Beta-agonists and secretory cell number and intracellular glycoproteins in airway epithelium. The effect of isoproterenol and salbutamol.

This study describes the effect of systemic administration of the beta-adrenergic agonists isoproterenol and salbutamol on the secretory cell populations in seven regions of rat airway epithelium (three extrapulmonary and four intrapulmonary) and on the size of salivary glands and heart. Isoproterenol (a nonselective beta-adrenergic agonist) significantly increases secretory cell number in all airway regions except the midtrachea; salbutamol (a selective beta 2 agonist) increases secretory cell number only in proximal and peripheral regions. The absolute number of secretory cells is greatest in the most peripheral region after isoproterenol administration and in the most proximal region after salbutamol, although both drugs produce the greatest relative increase at the periphery. In proximal and, particularly, peripheral regions, the increase by isoproterenol (less than 3- and 14-fold, respectively) is greater than by salbutamol (less than 2- and less than 3-fold, respectively). In all airway regions, both drugs modify intracellular glycoprotein in the secretory cell population; within a given region, modification is much the same. In the most proximal region, the population of cells synthesizing only granules of neutral glycoprotein significantly increases while in other regions increase is in cells synthesizing only granules of acid. A significant shift in glycoprotein synthesis occurs whether or not the secretory cell population is increased, which suggests that existing as well as newly appearing cells modify their product. Isoproterenol significantly increases the size of the parotid and submaxillary glands; salbutamol increases the size of the parotid only. Isoproterenol significantly increases the weight of both ventricles of the heart; salbutamol has no such effect.     

Functional beta 1- and beta 2-adrenoceptors in the human myocardium

Functional beta-adrenoceptor populations in the human heart were studied in vitro in electrically-paced strips of the right auricular and ventricular myocardium. The relative potency of selected agonists in producing inotropic responses (Tmax, T'max) in the presence of blockers for neuronal and extraneuronal uptakes was found to be as follows: isoprenaline greater than noradrenaline = adrenaline = salbutamol greater than dobutamine. Prenalterol had a negative inotropic effect in these preparations. The selective beta 1-(practolol) and beta 2-(H 35/25) blockers reduced inotropic responses to adrenaline (Tmax, T'max) and noradrenaline (T'max) in the auricular strips. These results indicate the participation of beta 2-adrenoceptors in inotropic responses in the human auricular and ventricular myocardium. For comparison, inotropic responses of electrically-paced rat myocardium to beta-adrenergic agonists in the presence of blockers for neuronal and extraneuronal uptakes were likewise studied. The relative potencies for Tmax were: noradrenaline = adrenaline greater than prenalterol greater than dobutamine = salbutamol. Given the high relative potency of salbutamol in the human myocardial strips (analogous to that previous shown in the beta 2-dominated atria of the frog and trout) and the low relative potency of salbutamol in the rat tissue, these findings indicate a greater population of functionally active beta 2-adrenoceptors in the human than in the rat myocardium.     

Oral β-stimulants can inhibit passive cutaneous anaphylaxis in rats through an indirect inhibitory mechanism: possible involvement of afferent and efferent nervous system via gastric β 2-adrenoceptor stimulation

OBJECTIVE AND DESIGN: We previously demonstrated that oral l-ephedrine exerts an extremely rapid (within 20 s) inhibition of 48-h passive cutaneous anaphylaxis reaction (PCA) in rats by a possibly unidentified mode of action. In the present experiments, we elucidated the mechanism of the PCA inhibition by l-ephedrine using adrenoceptor agonists and antagonists. MATERIALS: Rat antiserum was prepared with dinitrophenylated Ascaris suum extract + Bordetella pertussis. TREATMENT: Passively skin-sensitised Wistar rats were mainly used. l-Ephedrine, and adrenoceptor agonists and antagonists were orally administered immediately before PCA provocation. Catecholamine depleting (6-hydroxydopamine, 6-OHDA), amine depleting (reserpine) or ganglion blocking (hexamethonium) agent was intraperitoneally or intravenously administered before the provocation. METHODS: The effects of the drugs on PCA were assessed by inhibition of the dye leakage. RESULTS: beta-(propranolol) and beta2-(butoxamine) blocking agents reduced the inhibition of PCA by l-ephedrine, while the inhibition was not altered by either an a-blocking agent (phentolamine) or a beta1-(atenolol) selective antagonist. On the other hand, beta-(isoproterenol) and beta2-selective (salbutamol) agonists showed extremely rapid inhibition of PCA. However, the beta-selective agonist (dobutamine) had no effect on the reaction. The pretreatment with hexamethonium, reserpine or 6-OH-DA substantially attenuated the inhibitory effect of l-ephedrine on PCA. CONCLUSIONS: The results strongly suggest that beta2-adrenoceptors locate in the stomach and that their receptor excitement finally may lead to the inhibition of PCA via the stimulation of the central and peripheral nervous systems.     

Influence of castration on isoprenaline-induced amylase release in parotid gland from male rats

The purpose of this study was to determine the influence of testosterone, the male sex hormone, on beta-adrenergic agonist-induced amylase secretion from rat parotid glands. Isoprenaline (isoproterenol)-induced amylase secretion was measured in vitro from the parotid glands of control and castrated rats with and without testosterone replacement. The isoprenaline-induced amylase release was reduced in parotid glands from castrated rats compared to controls. The reduction of amylase release by isoprenaline in parotid glands of castrated rats, could be reversed by administration of testosterone. Furthermore, beta-adrenergic receptor density and the level of isoprenaline-evoked cAMP in parotid glands from castrated rats was lower compared to intact rats. Using SQ-22536 (an adenylyl cyclase inhibitor), dibutyryl cAMP (a cAMP analogue) and verapamil (a calcium channel blocker), we conclude that the impairment of amylase release from parotid glands after castration was not related to either adenylyl cyclase activity or cAMP accumulation. Amylase release from the parotid glands of castrated rats appears to be mediated by an increase in calcium ion influx.     

Inhibition of Paf-acether-induced Edema of the Rat's Paw

Three classes of drugs were found, after their i.p. administration, to inhibit Paf-acether-induced edema of the rat's paw. These were beta-adrenergic agonists (isoproterenol, salbutamol), alpha-adrenergic antagonists (prazosin, ergotamine, yohimbine, phenoxybenzamine), and calcium entry blockers (nifedipine, verapamil, diltiazem). A number of other drugs including steroidal and nonsteroidal antiinflammatory agents, alpha-agonists, beta-antagonists, pyrilamine, atropine, methysergide, a lipoxygenase inhibitor, and a leukotriene antagonist did not inhibit the development of the edema. Propranolol, but not practolol, antagonized the inhibitory effect of isoproterenol which provided evidence for involvement of beta-2 receptors in the mechanism of action of the beta agonists. It is suggested that cellular calcium influx is involved in the edemagenic response observed after the injection of Paf-acether into the rat's paw.     

The human promyelocytic leukemia cell (HL-60 cell) beta-adrenergic receptor

We have characterized the beta-adrenergic receptor binding site and the beta-adrenergic cAMP response of the HL-60 cell. The hydrophilic ligand [3H]-(-)-CGP-12177 was specifically and reversibly bound to one single class of binding sites (Kd 220 pM and Bmax 1,970 sites/cell). The adrenergic agonists inhibited the specific radioligand binding. The order of potency was isoproterenol greater than epinephrine greater than norepinephrine. The beta-2 selective antagonist ICI 118551 had a binding affinity 3 orders of potency higher than the beta-1 selective antagonist, atenolol. The adrenergic agonists elevated the cAMP accumulation in a concentration-dependent mode. The order of potency was isoproterenol greater than epinephrine greater than norepinephrine. Both the binding and the functional studies revealed stereospecificity and reversibility. The present data show that HL-60 cells possess beta-2 adrenergic receptors functionally coupled to adenylate cyclase.     

Molecular pharmacology of the beta-adrenergic receptor on THP-1 cells

The beta-adrenergic receptor, its occupancy and subsequent modulation of intracellular cAMP, and mRNA expression were characterized for the promonocytic leukemia cell line THP-1. We report that THP-1 cells appear to express a beta-1 receptor with a K_d of 1.8 ± 0.3 × 10⁻¹¹μM and a B max of 108 ± 0.07 fmole/mg protein using ¹²⁵I-iodocyanopindolol (¹²⁵I-ICYP). The potency of various beta-adrenergic agonists to compete for the ¹²⁵I-ICYP binding site followed the order: isoproterenol (0.8 μM)>dobutamine (2.1 μM)>salbutamol (3 μM)>epinephrine (3.8 μM)>soterenol) (4.6 μM)>terbutaline (11.1 μM)>norepinephrine (13.8 μM). Occupancy of the beta receptor on THP-1 cells results in activation of adenyl cyclase suggesting that these cells have a functional beta-adrenergic receptor. This receptor also has specific immunoregulatory properties, reducing message levels for tumor necrosis factor — but not interleukin 1, following treatment with isoproterenol (approximate EC-50 of 0.01 μM). We conclude, based on the above criteria, that THP-1 cells express a beta-1 receptor which, following ligand binding, results in increased cAMP leading to downregulation of TNF expression.     

Effects of dobutamine and salbutamol on haemodynamics and atrial natriuretic factor in patients with severe congestive heart failure.

The influence of two cardiac inotropic drugs, dobutamine and salbutamol, on plasma atrial natriuretic factor (ANF) was investigated in 20 patients with congestive heart failure. All were in New York Heart Association class-III or IV. The patients underwent right heart catheterization with determination of central pressures, cardiac output, and pulmonary arterial plasma ANF during incremental infusions with dobutamine or salbutamol. Fourteen patients completed the study. Both drugs induced comparable increases in cardiac index and decreases in total systemic vascular resistance (P less than 0.01) without significant changes in central pressures. Heart rate rose after salbutamol (P less than 0.05), but not after dobutamine. No changes in plasma ANF were observed after either of the drug infusions. ANF secretion rate was calculated from simultaneous measurements of ANF in right atrial and pulmonary arterial plasma before and after salbutamol infusion, and median values rose more than seven-fold (P less than 0.05). The results demonstrate that ANF secretion rate is augmented after beta-adrenergic agents, possibly by a direct beta 2-adrenergic stimulation, in patients with severe congestive heart failure, and that changes in plasma ANF are an insufficient measure of ANF release when patient samples are small.     

Sympathetic nervous system and renin release from submaxillary glands in vitro.

We previously reported that alpha- but not beta-adrenergic agonists stimulate renin release from mouse submaxillary glands in vivo. The present studies were undertaken to determine if these in vivo effects were due to a direct action on the submaxillary glands and to find out if cyclic AMP (cAMP) might be involved in submaxillary renin release. Pooled mouse submaxillary gland slices were incubated in Krebs-Ringer bicarbonate medium following a preincubation period, and renin release was measured by a radioimmunoassay for the direct measurement of submaxillary gland renin. Tissue cAMP levels were also measured. Addition of the alpha-adrenergic agonists, phenylephrine or norepinephrine, significantly increased renin release (P less than 0.01 vs. control) while decreasing tissue cAMP levels (P less than 0.01 vs. control). In contrast, addition of the beta-adrenergic agonist isoproterenol markedly increased cAMP levels (P less than 0.01 vs. control) and decreased renin release (P less than 0.05 vs. control). Pretreatment of the slices with the alpha-blocker phenoxy genzamine inhibited the effect of phenylephrine. These results indicate that alpha-adrenergic agonists cause renin release from submaxillary glands which is accompanied by a fall in tissue cAMP levels. This is in contrast to renin release from the kidney which is stimulated by beta-adrenergic agonists.     

Subchronic infusion of clenbuterol, a beta-adrenergic agonist, decreases the cerebellar beta receptor

Subchronic, peripheral infusion of clenbuterol, a beta-adrenergic agonist, markedly reduced beta receptor density and isoproterenol-sensitive adenylate cyclase activity in the cerebellum of the rat. In contrast, infusion of salbutamol, isoproterenol or desipramine did not alter the beta receptor. The result of clenbuterol administration demonstrates, for the first time, a significant alteration of the cerebellar beta 2 receptor to a pharmacologic manipulation. This alteration may influence physiological and behavioral processes regulated by the cerebellum.     

Cardiovascular effects of salbutamol in rabbits anesthetized with sodium pentobarbital

1) Heart rate, instantaneous carotid blood flow (electromagnetic probe) and arterial blood pressure were recorded for 60 minutes in rabbits anesthetized with sodium pentobarbital (40 mg/kg). Anesthetic induction was made one hour before starting the measurements to allow animal preparation. These measurements were performed on three experimental groups--(A) group: anesthetized animals without any treatment (control group); (A + SA) group: anesthetized animals + intravenous (I.V.) infusion of salbutamol (300 micrograms/kg); (A + SE) group : anesthetized animal + I.V. infusion of a saline solution in the same volume and time conditions than for (A + SA) group, that is to say (10 ml within 10 min): this series was conducted to explore the specific effects of hypervolemia. 2) Comparing the SE and SA groups, it appeared, within 30 to 120 seconds, that I.V. infusion of salbutamol induced a decrease in systolic and diastolic blood pressures and a significant increase in heart rate and carotid blood flow. While heart rate and blood pressures returned progressively to their control values (A group), carotid blood flow was still higher 60 minutes after starting salbutamol infusion. 3) The possible mechanisms involved in the observed cardiovascular responses to salbutamol are discussed. The predominant effect is probably the hypotension resulting from a peripheral vasodilatation by direct stimulation of beta 2-adrenergic receptors in vascular smooth muscle. The increase in heart rate and carotid blood flow may be explained by a two fold mechanisms: direct stimulation of the beta-adrenergic receptors (beta 1 and/or beta 2) and consequences of the vasodilatation.     

Adrenaline inhibits macrophage nitric oxide production through beta1 and beta2 adrenergic receptors

This study was conducted to investigate the role of the acute stress hormone adrenaline on macrophage nitric oxide (NO) production. Murine peritoneal macrophages were stimulated in vitro with lipopolysaccharide (LPS) in the absence or presence of adrenaline. Adrenaline inhibited the LPS-induced nitrite response in a dose-dependent manner. The suppressive effect of adrenaline on NO production was mediated via beta1 and beta2 adrenergic receptors since isoprenaline (a non-selective beta1 and beta2 agonist), dobutamine and salbutamol (selective beta1 and beta2 agonists, respectively) had similar effects on the NO response. In addition, the inhibitory effect of adrenaline on NO was abrogated by both propranolol (a non-specific beta blocker) and atenolol (a specific beta1 inhibitor). In contrast to beta receptor activation, the alpha adrenergic agonist phenylephrine had no effect on the LPS NO response, and furthermore, phentolamine (an alpha receptor antagonist) did not ameliorate adrenaline's inhibitory action.     

Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.

With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed to restore CFTR function in CF. Hence, with the objective of defining optimal conditions for stimulating beta-adrenergic sweating, we have investigated the components and pharmacology of sweat secretion using cell cultures and intact sweat glands. We studied the electrical responses and ionic mechanisms involved in beta-adrenergic and cholinergic sweating. We also tested the efficacy of different beta-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca(2+)-dependent Cl(-) conductance as well as K(+) conductances. In contrast, the beta-adrenergic secretory response is mediated exclusively by activation of a cAMP-dependent CFTR Cl(-) conductance without a concurrent activation of a K(+) conductance. Thus, the electrochemical driving forces generated by beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-adrenergic agonists, isoproprenaline and salbutamol, induced sweat secretion only when applied in combination with an adenylyl cyclase activator (forskolin) or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, aminophylline or theophylline). We surmise that to obtain consistent beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are essential. beta-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects.     

Regulation of canine platelet function II. Catecholamines

The action of epinephrine (E) on canine platelet aggregation is described. Although E did not induce a change in platelet shape or aggregation, potentiation of aggregation induced by the following agents was observed at physiological E concentrations (that is, less than 10 nM/1): arachidonic acid; the dense granule agonists, ADP and serotonin (5-HT); and collagen. Epinephrine-induced potentiation was in part independent of formation of arachidonic acid metabolites, and E potentiated the aggregating action of the bivalent cationophore A23187. Potentiation was inhibited by alpha-adrenergic receptor antagonists phenoxybenzamine, phentolamine, and ergotamine, and mimicked by alpha-adrenergic receptor agonists norepinephrine, clonidine, and in some cases, phenylephrine. The beta-adrenergic receptor agonists isoproterenol and dobutamine inhibited ADP-induced aggregation, and this action was presented by pretreating the platelets with propranolol and dichloroisoproterenol. An augmentation of the aggregation response of platelets to arachidonic acid was observed in blood samples withdrawn when circulating catecholamines were elevated. The physiological implication of epinephrine acting as a gain controller that alters the relationship between actuating signal and the platelet response to an agonist is discussed.     

Divergent regulation of beta 2-adrenoceptors and adenylate cyclase in the Cyc- mouse T lymphoma cell line TL2-9

The radiation leukemia virus-induced murine Cyc- T lymphoma cell line TL2-9 expressed one homogeneous population of beta 2-adrenoceptors based on competition curves of [125I]cyanopindolol with the specific antagonist ICI 118.551 and three beta-adrenergic agonists. These receptors were uncoupled from adenylate cyclase due to the absence of Gs. The catalytical unit was directly stimulated by MnCl2, forskolin, and even more markedly in the simultaneous presence of both reagents. In contrast, the enzyme was inhibited in the presence of Gpp[NH]p, probably through interaction with Gi. Indeed, this inhibitory effect was constrained by preincubating cells in the presence of pertussis toxin and a 41 kDa protein was specifically ADP-ribosylated in the presence of the toxin. This cell line was therefore analogous to the Cyc- cell line derived from the murine S49 lymphoma cell line. When added to the culture medium, butyrate (2 mM) induced beta 2-adrenoceptors, the expression of these uncoupled receptors depending on protein synthesis, as judged by inhibitory effects of cycloheximide. In contrast, dBcAMP (1 mM) and TPA (tumor-promoting agent phorbol ester) increased the rate of disappearance of beta 2-adrenoceptors. Butyrate, dBcAMP and TPA systematically decreased adenylate cyclase activity. Besides, TPA (but neither butyrate nor dBcAMP) reduced the efficacy of Gpp[NH]p in inhibiting adenylate cyclase, suggesting a proportionately higher alteration of Gi. We conclude that beta 2-adrenoceptors, uncoupled from adenylate cyclase, are regulated independently from the catalytical unit and Gi, in this Cyc- T lymphoma cell line.     

Alteration in alpha- and beta-adrenoceptor profile of rabbit knee joint blood vessels due to acute inflammation

Experiments were performed to investigate the nature of - and -adrenoceptors in blood vessels supplying the posterior capsule of the acutely inflamed rabbit knee joint, and results were compared to findings from previous experiments on the normal joint, to assess any alteration which may occur in the adrenoceptor profile due to the inflammation process. Electrical stimulation of the posterior articular nerve resulted in vasoconstriction which was reversed to vasodilatation by phentolamine and yohimbine. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: adrenaline = phenylephrine = clonidine. The adrenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: phentolamine = yohimbine = prazosin. At this stage of the experiments there was an equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. In another group of animals the neurally mediated vasodilatation, which appeared after administration of phentolamine, was completely blocked by propranolol, and was reduced by about 50 % by atenolol. The dose-response curves to close intra-arterial injection of -adrenoceptor agonists showed a rank-order potency of: isoprenaline > salbutamol = dobutamine. The isoprenaline dose-response curve was shifted to the right by administration of antagonists with a rank-order potency of: propranolol > atenolol. These experiments also showed an almost equal response of 1- and 2-adrenoceptors in blood vessels of the acutely inflamed rabbit knee joint. Overall, compared to previous experiments on the normal joint in which 2- and 1-adrenoceptor responses predominated, acute inflammation resulted in a shift from 2- towards 1- and from 1- towards 2-adrenoceptor responses.     

The chronically isoproterenol-treated rat in the study of cystic fibrosis: X-ray microanalysis of the submandibular gland

The chronically isoproterenol-treated rat has been proposed as an animal model for cystic fibrosis. Ultrastructural studies showed enlarged cells with abnormally large mucus granules that were more often fused than in control animals. X-ray microanalysis of mucous acinar cells showed a significant increase in calcium levels, but unaffected magnesium levels. Combined treatment with isoproterenol and reserpine caused a very large increase in cellular calcium levels that appeared to be an addition of the single effects and increased magnesium levels (as in glands of rats treated with reserpine only). Chronic treatment with isoproterenol, reserpine, or both substances tended to decrease cellular potassium levels. Chronic exposure to the specific beta 1-agonist prenalterol or the specific beta 2-agonist terbutaline did not affect cellular calcium or potassium levels. It is concluded that chronic isoproterenol treatment affects the elemental composition of mucous acinar cells of rat submandibular gland differently from chronic reserpine treatment. The increase in cellular calcium concentration after chronic isoproterenol treatment does not appear to be due to an effect via beta-adrenergic receptors.     

Mechanism of regulation of amylase release by alpha- and beta-adrenergic agonists in rat parotid tissue

The effect of forskolin and isobutyl-methylxanthine on amylase release and cyclic AMP accumulation by alpha- and beta-adrenergic agonists was studied in rat parotid slices. A small increase in cyclic AMP by beta-adrenergic agonists was sufficient for maximum stimulation of amylase release (Yoshimura et al., 1982a), but a similar increase in cyclic AMP by forskolin did not stimulate the maximum amount of amylase release. The amount of amylase release and cyclic AMP changed in parallel when lower doses of isobutyl-methylxanthine were used, but higher doses of isobutyl-methylxanthine further increased cyclic AMP without causing a significant increase in amylase release. Amylase release stimulated to its maximum by isobutyl-methylxanthine was much lower than that by isoproterenol. These results suggest that cyclic AMP is not the only chemical correlate for the activation of amylase release by beta-adrenergic agonists. The effect of phenylephrine and methoxamine on amylase release was augmented by either forskolin or isobutyl-methylxanthine, but the effect of methacholine was not. Phenylephrine increased the cyclic AMP concentration under the same conditions, but methoxamine did not. The inhibition of the effect of phenylephrine plus forskolin on cyclic AMP accumulation by propranolol was almost complete and stereospecific, but the inhibition of their effects on amylase release was incomplete and not stereospecific. Synergism of amylase release was observed in the effect between methoxamine and dibutyryl-cyclic AMP. These results suggest that the augmentation of the effect of alpha-adrenergic agonists on amylase release by forskolin or isobutyl-methylxanthine cannot be explained only on changes in cyclic AMP and that some other factor in collaboration with cyclic AMP may participate in the regulation of amylase release by alpha-adrenergic agonists.     

Difference between lung and spleen susceptibility of beta-adrenergic receptors to desensitization by terbutaline

There are many reports about a marked down-regulation of beta-adrenergic receptors by beta agonists in human leukocytes. To determine whether beta receptors in lung tissue are down regulated by the long-term administration of beta agonists, as are those in the spleen (which consists largely of lymphocytes), we injected terbutaline (0.1 mg/kg, t.i.d.) intramuscularly into rats for either 3 or 6 days. We observed a significant decrease in beta-receptor density in spleen tissue but not in lung parenchyma, associated with terbutaline injection. The affinity for an antagonist did not change significantly in any group in either tissue. We did not observe any change in alpha 1-adrenergic receptors in the lung after this treatment. In in vitro studies, we also observed reduced beta-receptor density in spleen cells but not in lung parenchyma after incubation of these tissues with terbutaline. However, there was agonist-specific alteration in lung beta receptors. It was found that the isoproterenol competition curve for 3H-dihydroalprenolol binding shifted to the right and steepened, suggesting reduced affinity of the receptors for isoproterenol. We used whole lung and did not examine bronchial smooth muscle per se, nor were functional studies performed. Our results show a difference between lung parenchyma and spleen tissue in the susceptibility of beta receptors to desensitization by an adrenergic agonist and suggest that there may be such a difference in sensitivity between beta receptors in human lung and leukocytes.