects of adenosine receptor agonists in the microvasculature of the hamster cheek pouch in vivo

1 The aim of this study was to characterize the adenosine receptor mediating vasodilation in the microvasculature of the hamster cheek pouch in vivo. A range of adenosine agonists was used including N6-cyclopentyladenosine (CPA) (A1 agonist), 5'-N-ethylcarboxamidoadenosine (NECA) (non-selective), 2-chloroadenosine (2CADO) (non-selective), 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) (A2A agonist), N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IBMECA) (A3 agonist) and adenosine, as well as the adenosine antagonists 8-sulphophenyltheophylline (8-SPT) (A1/A2 antagonist), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (A1 antagonist) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) (A2A antagonist). 2 All the adenosine analogues used induced vasodilation at concentrations between 10 nm and 1 microm, and the potency order was NECA > CGS 21680 > 2CADO > CPA=IBMECA > adenosine, indicating an action at A2A receptors. 8-SPT (50 microm) antagonized vasodilator responses to NECA with an apparent pKB of 5.4, consistent with an action at A1 or A2 receptors and confirming that A3 receptors are not involved in this response. 3 DPCPX (10 nm) had no effect on vasodilation evoked by NECA, suggesting that this response was not mediated via A1 receptors, while ZM 241385 (10 nm) antagonized dilator responses to NECA with an apparent pKB of 8.9 consistent with an action via A2A receptors. 4 Overall these results suggest that adenosine A2A receptors mediate vasodilation in the hamster cheek pouch in vivo.     

Comparative effects of beta-adrenoceptor partial agonists on isolated rat atrium.

The chronotropic effect of three beta-1-adrenoceptor partial agonists prenalterol, xamoterol and epanolol has been compared on the right atria of the rat in order to evaluate their intrinsic activity and to place them in rank order of effectiveness. The results show that prenalterol, xamoterol and epanolol are all partial agonists. The intrinsic activities relative to that of isoprenaline are 0.84 for prenalterol, 0.59 for xamoterol and 0.29 for epanolol. This rank order of intrinsic activities should remain the same in different species and in man. Both atenolol and propranolol reversed the chronotropic effects of the three agonists. The KB of the two blockers was similar against prenalterol and xamoterol, which indicates that the two partial agonists are probably competing for the same population of receptors. The EC50 is twice as large than KB for xamoterol, which is consistent with isoprenaline working through both beta-1- and beta-2- receptors and xamoterol finds it more difficult to block the beta-2-receptors.     

Influence of the thr164ile polymorphism in the beta2-adrenoceptor on the effects of beta-adrenoceptor agonists on human lung mast cells

We have examined the influence of the thr164ile polymorphism in the beta(2)-adrenoceptor on the ability of the beta-adrenoceptor agonists, isoprenaline and salbutamol, to stabilise human lung mast cells. A total of 124 mast cell preparations were genotyped and, of these, 120 were found to be homozygous (thr164thr) at position 164 of the beta(2)-adrenoceptor and 4 were heterozygous (thr164ile). None of the preparations was homozygous for ile at position 164. In these preparations, the effects of isoprenaline and salbutamol on the IgE-mediated release of histamine from mast cells were studied. Both isoprenaline and salbutamol inhibited histamine release in a concentration-dependent manner. Average inhibitory potencies for both agonists, as assessed by pD(2) values, were higher in homozygous than in heterozygous preparations. For isoprenaline, this difference was statistically significant (P < 0.005), whereas for salbutamol, it was not (P = 0.21). These data suggest that the thr164ile polymorphism in the beta(2)-adrenoceptor may influence the extent to which certain beta-adrenoceptor agonists inhibit the responses of mast cells.     

The beta-adrenoceptor of the human lymphocyte and human lung parenchyma.

1 The response of the beta-adrenoceptors of human lymphocytes to selective agonists and antagonists has been studied quantitatively by measuring changes in cyclic adenosine-3',5'-monophosphate (cyclic AMP) levels. 2 The receptor was activated by isoprenaline and by salbutamol, and blocked by propranolol but not by practolol. A similar pattern of response was obtained with fragments of human lung tissue. 3 The mean value for pA2 for propranolol was 8.34 and for practolol was 3.95. 4 These findings indicate that the lymphocyte beta-adrenoceptor is a beta2-receptor and support the solidity of using lymphocytes to study beta-adrenoceptor function in bronchial asthma. It may also be of use in the evaluation of selective beta2-blocking drugs in man.     

Antagonism by beta-adrenoceptor blocking agents of the antianaphylactic effect of isoprenaline

1. beta-Adrenoceptor blocking agents antagonized the inhibitory (antianaphylactic) effect of isoprenaline on antigen-induced histamine release in isolated, passively sensitized, human lung and actively sensitized guinea-pig lung suggesting that the effect is exerted through beta-adrenoceptors. No antagonism was obtained with the human allergic leucocyte preparation.2. The antianaphylactic effect of isoprenaline was antagonized not only by propranolol but also by the ;selective' beta-adrenoceptor blocking agents, practolol and butoxamine.3. The classification of beta-adrenoceptors is discussed. Certain similarities between antianaphylactic and lipolytic beta-adrenoceptors are noted.     

In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline.

Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2-adrenoceptor function.     

Characterization of the PGE receptor subtype mediating inhibition of superoxide production in human neutrophils.

1. The aims of this study were to characterize the EP receptor subtype mediating the inhibition of superoxide anion generation by formyl methionyl leucine phenylalanine (FMLP)-stimulated human neutrophils, and to test the hypothesis that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is the second messenger mediating the inhibition of the neutrophil by prostaglandin (PG)E2. 2. PGE2 (0.001-10 microM) inhibited FMLP (100 nM)-induced O2-generation from human peripheral blood neutrophils in a concentration-dependent manner, with an EC50 of 0.15 +/- 0.03 microM, and a maximum effect ranging from 36-84% (mean inhibition of 68.7 +/- 2.5%, n = 32). 3. The EP2-receptor agonists, misoprostol, 11-deoxy PGE1, AH13205 and butaprost, all at 10 microM, inhibited O2- generation, causing 95.5 +/- 2.9%, 56.8 +/- 5.2%, 37.1 +/- 6.6% and 18.9 +/- 4.4% inhibition respectively, the latter two being much less effective than PGE2. Similarly, the EP1-receptor agonist, 17-phenyl PGE2 (10 microM), and the EP3/EP1-receptor agonist, sulprostone (10 microM), also inhibited O2- generation, causing 32.2 +/- 7.0% and 15.3 +/- 3.4% inhibition respectively. 4. The non-selective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX, 0.25 mM) inhibited the FMLP response by 54.5 +/- 5.0%. In addition, IBMX shifted concentration-effect curves for PGE2, misoprostol, 11-deoxy PGE1, butaprost, and AH 13205 to the left, to give EC50s of 0.04 +/- 0.03 (n = 13), 0.07 +/- 0.03 (n = 4), 0.08 +/- 0.03 (n = 4), 0.33 +/- 0.13 (n = 4) and 0.41 +/- 0.2 microM (n = 3) respectively, allowing equieffective concentration-ratios (EECs, PGE2 = 1) of 11.5, 5.3, 50.7 and 12.7 to be calculated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the receptor mediating contraction of human umbilical artery by 5-hydroxytryptamine.

The 5-hydroxytryptamine (5-HT) receptor in human umbilical artery was found to be similar to that in rabbit aorta. The pD2 was 7.45, pA2 for methysergide 8.63 and pA2 for phentolamine 6.21. Noradrenaline gave only very weak contractions at non-physiological concentrations. Amidephrine and xylazine did not contract human umbilical artery. It is concluded that there is no significant population of functional alpha-adrenoceptors in this vessel. The implications of these findings are discussed in relation to the control of the umbilical circulation.     

Characterization of the dopamine receptor mediating the hyperpolarization of cockroach salivary gland acinar cells in vitro.

1. Intracellular recordings have been made of the hyperpolarization of cockroach salivary gland cells induced by nerve stimulation and dopamine. 2. The relative potency of a number of dopamine antagonists in inhibiting the dopamine- and nerve-mediated hyperpolarization was studied. SCH23390 (10-50 microM), chlorpromazine (0.1-5 microM), haloperidol (10-100 microM) and metoclopramide (1 mM) inhibited the hyperpolarization. 3. In contrast, domperidone and (+/-)-sulpiride potentiated the hyperpolarization induced by both nerve stimulation and dopamine. 4. Apparent dissociation constants (KDapp) were obtained for the blockade of the dopamine-induced hyperpolarization. The rank order of potency (KDapp in parentheses) was as follows: chlorpromazine (0.2 microM); haloperidol (3.3 microM); SCH23390 (4.1 microM); metoclopramide (265 microM); domperidone and (+/-)-sulpiride (inactive). 5. It is concluded that the receptor subserving the dopamine-induced hyperpolarization of the salivary gland acinar cells is the same as that mediating the secretory response to dopamine. In addition these data support our findings, which suggested that this receptor is similar to the D1 dopamine receptor, but distinct from the D2 receptor found in mammalian systems.     

Tachyphylaxis to beta-adrenoceptor agonists in guinea pig airway smooth muscle in vivo and in vitro.

Beta-Adrenoceptor tachyphylaxis was induced by incubating spirally cut guinea pig tracheas with isoproterenol (2.4 x 10(-7) M) for 20 min. This incubation reduced the relaxant effects of catecholamines but not of dibutyryl cyclic AMP, theophylline or sodium nitrite. Tracheas incubated with norepinephrine, phosphodiesterase inhibitors or cyclic nucleotides became tachyphylactic to isoproterenol. Pretreatment with indomethacin prevented induction of tachyphylaxis. Incubation with adenosine, methoxamine or sodium nitrite did not induce beta-adrenoceptor tachyphylaxis. When we gave isoproterenol intramuscularly to guinea pigs, airway sensitivity to aerosolized histamine was unchanged but the toxicity of parenterally administered histamine was increased. A prolonged treatment with isoproterenol reduced airway sensitivity to histamine aerosols; this reduced sensitivity was reversed by indomethacin. Thus, beta-adrenoceptor tachyphylaxis may not explain increased toxicity of parenteral histamine after isoproterenol treatment. Elevated levels of cyclic AMP and an increased synthesis of prostaglandins may result in diminished response to beta-receptor stimulation.     

The antianaphylactic action of histamine H2-receptor agonists in the guinea-pig isolated heart.

The effects of histamine and of H1- and H2-receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea-pigs. Histamine and H2-receptor agonists (dimaprit, impromidine) dose-dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen. Nordimaprit and the selective H1-receptor agonist 2-pyridyl-ethyl-amine (2-PEA) did not modify the patterns of cardiac anaphylaxis. The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit. The H2-receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2-receptors in cardiac anaphylaxis.     

Early metabolic and endocrine effects of perorally administered beta-adrenoceptor agonists in calves

Early metabolic and endocrine changes in calves in response to two beta-adrenoceptor agonists in the absence and presence of the beta-adrenoceptor blocking agent propranolol have been studied in calves. The agonists were administered p.o. with milk in different amounts, whereas propranolol was infused i.v. for 10 h. Respiration volume, O2 consumption, CO2 production, respiratory quotient, blood glucose, lactate, non-esterified fatty acids and insulin transiently increased within 2-4 h in a dose-dependent manner, whereas glucagon, adrenaline, noradrenaline, triiodothyronine, urea, albumin and protein did not change significantly. Propranolol completely inhibited the effects on glucose, lactate, non-esterified fatty acids and insulin. Six hours after the administration of the beta-adrenoceptor agonists, the glucose clearance rates following i.v. infusion of glucose were markedly reduced and the glucose decrements in response to an i.v. injection of insulin were much smaller than in the absence of the beta-adrenoceptor agonists. The metabolic changes demonstrate an enhanced glycogenolysis and fat mobilisation, an increased metabolic rate and the development of insulin resistance within 6 h after the administration of the beta-adrenoceptor agonists.     

A comparison of the antianaphylactic activities of salbutamol and disodium cromoglycate in the rat, the rat mast cell and in human lung tissue

1 Salbutamol and disodium cromoglycate were compared for anti-anaphylactic activity against passive anaphylaxis in rat skin and peritoneum in vivo and in rat mast cells and human lung fragments in vitro.

2 Salbutamol administered intravenously to rats inhibited cutaneous anaphylaxis, but also inhibited cutaneous responses to histamine and 5-hydroxytryptamine. Salbutamol administered intraperitoneally inhibited the release of slow reacting substance of anaphylaxis (SRS-A) but not the release of histamine in the peritoneum. It was a very weak inhibitor of histamine release from rat mast cells in vitro.

3 Disodium cromoglycate administered intravenously to rats inhibited cutaneous anaphylaxis. Disodium cromoglycate administered intraperitoneally to rats inhibited the release of histamine and, to a lesser extent, SRS-A in the peritoneum. It was an effective but short-acting inhibitor of histamine release from rat mast cells in vitro.

4 Salbutamol was a potent inhibitor of the anaphylactic release of histamine and SRS-A from fragments of human lung.

5 Disodium cromoglycate was a weak inhibitor of the anaphylactic release of histamine and SRS-A from fragments of human lung. The inhibition was variable and not dose-related.

6 The concentration of salbutamol required to inhibit anaphylaxis in human lung is of the same order as that required to relax human bronchial muscle. It is suggested that salbutamol may be more effective in allergic asthma if given in a prophylactic regimen.

     

The antinociceptive action of some beta-adrenoceptor agonists in mice.

The antinociceptive actions of several beta-adrenoceptor agonist drugs have been studied in mice by use of a modified abdominal constriction test. All the drugs studied had high antinociceptive activity, with ID50 values in the nmol kg-1 range. (-)-Isoprenaline and (+/-)-isoxsuprine were the most potent, being about ten times more active than salbutamol, the least potent drug studied. All these drugs produced their action very rapidly and appear to act within the peritoneum. (-)-Isoprenaline had about six times the potency of the (+)-isomer. (+/-)-Propranolol caused rightward shifts, usually parallel, of the dose-response curves for (-)-isoprenaline. (+)-Propranolol was more than ten times less potent than the racemic drug. Practolol also caused parallel, rightward shifts of the dose-response curves for (-)-isoprenaline, and was about twice as potent as (+/-)-propranolol, whether given by subcutaneous or intraperitoneal injection. Atenolol and ICI 118551 had intermediate potencies. Propranolol, practolol and ICI 118551 were all considerably less potent in antagonizing the antinociceptive actions of fenoterol and RO363, than (-)-isoprenaline. None of these antagonist drugs showed more than a slight ability to discriminate between the beta 1- and beta 2-selective agonist drugs. No evidence was found for the involvement of opioid, dopamine, or alpha-adrenoceptors in the antinociceptive action of the beta-adrenoceptor agonist drugs. Evidence for and against the involvement of beta-adrenoceptors is discussed, and it is concluded that if these receptors do mediate the antinociceptive action they appear to be atypical.     

Characterization of the rat parotid beta-adrenoceptor.

1 The effects of various beta-adrenoceptor agonists on amylase secretion from the rat parotid gland were studied by means of two different in vitro techniques. 2 The dose-response relation for each agonist was established, as also were the ED50 values. 3 All drugs appeared to act directly on the acinar cells, as reserpine-treatment did not abolish their secretagogic effects. 4 Two groups of agonists could be distinguished: one group consisting of adrenaline, noradrenaline and the B1-selective agonist prenalterol (H133/22) with a high enzyme discharge potency and a second group consisting of the beta 2-agonists, terbutaline and salbutamol, with a markedly lower effect. 5 The present data further support the theory that rat parotid acinar cells are supplied mainly with beta-adrenoceptors of the beta 1-subtype, similar to those present in heart and adipose tissue.     

Characterization and autoradiographic localization of beta-adrenoceptor subtypes in human cardiac tissues.

1 Receptor autoradiography using (-)-[125I]-cyanopindolol (CYP) was used to study the distribution of beta-adrenoceptor subtypes in human right atrial appendage, left atrial free wall, left ventricular papillary muscle and pericardium. 2 The binding of (-)-[125I]-CYP to slide-mounted tissue sections of human right atrial appendage was time-dependent (K1 = 4.11 +/- 1.01 X 10(8) M-1 min-1, K-1 = 1.47 +/- 0.25 X 10(-3) min-1, n = 3), saturable (42.02 +/- 2.96 pM, n = 4) and stereoselective with respect to the optical isomers of propranolol (pKD (-):8.97 +/- 0.02, (+):6.88 +/- 0.06, n = 3). 3 The proportions of beta-adrenoceptor subtypes were determined in slide-mounted tissue sections using the antagonists CGP 20712A (beta 1-selective) and ICI 118,551 (beta 2-selective). In right atrial appendage and left ventricular papillary muscle 40% (34-45%) of the beta-adrenoceptors were of the beta 2-subtype. 4 Images from X-ray film and nuclear emulsion coated coverslips exposed to (-)-[125I]-CYP-labelled sections showed an even distribution of beta-adrenoceptor subtypes over the myocardium of the right atrial appendage, left ventricular papillary muscle and left atrial free wall. Sections of pericardium exhibited predominantly beta 2-adrenoceptors. beta 2-Adrenoceptors were localized to the intimal surface of coronary arteries. 5 The selective beta 1-adrenoceptor agonist RO363 and beta 2-selective agonist procaterol produced concentration-dependent inotropic responses in right atrial appendage strips. Responses to RO363 were antagonized by CGP 20712A (pKB = 9.29) suggesting an interaction with beta 1-adrenoceptors. Responses to procaterol were antagonized by ICI 118,551 (pKB = 9.06) suggesting an interaction at beta 2-adrenoceptors. 6 The finding that a significant proportion of human myocardial adrenoceptors are of the beta 2-subtype has important clinical implications for the involvement of these receptors in the control of heart rate and force, and the autoradiographic evidence suggests other roles in the coronary vasculature and pericardium.     

Comparison of the tissue affinity of glucocorticoids to human lung, nasal and skin tissue in vitro.

High affinity binding of topically applied glucocorticoids to their target tissues is the basis for prolonged action of the drug and reduces efflux into the systemic circulation that might account for adverse effects. Since little information on the accumulation and depletion of glucocorticoids to tissues of therapeutic interest is available the binding behavior of different glucocorticoids to human lung, nasal and skin tissue is now evaluated and drug concentrations in different tissues are compared. Furthermore, the role of tissue lipids and proteins in glucocorticoid binding is investigated. Therefore, sliced human lung, nasal and skin tissues are incubated with glucocorticoid containing buffers and time course of adsorption and desorption is monitored. Two model glucocorticoids, the highly lipophilic fluticasone propionate (CAS 80474-14-2) and the rather hydrophilic hydrocortisone (CAS 50-23-7) are compared respecting their binding to native and lipid-depleted tissues. While total adsorption rates to different tissues were highly comparable for each glucocorticoid the observed initial desorption was clearly different. Highest initial depletion was seen for lung tissue, lowest for skin tissue. After initial depletion a prolonged desorption of very low concentrations is observed for all tissues. Lipid depletion of tissues did neither change accumulation not depletion behavior except that about twice as high concentrations were bound and depleted, probably due to protein denaturation. It is concluded that glucocorticoids primarily bind to protein components of human lung, nasal and skin tissues. Connective tissue proteins are discussed to bind glucocorticoids with higher affinity than other protein components, thus preventing high initial release rates. While total amounts of adsorption to different tissues are equivalent and initial desorption of glucocorticoids from saturated tissues varies, highest total remaining concentrations should be observed in skin tissue followed by nasal and lung tissue. Although tissue lipids seem to play no role in total glucocorticoid binding they are suggested to influence the rate constant of uptake and depletion.