Effects Of Beta-adrenergic Agonists Research Articles

Treatment of vascular smooth muscle cells with estradiol and beta-adrenergic agonists has an additive effect on cAMP levels, but no additive effect on inhibition of collagen synthesis

Several studies have suggested that increased cell levels of cAMP result in decreased rates of collagen synthesis. Oestrogen treatment of vascular smooth muscle cells (VSMCs) has been shown to cause increased levels of cAMP and decreased rates of collagen synthesis. Beta-adrenergic agonists are also known to increase cellular levels of cAMP in VSMCs, although the effect of beta-adrenergic agonists on collagen synthetic rates in VSMCs is unknown. Since beta-agonists and oestrogens are commonly used clinical agents these studies were conducted to determine the potential of these agents to have an additive effect on cell cAMP levels and inhibition of collagen synthetic rates. When VSMCs were treated with both oestrogen and isoproterenol there was an additive effect on cellular cAMP levels although the observed decrease in collagen synthetic rates was the same as observed in cells treated with just oestrogen. Treatment of VSMCs with propranolol inhibited isoproterenol-induced changes in cAMP but had no effect on either oestrogen-induced increases in cAMP levels or inhibition of collagen synthesis. The cellular location of cAMP following beta-adrenergic agonist treatment was different from the distribution of cAMP in control or oestrogen-treated VSMCs. This difference in cellular distribution of cAMP may partially explain the absence of collagen synthesis inhibition following beta-adrenergic agonist treatment of VSMCs.

Chronic pulmonary artery occlusion increases alveolar fluid clearance in rats

We had observed that pulmonary artery ligation for 14 days did not induce lung infiltration in a patient who had undergone a lobectomy for lung cancer. Our hypothesis was that long-term pulmonary artery ligation decreased lung water volume and/or increased alveolar fluid clearance. We determined the mechanism responsible for lung water balance in rats with chronic pulmonary artery occlusion for 14 days. Sprague-Dawley rats (n = 45) were used. Through a left thoracotomy, the left pulmonary artery was ligated for 14 days. Then, we measured lung water volume, alveolar fluid clearance, the effects of beta-adrenergic agonist and antagonist, mRNA expression, and protein expression in the lungs. Chronic left pulmonary artery occlusion increased both lung water volume and alveolar fluid clearance in the left lungs, but not in the right lungs with pulmonary perfusion. Neither a beta-agonist nor a beta-antagonist changed the increase in alveolar fluid clearance. Real-time polymerase chain reaction revealed an increase in alpha1-Na,K-ATPase mRNA and a decrease of beta2-adrenoreceptor mRNA, but no change in beta1-Na,K-ATPase mRNA and alpha-, beta-, gamma-epithelial sodium channel mRNA, in the left lung without pulmonary perfusion. Western blot analysis revealed an increase in alpha1-Na,K-ATPase subunit, but no change in beta1-Na,K-ATPase subunit. Chronic pulmonary artery occlusion increases alveolar fluid clearance via alpha1-Na,K-ATPase overexpression in rats.

Terbutaline inhibits corticotropin-releasing hormone (CRH) expression in human trophoblast cells

Objective. To evaluate the effect of beta-adrenergic agonists on the regulation of the expression of the placental corticotropin-releasing hormone (CRH) gene.Study design. Term placentae were collected at the time of elective cesarean section, and trophoblast cells were harvested, isolated, and cultured. The isolated trophoblasts were plated, cultured and subsequently treated with cortisol, terbutaline, RU486, or vehicle control. CRH expression, mRNA abundance of CRH, and the housekeeping gene beta-actin were evaluated by Northern blot analysis.Results. Exposure of the trophoblasts to terbutaline (10−8 M) inhibited the expression of the CRH gene as depicted by Northern blot analysis. Co-addition of terbutaline (10−8 M) and RU486 (10−6 M) did not block the stimulatory effects of RU486 on placental trophoblast cells.Conclusion. The beta-adrenergic agonist terbutaline inhibits the expression of CRH in human trophoblasts. This finding may provide insight into the mechanism of action of terbutaline as a tocolytic agent.

Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats

Type 4 phosphodiesterase (PDE4) is critical for hydrolysis of cAMP formed by stimulation of beta adrenergic receptors. However, it is not known if PDE4 is associated with beta adrenergic receptors in the mediation of antidepressant-like effects. The aim of the study is to determine the relationship between PDE4 and beta adrenergic receptor-mediated cAMP signaling in mediating antidepressant-like effects. The effects of the PDE4 inhibitor rolipram, alone or combined with dobutamine or clenbuterol, selective beta-1 and beta-2 adrenergic agonists, respectively, on behavior were examined in rats under a differential reinforcement of low rate (DRL) schedule and rats trained to discriminate rolipram from vehicle. Their effects on cAMP in primary cultures of rat cerebral cortical neurons also were determined. Rolipram (0.01-0.3 mg/kg), dobutamine (1-30 mg/kg), and clenbuterol (0.03-0.3 mg/kg) dose-dependently produced antidepressant-like effects on DRL behavior, decreasing response rate and increasing reinforcement rate. The effects of beta adrenergic agonists were potentiated by rolipram. Isobolographic analysis revealed that rolipram enhanced the antidepressant-like effect of dobutamine additively and that of clenbuterol synergistically. Consistently, a combination of ineffective doses of rolipram (0.03 mg/kg) and dobutamine (3 mg/kg) or clenbuterol (0.03 mg/kg) completely substituted for the rolipram discrimination stimulus. Further, incubation with an ineffective concentration of clenbuterol, but not dobutamine, in the presence of a subeffective concentration of rolipram, significantly increased cAMP in cultured cortical neurons. PDE4 plays an important role in regulating cAMP signaling by either beta-1 or beta-2 adrenergic receptors that mediate antidepressant-like actions; beta-2 adrenergic receptor-mediated cAMP signaling appears more responsive than beta-1 cAMP signaling to PDE4 inhibition.

Effect of beta-adrenergic agonist on alveolar fluid clearance in rats

Effect of beta-adrenergic agonist on alveolar fluid clearance in rats

Effect of beta-adrenergic agonist on alveolar fluid clearance in rats with acute lung injury

Effect of beta-adrenergic agonist on alveolar fluid clearance in rats with acute lung injury

Src-kinase-dependent epidermal growth factor receptor transactivation in salivary mucin secretion in response to β-adrenergic G-protein-coupled receptor activation

The principal regulatory factors that control the flow and make-up of salivary secretion are neurotransmitters, released by parasympathetic and sympathetic innervation, that trigger activation of G protein-coupled receptors (GPCRs) on the acinar cells of salivary glands and stimulate the generation of soluble second messengers. In this study, we report that activation of GPCR by beta-adrenergic agonist leading to stimulation in salivary mucin secretion occurs with the involvement of epidermal growth factor receptor (EGFR). Using [(3)H]glucosamine-labeled mucous acinar cells of sublingual salivary gland in culture, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited in a concentration-dependent manner by EGFR kinase inhibitor, PD153035, as well as wortmannin, an inhibitor of PI3K. Moreover, both inhibitors caused the impedance in the acinar cell mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP, as well as adenylate cyclase activator, forskolin. The acinar cell secretory responses to isoproterenol, furthermore, were blunted in a concentration-dependent fashion by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation. However, no significant alterations in the acinar cell mucin secretory responses to isoproterenol, cAMP or forskolin were attained with an inhibitor of the ERK pathway, PD98059. Our findings underline the role of EGFR as a convergence point in modulation of salivary mucin secretion triggered by beta-adrenergic agonist GPCR activation and demonstrate the importance of Src kinase in the EGFR transactivation process.

Beta adrenoceptor agonists, clenbuterol, and isoproterenol retard denervation atrophy in rat gastrocnemius muscle: use of 3-methylhistidine as a marker of myofibrillar degeneration.

The effects of beta adrenergic agonists, clenbuterol (2 mg/kg body weight/d) and isoproterenol (12 mg/kg body weight/d), in normal innervated and denervated rat gastrocnemius muscle were investigated. The daily administration of beta adrenergic agonists to normal innervated rats for a short period (7 d) resulted in the hypertrophy of gastrocnemius as confirmed from the measurement of total tissue protein contents. The development of denervation atrophy witnessed a stimulation in the expression of acid and alkaline phosphatases, pointing to an enhanced myofibrillar degeneration. An administration of beta adrenergic agonists inhibited the expression of raised levels of these enzymes in denervated muscle. A measurement of 3-methylhistidine in muscle revealed a loss of amino acid with the progress in the development of denervation atrophy. Serum and urine samples from denervated rats showed a progressive accumulation of 3-methylhistidine. Clenbuterol and isoproterenol treatment to these rats resulted in an inhibition of 3-methylhistidine accumulation. When 3-methylhistidine was used as a marker of myofibrillar degeneration, the results seemed to suggest that the degeneration of cyto-contractile apparatus accompanying denervation atrophy is attenuated in the presence of beta adrenergic agonists, implying that these sympathomimetic drugs are capable of reversing denervation atrophy in rat gastrocnemius.

Effect of beta-adrenergic agonists on mucociliary clearance.

The mucociliary clearance apparatus, an important defense mechanism for clearing the lung of bacteria and foreign particulate matter, is a well-coordinated system consisting of airway secretory cells that produce a sol and gel (or mucus) fluid layer on the airway surface and ciliated cells that propel the mucus out of the lung towards the mouth. In vivo mucociliary clearance rates can be measured by following the rate of egress of deposited, radiolabeled markers by gamma camera. Short-acting beta-adrenergic agonists have been shown to enhance mucociliary clearance rates to varying degrees in patients with various lung diseases (eg, asthma, chronic bronchitis, and cystic fibrosis), although the enhancement is generally less than that seen in the normal lung. Limited data on the in vivo dose-response relationships of these mucociliary clearance effects suggest that larger doses are required for enhancement of mucociliary clearance than are needed for bronchodilatation. Little is known about chronic effects, but studies with dosing for up to a week also suggest an enhancement of mucociliary clearance, primarily by agonists that are lipophilic. Issues for future research include the effects of the newer long-acting beta-agonists, large versus small airway effects, and combination effects with other inhaled therapeutic agents (eg, steroids and ion-channel blockers).

Membrane phosphorylation protects the cardiac sarcoplasmic reticulum Ca(2+)-ATPase against chlorinated oxidants in vitro.

The calcium (Ca) pump of cardiac sarcoplasmic reticulum (SR) membranes is vulnerable to oxidation and hence likely to be damaged by chlorinated compounds, specifically hypochlorite (NaOCl) and monochloramine (NH2Cl), the most potent oxidants produced upon neutrophil activation. This could occur during prolonged ischemia or myocardial infarction when tissue levels of catecholamines are high. Phospholamban (PLN), the phosphorylatable regulator of the Ca pump, plays a central role in the effects of beta-adrenergic agonists on the heart. The purpose of this study was to investigate a possible role of PLN in determining the pump's sensitivity to NaOCl and NH2Cl. Ca-uptake and Ca(2+)-ATPase activities in purified phosphorylated and control canine cardiac microsomes, incubated at increasing concentrations of NaOCl or NH2Cl, were related to the extent of PLN phosphorylation by protein kinase A, which was quantitated by PhosphorImager analysis. Our data indicate that microsomal phosphorylation protects the Ca pump fully against 10 microM NaOCl or NH2Cl, which inhibit Ca-uptake by 21-41% when assayed at 25 or 37 degrees C and saturating Ca2+ in unphosphorylated microsomes, and protects partially at higher oxidant concentrations. The protective effect of protein kinase A on Ca-uptake is proportional to the amount of phosphorylated PLN. No comparable protection against similar oxidative damage of the Ca pump is observed when light fast skeletal muscle microsomes, which lack PLN, are incubated under conditions favorable for phosphorylation nor when PLN's inhibition of the cardiac Ca pump is relieved by proteolytic cleavage of its cytoplasmic domain. Our findings contribute toward an understanding of possible endogenous protective mechanisms that may promote calcium homeostasis in myocardial cells in inflammatory states associated with neutrophil activation and may suggest an approach toward development of protective strategies against oxidative damage in the heart.

Beta-Adrenergic regulation of cAMP and protein phosphorylation in phospholamban-knockout mouse hearts

The stimulatory effects of beta-adrenergic agonists reflect increases in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels and phosphorylation of key regulatory proteins in the heart. One of these phosphoproteins is phospholamban (PLB) in sarcoplasmic reticulum, and ablation of PLB is associated with attenuation of the contractile responses to beta-adrenergic stimulation in the mouse heart. To determine whether this attenuation of beta-stimulation is due to altered phosphorylation characteristics of the other key cardiac phosphoproteins and/or to compensatory responses occurring in the absence of PLB, PLB-knockout and wild-type hearts were perfused and their protein phosphorylation patterns examined. The beta-adrenergic receptor density, adenylyl cyclase activity, tissue cAMP levels, and the basal phosphoprotein pattern were similar between PLB-knockout and wild-type hearts. Isoproterenol perfusion resulted in similar increases in the tissue cAMP levels and the degree of phosphorylation of troponin I, C protein, and the 21-kDa microsomal protein in wild-type and PLB-knockout hearts. These findings indicate that the attenuation of isoproterenol-mediated increases in contractility of the PLB-knockout hearts is not due to alterations in the beta-adrenergic signal transduction pathway or the degree of phosphorylation of the key cardiac regulatory phosphoproteins in myofibrils and sarcolemma.

Beta-adrenergic modulation of FMLP- and zymosan-induced intracellular and extracellular oxidant production by polymorphonuclear leukocytes.

Evaluation of catecholamine modulation of PMNL extracellular and intracellular oxidant production may reflect beneficial and harmful effects of beta-adrenergic agonists in various disease states. We investigated the kinetics and potency of adrenaline-mediated inhibition of oxidant generation in FMLP- and zymosan-stimulated PMNLs. In FMLP-stimulated cells, the short-term burst of oxidant generation was inhibited by adrenaline in a dose-dependent fashion. Intra- and extracellular chemiluminescence and extracellular superoxide anion and hydrogen peroxide generation showed similar IC50 values for adrenaline (1.3-3.0 x 10(-8) M) indicating that both extracellular and intracellular events were inhibited with the same potency. In contrast, intracellular oxidant production evoked by the phagocytosis of zymosan was only minimally affected by 3 x 10(-5) -3 x 10(-12) M adrenaline. Extracellular inhibition of oxidant production was also apparent in zymosan-stimulated cells. In conclusion, adrenaline's ability to depress extracellular generation of oxygen metabolites while retaining prolonged intracellular oxidant production for phagocytosis supports its beneficial role as selectively targeted physiological protector.

Beta-adrenergic agonists attenuate fibroblast-mediated contraction of released collagen gels.

The effects of beta-adrenergic agonists on fibroblast-mediated collagen gel contraction were investigated. beta-Agonists isoproterenol and epinephrine significantly attenuated fibroblast-mediated gel contraction in a concentration-dependent manner, whereas alpha-agonist norepinephrine had no effect. The biologically active form of isoproterenol, (-)-isoproterenol, was 10-fold more effective than the optical isoform, (+)-isoproterenol. beta-Antagonists sotalol and propranolol reversed the attenuation caused by 10(-7) M isoproterenol or epinephrine at the concentration of 10(-7) M or 10(-6) M, but the alpha-antagonist phentolamine did not. However, beta1- or beta2-specificity of these effects is not clear. Isobutyl methylxanthine augmented the effect of isoproterenol and also prolonged the duration. Two reagents which are known to increase intracellular adenosine 3',5'-cyclic monophosphate (cAMP), prostaglandin E2 and dibutyryl adenosine 3',5'-cyclic monophosphate, attenuated gel contraction in a concentration-dependent manner. These data suggest that the fibroblast-mediated collagen gel contraction can be modulated by beta-adrenergic agonists and that the effect depends on cAMP.

Dietary magnesium deficiency increases Gi levels in the rat heart after myocardial infarction

Magnesium (Mg) is crucial for the function of G proteins which play important roles in mediating the inotropic effects of beta adrenergic agonists in the heart and are altered in heart failure. This study was performed to determine whether or not dietary Mg deficiency alters functional activity and levels of the two major ventricular G proteins, Gi alpha and Gs alpha in the heart after myocardial infarction (MI). Six week old rats were fed an Mg adequate or deficient diet for 6 weeks. At the end of week 3, MI was induced by coronary artery ligation. A sham operation was performed as control. After surgery, surviving animals were maintained on their assigned diets for another 3 weeks. Then, cardiac function was measured, plasma and tissue were collected. Severe hypomagnesemia and increased plasma catecholamine level were observed in all animals fed the Mg deficient diet. A significant reduction of myocardial Mg concentration accompanied by elevated plasma and myocardial calcium concentrations was observed in MI animals with existing Mg deficiency vs. animals fed the Mg adequate diet. Cardiac function was impaired in MI rats and further reduced in MI rats with existing Mg deficiency. Gi alpha level was not altered by either Mg deficiency or MI alone, but was dramatically elevated in animals with combined Mg deficiency and MI (9.9 +/- 0.7 arbitrary unit.mg-1 protein) as compared to MI alone (5.8 +/- 0.6, P < 0.05) and Mg deficiency alone (6.1 +/- 0.8, P < 0.05). Gs alpha level did not differ between groups. GppNHp-, but not fluoride-stimulated adenylyl cyclase activity was slightly reduced in MI animals with existing Mg deficiency. The findings suggest that dietary Mg deficiency increases the expression of Gi alpha in the heart after MI, while levels and function of Gs alpha are not compromised during dietary Mg deficiency either with or without MI.

Short-term and long-term effects of beta-adrenergic agonist on Na-K-ATPase in cultured rat alveolar type II cells

Short-term and long-term effects of beta-adrenergic agonist on Na-K-ATPase in cultured rat alveolar type II cells

Functional behavior of the beta-adrenergic receptor-adenylyl cyclase system in rabbit airway epithelium.

Stimulation of adenylyl cyclase mediates the effects of beta-adrenergic agonists and prostaglandin E2 (PGE2) on tracheobronchial epithelial cell function by increasing intracellular cyclic adenosine monophosphate (cAMP). In turn, increases in cAMP affect airway function by modulating ciliary beating, chloride and water transport, mucus secretion, and release of bronchoactive substances. This study examined the function and regulation of the beta-adrenergic receptor-adenylyl cyclase system (beta AR-AC) in tracheal epithelial cells isolated from the rabbit, a frequently used animal model of airway reactivity, inflammation, and electrolyte transport. beta AR number, assessed by ligand binding using the non-subtype-specific beta-antagonist [125I]iodopindolol, averaged approximately 10,700 beta AR/cell (400 fmol/mg membrane protein). Greater than 85% of the receptors were of the beta 2 subtype as determined by competitive antagonist displacement of iodopindolol by selective beta 1- (betaxolol) and beta 2- (ICI 118,551) antagonists. cAMP synthesis was stimulated with isoproterenol, PGE2, and forskolin in a time- and concentration-dependent fashion. Preincubation of epithelial cells for 30 min with either isoproterenol (10 microM) or the peptide inflammatory mediator, bradykinin (100 microM), markedly depressed subsequent isoproterenol-stimulated cAMP synthesis. Isoproterenol-induced beta AR-AC desensitization appeared to be homologous since cAMP responses to PGE2 and forskolin, a direct activator of adenylyl cyclase, were not reduced. The effect of bradykinin on isoproterenol-stimulated cAMP response was mimicked by preincubation with either dioctanoyl glyceride or phorbol myristate acetate, activators of protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta-adrenergic agonists on splanchnic vascular volume and cardiac output

The effect of beta-adrenergic agonists on splanchnic intravascular volume (SIV), measured with radionuclide imaging, and the subsequent influence of such volume changes on cardiac output (CO) were examined in 40 anesthetized dogs. Isoproterenol (6 micrograms/min) caused a decrease in total SIV of 12 +/- 1% (P less than 0.001). The decrease was due entirely to a decrease in splenic volume of 24 +/- 3% (P less than 0.001), since volume increased in the remainder of the splanchnic vasculature [hepatic and mesenteric volume increased 12 +/- 2% (P less than 0.001) and 11 +/- 3% (P less than 0.02), respectively]. CO increased from 1,724 +/- 187 to 3,138 +/- 321 ml/min (P less than 0.001); after subsequent splenectomy, isoproterenol caused a similar increment. Isoproterenol-associated SIV changes were not altered by carotid denervation and vagotomy or by beta 1-adrenergic inhibition with metoprolol but were abolished by nonselective beta-adrenergic inhibition with propranolol. With a larger dose of metoprolol and smaller dose of isoproterenol to minimize beta 1-adrenergic effects, the isoproterenol-associated CO increment was attenuated (P less than 0.01) by splenectomy. With the beta 2-agonist terbutaline (41 micrograms/min) after metoprolol, total SIV decreased 15 +/- 4% (P less than 0.001). After subsequent alpha-adrenergic inhibition with phenoxybenzamine, terbutaline caused no change in SIV and an attenuated (P less than 0.05) increase in CO. Thus beta-adrenergic agonist administration causes a decrease in total SIV due entirely to a decrease in splenic volume. The SIV decrement is dependent on beta 2- and alpha-adrenoceptor stimulation and appears to enhance CO only if beta 1-adrenergic effects are minimized.

Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation

The positive inotropic effect of the sympathetic nervous system on the heart is partly mediated by an increase in the voltage-gated Ca2+ current (ICa). This increase is generally attributed to beta-adrenergic receptor-stimulated cyclic AMP-dependent phosphorylation of the Ca2+ channel. It has been suggested that cAMP-dependent phosphorylation cannot explain all the effects of beta-adrenergic agonists on ICa and that a parallel membrane-delimited pathway involving the 'direct' action of the G protein Gs also stimulates ICa. A precedent exists for such a membrane-delimited pathway in the activation of a K+ channel by acetylcholine in heart. A membrane-delimited pathway for stimulation of ICa might be important in rapid beat-to-beat regulation of contraction by the sympathetic nervous system, because isoproterenol may produce a biphasic increase in ICa with the rapid phase (tau = 150 ms) putatively mediated by the direct pathway and the slow phase (tau = 35 s) by cAMP-dependent phosphorylation. Here we report that in frog, rat, and guinea pig ventricular myocytes ICa increases slowly and monophasically in response to isoproterenol. The increase is completely blocked by inhibitors of cAMP-dependent phosphorylation. Furthermore, the time course of the increase in ICa closely parallels the increase in contractile force produced by sympathetic nerve stimulation. These data refute earlier suggestions that regulation of Ca2+ channels by the sympathetic nervous system involves or requires a direct G-protein pathway.

Coexistence of β1‐ and β2‐Adrenoceptors in the Melanophore of the Goby Tridentiger obscurus*

The effects of beta-adrenergic agonists and antagonists on the pigmentary state of denervated melanophores in isolated, split, caudal fins of the goby Tridentiger obscurus were examined to investigate the function and the subtype of the beta-adrenoceptors of the melanophores. Salbutamol, terbutaline, and dobutamine partially inhibited the pigment-aggregating response of melanophores to norepinephrine. The effects of these beta-agonists were inhibited by propranolol. It was confirmed that the melanophores possess both alpha- and beta-adrenoceptors, and that the activation of the beta-adrenoceptors induces the dispersion of pigment in the melanophores. Norepinephrine, epinephrine, isoproterenol, dobutamine, salbutamol, and terbutaline evoked the dispersion of pigment in the melanophores in which pigment had previously been aggregated by treatment with verapamil in the presence of phentolamine. The pigment-dispersing effects of two beta 1-selective agonists, norepinephrine and dobutamine, were effectively inhibited by metoprolol, a selective antagonist of beta 1-receptors. By contrast, the pigment-dispersing effects of two beta 2-selective agonists, salbutamol and terbutaline, were not inhibited by metoprolol. Both the effects of nonselective agonists, epinephrine and isoproterenol, were partially inhibited by metoprolol. The actions of all of the beta-agonists used were effectively inhibited by propranolol, and they were partially inhibited by butoxamine. These results suggest co-existence of beta 1- and beta 2-adrenoceptors in the melanophores. The relative numbers of beta 1- and beta 2-adrenoreceptors as a percentage of the total population of beta-adrenoceptors were estimated to be 18.6% and 81.4%, respectively, from analyses of Hofstee plots of the effects of the beta-agonists on the melanophores in the presence of butoxamine or metoprolol.

Reduced sensitivity to beta-adrenergic agonists in Basenji-Greyhound dogs

To investigate the inhibitory effects of beta-adrenergic agonists and aminophylline on pulmonary responsiveness, we evaluated the ability of albuterol and aminophylline to attenuate pulmonary responses to aerosol challenge with methacholine and histamine in intact Basenji-Greyhound (BG) and selected mongrel dogs. Pulmonary responses were measured in untreated dogs and in dogs pretreated with albuterol (1 and 2.5 micrograms/kg) or aminophylline. Before aerosol challenge, baseline pulmonary resistance (RL) and dynamic compliance (Cdyn) were not significantly different between the BGs and the mongrels. In the untreated dogs, pulmonary responses to methacholine and histamine aerosols were not different between the BGs and the mongrels. Pretreatment with albuterol (1 microgram/kg) or aminophylline significantly attenuated the pulmonary response to methacholine in the mongrels but was without effect in the BGs. Albuterol (2.5 micrograms/kg) significantly attenuated the pulmonary response to methacholine in the BGs and the mongrels; however, this attenuation was significantly greater (P less than 0.05) in the mongrels than in the BGs. In response to histamine challenge, no differences were seen between the BGs and the mongrels in the control state (no pretreatment) or after pretreatment with albuterol or aminophylline. This study demonstrates that in BGs pulmonary responsiveness to methacholine but not histamine is resistant to inhibition by beta-adrenergic agonists. This may result from a qualitative or quantitative defect in either the cholinergic or beta-adrenergic receptor or to an abnormality distal to the receptors in the signal transduction mechanism at a site where the two signals interact.