Beta-adrenergic Hyporesponsiveness Research Articles

Disruption of inducible nitric oxide synthase improves beta-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy.

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-alpha develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates beta-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dt(max) was significantly suppressed, and its beta-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved beta-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of beta-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.

Cardiac function and electrical remodeling of the calcineurin-overexpressed transgenic mouse

To study the specificity of contractile phenotype and electrophysiological remodeling in transgenic (Tg) mice with cardiac directed calcineurin (phosphatase 2B) overexpression and evaluate a possible negative role of chronically activated calcineurin in beta-adrenergic mediated contractile response. The patch-clamp technique was used to characterize electrophysiological properties of action potentials and inward rectifier (I(K1)), and transient outward potassium currents (I(to)). The analysis of the contractile performance was carried out on isolated retrograde perfused hearts at constant aortic pressure. Tg mice demonstrated a hypercontractile phenotype characterized by a profound beta-adrenergic hypo-responsiveness at 2.0 mM [Ca2+](o). Transgenic cardiomyocytes showed marked action potential prolongation (209% in APD(90)) with increased I(to,peak) and I(sus) and decreased protein expression level of Kv1.5 and Kv2.1. Lowering [Ca2+](o) to 0.75 mM restored the beta-adrenergic response, indicating that the calcineurin/calmodulin/adenylyl cyclase (AC) pathway may not be directly responsible for the blunted beta-adrenoreceptor mediated inotropism. Calcineurin overexpression leads to development of a hyperdynamic phenotype with a cellular profile of increased calcium influx. This type of functional hypertrophic remodeling is accompanied by a negative feedback regulation between increased calcium handling and beta-adrenergic contractile activation.

Expression of inducible nitric oxide synthase depresses beta-adrenergic-stimulated calcium release from the sarcoplasmic reticulum in intact ventricular myocytes.

beta-adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR) during beta-adrenergic stimulation. Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca(2+) spark frequency (CaSpF, reflecting resting RyR openings) and Ca(2+) transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 micromol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca(2+) transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca(2+) load). iNOS/NO depresses beta-adrenergic-stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits beta-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

Selected contribution: synergism between TNF-alpha and IL-1 beta in airway smooth muscle cells: implications for beta-adrenergic responsiveness.

In human cultured airway smooth muscle cells, interleukin (IL)-1 beta increases cyclooxygenase (COX)-2 expression and PGE(2) release, ultimately resulting in decreased beta-adrenergic responsiveness. In this study, we aimed to determine whether tumor necrosis factor-alpha (TNF-alpha) synergizes with IL-1 beta in the induction of these events. TNF-alpha alone, at concentrations up to 10 ng/ml, had no effect on COX-2 protein expression; at concentrations as low as 0.1 ng/ml, it significantly enhanced the ability of IL-1 beta (0.2 ng/ml) to induce COX-2 and to increase PGE(2) release. IL-1 beta and TNF-alpha in combination also significantly enhanced COX-2 promoter activity, indicating that synergism between the cytokines is mediated at the level of gene transcription. Although IL-1 beta and TNF-alpha each increased nuclear factor-kappa B activation and induced extracellular regulated kinase and p38 phosphorylation, combined administration of the cytokines did not enhance either nuclear factor-kappa B or mitogen-activated protein kinase activation. Combined administration of IL-1 beta (0.2 ng/ml) and TNF-alpha (0.1 or 1.0 ng/ml) reduced the ability of isoproterenol to decrease human airway smooth muscle cell stiffness, as measured by magnetic twisting cytometry, even though individually these cytokines, at these concentrations, had no effect on isoproterenol responses. Treatment with the selective COX-2 inhibitor NS-398 abolished the synergistic effects of TNF-alpha and IL-1 beta on beta-adrenergic responsiveness. Our results indicate that low concentrations of IL-1 beta and TNF-alpha synergize to promote beta-adrenergic hyporesponsiveness and that effects on COX-2 expression and PGE(2) are responsible for these events. The data suggest that the simultaneous release in the airway, of even very small amounts of cytokines, can have important functional consequences.

Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

P38 MAP kinase regulates IL-1 beta responses in cultured airway smooth muscle cells.

We have previously reported that interleukin (IL)-1 beta causes beta-adrenergic hyporesponsiveness in cultured human airway smooth muscle (HASM) cells by increasing cyclooxygenase (COX)-2 expression. The purpose of this study was to determine whether p38 mitogen-activated protein (MAP) kinase is involved in these events. IL-1 beta (2 ng/ml for 15 min) increased p38 phosphorylation fourfold. The p38 inhibitor SB-203580 (3 microM) decreased IL-1 beta-induced COX-2 by 70 +/- 7% (P < 0.01). SB-203580 had no effect on PGE(2) release in control cells but caused a significant (70-80%) reduction in PGE(2) release in IL-1 beta-treated cells. IL-1 beta increased the binding of nuclear proteins to the oligonucleotides encoding the consensus sequences for activator protein (AP)-1 and nuclear factor (NF)-kappa B, but SB-203580 did not affect this binding, suggesting that the mechanism of action of p38 was not through AP-1 or NF-kappa B activation. The NF-kappa B inhibitor MG-132 did not alter IL-1 beta-induced COX-2 expression, indicating that NF-kappa B activation is not required for IL-1 beta-induced COX-2 expression in HASM cells. IL-1 beta attenuated isoproterenol-induced decreases in HASM stiffness as measured by magnetic twisting cytometry, and SB-203580 abolished this effect. These results are consistent with the hypothesis that p38 is involved in the signal transduction pathway through which IL-1 beta induces COX-2 expression, PGE(2) release, and beta-adrenergic hyporesponsiveness.

Role of ERK MAP kinases in responses of cultured human airway smooth muscle cells to IL-1beta.

We have previously reported that interleukin (IL)-1beta causes beta-adrenergic hyporesponsiveness in cultured human airway smooth muscle cells by increasing cyclooxygenase-2 (COX-2) expression and prostanoid formation. The purpose of this study was to determine whether extracellular signal-regulated kinases (ERKs) are involved in these events. Levels of phosphorylated ERK (p42 and p44) increased 8.3- and 13-fold, respectively, 15 min after treatment with IL-1beta (20 ng/ml) alone. Pretreating cells with the mitogen-activated protein kinase kinase inhibitor PD-98059 or U-126 (2 h before IL-1beta treatment) decreased ERK phosphorylation. IL-1beta (20 ng/ml for 22 h) alone caused a marked induction of COX-2 and increased basal PGE(2) release 28-fold (P < 0.001). PD-98059 (100 microM) and U-126 (10 microM) each decreased COX-2 expression when administered before IL-1beta treatment. In control cells, PD-98059 and U-126 had no effect on basal or arachidonic acid (AA; 10 microM)-stimulated PGE(2) release, but both inhibitors caused a significant decrease in bradykinin (BK; 1 microM)-stimulated PGE(2) release, consistent with a role for ERK in the activation of phospholipase A(2) by BK. In IL-1beta-treated cells, prior administration of PD-98059 caused 81, 92 and 40% decreases in basal and BK- and AA-stimulated PGE(2) release, respectively (P < 0.01), whereas administration of PD-98059 20 h after IL-1beta resulted in only 38 and 43% decreases in basal and BK-stimulated PGE(2) release, respectively (P < 0.02) and had no effect on AA-stimulated PGE(2) release. IL-1beta attenuated isoproterenol-induced decreases in human airway smooth muscle stiffness as measured by magnetic twisting cytometry, and PD-98059 or U-126 abolished this effect in a concentration-dependent manner. These results are consistent with the hypothesis that ERKs are involved early in the signal transduction pathway through which IL-1beta induces PGE(2) synthesis and beta-adrenergic hyporesponsiveness and that ERKs act by inducing COX-2 and activating phospholipase A(2).

Prostanoids mediate IL-1beta-induced beta-adrenergic hyporesponsiveness in human airway smooth muscle cells.

We have previously reported that pretreatment of cultured human airway smooth muscle (HASM) cells with interleukin-1beta (IL-1beta) results in decreased beta-adrenergic responsiveness. The purpose of this study was to determine whether prostanoids released as a result of cyclooxygenase-2 (COX-2) induction by IL-1beta contribute to this effect of the cytokine. Confluent serum-deprived HASM cells were studied in passages 4-7. IL-1beta (20 ng/ml for 22 h) reduced the ability of the beta-agonist isoproterenol (Iso) to decrease stiffness of HASM cells as measured by magnetic twisting cytometry. The effect of IL-1beta on Iso-induced changes in cell stiffness was abolished by nonselective [indomethacin (Indo), 10(-6) M] and selective (NS-398, 10(-5) M) COX-2 inhibitors. Indo and NS-398 also inhibited both the increased basal cAMP and the decreases in Iso-stimulated cAMP production induced by IL-1beta. IL-1beta (20 ng/ml for 22 h) caused an increase in both basal (15-fold) and arachidonic acid (AA)-stimulated (10-fold) PGE2 release. Indo blocked basal and AA-stimulated PGE2 release in both control and IL-1beta-treated cells. NS-398 also markedly reduced basal and AA-stimulated PGE2 release in IL-1beta-treated cells but had no significant effect on AA-stimulated PGE2 release in control cells. Western blot analysis confirmed the induction of COX-2 by IL-1beta. Exogenously administered PGE2 (10(-7) M, 22 h) caused a significant reduction in the ability of Iso to decrease cell stiffness, mimicking the effects of IL-1beta. Cycloheximide (10 microg/ml for 24 h), an inhibitor of protein synthesis, also abolished the effects of IL-1beta on Iso-induced cell stiffness changes and cAMP formation. In summary, our results indicate that IL-1beta significantly increases prostanoid release by HASM cells as a result of increased COX-2 expression. The prostanoids appear to contribute to beta-adrenergic hyporesponsiveness, perhaps by heterologous desensitization of the beta2 receptor.

Allergic responses reduce the relaxant effect of beta-agonists but not potassium channel openers in guinea-pig isolated trachea

This study was conducted to determine whether the relaxant effect of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) openers on airway smooth muscle are reduced during the hyporesponsiveness of beta-adrenergic receptors. Isometric tension was measured and dose-response curves were constructed for levcromakalim (a KATP opener), Y-26763 (another KATP opener), isoprenaline and theophylline in guinea-pig isolated trachea that was challenged with ovalbumin or pretreated in vitro with either isoprenaline or the KATP openers. Antigen challenge in vitro significantly reduced the potency but not the efficacy of isoprenaline in tracheal strips from actively sensitized guinea-pigs. The concentration of drug that produced a half-maximum inhibition (IC50) was 0.014 +/- 0.004 microM in the challenge group versus 0.006 +/- 0.001 microM in the control group (p < 0.05; n = 9). The IC50 of levcromakalim (1.73 +/- 0.17 microM; n = 6) and of theophylline (110 +/- 3.1 microM; n = 6) were unaffected. Exposure to 4 microM isoprenaline for 30 min evoked beta-adrenergic hyporesponsiveness: the IC50 of isoprenaline rose significantly from 0.010 +/- 0.001 to 0.017 +/- 0.002 microM (p < 0.01; n = 6). No effect was observed on the relaxant actions of levcromakalim and theophylline. In contrast, prior incubation with either levcromakalim or Y-26763 (300 microM for 30 min) significantly reduced the subsequent potency and efficacy of levcromakalim, but did not alter the effects of isoprenaline and theophylline. We conclude that the relaxant effect of the adenosine triphosphate-sensitive potassium channel openers was independent of beta-adrenergic hyporesponsiveness in airway smooth muscle of guinea-pigs.

Effects of in vitro mast cell degranulation on human lung beta-receptor binding parameters.

Numerous studies have demonstrated that subjects with allergic asthma have beta-adrenergic hyporesponsiveness, predisposing these individuals toward bronchospasm, mucous production, and mast cell degranulation. Since sympathetic innervation of the human respiratory tract is sparse, reduced beta-responsiveness probably results from alterations at or beyond the receptor level. We therefore examined whether anaphylaxis of human lung tissue acutely modulated the human lung beta-receptor system in ways that might lead to decreased beta-adrenergic responsiveness. Fresh thoracotomy peripheral lung samples from 26 patients were incubated with (anaphylaxis) or without (control) anti-IgE (1:100) for up to 90 minutes and histamine release was documented. Lung fragments were quick frozen at various times after anti-IgE for analyses of beta-receptor binding parameters. Antagonist Kd (dissociation constant) and receptor concentration values were determined using (-)[125I]pindolol and agonist IC50 values were determined using isoproterenol. In comparison with time O, neither anaphylaxis nor control samples had differences in receptor binding parameters with time. There were also no differences between anaphylaxis and control lung samples at any time point, and ratios of log control binding parameter/log anaphylaxis binding parameter ranged from 0.96 to 1.01. Anaphylaxis of lung does not lead to acute changes in antagonist or agonist affinity for beta-receptors or changes in receptor concentration. Under the conditions studied, lung mast cell degranulation does not acutely alter the human lung beta-receptor system in ways that might account for the beta-adrenergic hyporesponsiveness found in allergic asthma.

Role of nitric oxide in the regulation of myocardial function

Nitric oxide (NO), produced by either constitutive or inducible isoforms of NO synthase (cNOS or iNOS), influences myocardial inotropic and chronotropic responses. This pathway has been studied using NO donors or NOS inhibitors or by immune-mediated stimulation of iNOS. Although inhibition of constitutive NO activity in the heart does not influence indices of myocardial contractility, NO donors, in some species and preparations, may exert a negative inotropic effect as well as an enhancement of diastolic relaxation. The best documented cardiac action of NO is inhibition of the positive inotropic and chronotropic responses to beta-adrenergic receptor stimulation. Basal NO production, presumable via cNOS, appears to exert a mild tonic inhibition of beta-adrenergic responses. On the other hand, excessive NO production mediated by iNOS may contribute to the myocardial depression and beta-adrenergic hyporesponsiveness associated with conditions such as sepsis, myocarditis, cardiac transplant rejection, and dilated cardiomyopathy. Muscarinic cholinergic stimulation of the heart appears to stimulate NO production that mediates, at least partially, parasympathetic slowing of heart rate and inhibition of beta-adrenergic contractility. NO-stimulated production of 3',5'-cyclic guanosine monophosphate via guanylyl cyclase accounts for many of the observed physiological actions of NO. 3',5'-Cyclic guanosine monophosphate inhibits the beta-adrenergic-stimulated increase in the slow-inward calcium current and reduces the calcium affinity of the contractile apparatus, actions that could contribute to a negative inotropic effect, an abbreviation of contraction, and an enhancement of diastolic relaxation. Biochemical, immunocytochemical, and molecular biological techniques have been used to show the presence of both cNOS and iNOS within the myocardium. cNOS is expressed in myocytes, endothelial cells, and neurons in the myocardium, and there is evidence for iNOS in myocytes, small vessel endothelium, vascular smooth muscle cells, and immune cells that infiltrate the heart. Taken together, these observations suggest that NO influences normal cardiac physiology and may play an important role in the pathophysiology of certain disease states associated with cardiac dysfunction.

The effect of age on the β-adrenergic lipolytic response in healthy humans

We evaluated the effect of age on the lipolytic response to intravenous infusion of isoproterenol in 12 elderly (age, > 60 years) and 12 young (age, 21 to 34 years) volunteers to examine if there is alteration in innervated beta-adrenergic responsiveness in tissues other than the heart. Lipolysis was evaluated by measuring the plasma concentrations of free fatty acids and glycerol. We also measured the plasma concentration of isoproterenol during infusion so that we could calculate comparable plasma isoproterenol concentrations to lipolytic responses in the two age groups. Our data show that, at equivalent infusion rates of isoproterenol, the two age groups achieved equivalent isoproterenol concentrations. The elderly had a higher concentration of free fatty acids but equivalent concentrations of glycerol as compared with the young subjects at equivalent isoproterenol plasma concentrations. However, our data were complicated by the fact that at the higher infusion rates of isoproterenol, the elderly showed a greater sympathetic stimulation than the young subjects as measured by plasma norepinephrine concentrations. Nonetheless, our data could not show that the elderly subjects were more resistant to beta-adrenergic receptor-mediated stimulated lipolysis. Thus innervated beta-adrenergic receptor hyporesponsiveness caused by aging may not necessarily extend to all organ systems.

Allergy and depression: a neurochemical threshold model of the relation between the illnesses.

Empirical studies suggest a very high prevalence of atopic disorder in people with depression. Research indicates that individuals with allergy have cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic-adrenergic activity play a casual role in depression behaviors. It is hypothesized that the allergic state or allergic reactions can accentuate cholinergic-adrenergic activity imbalances in the central nervous system of a small subgroup of people at risk for endogenous depression thereby producing depression symptomatology.

Autonomic Nervous System Abnormalities and Asthma

Autonomic nervous system function has been studied both in vitro and in vivo using a variety of methodologies. In asthmatic patients, beta-adrenergic hyporesponsiveness and alpha-adrenergic and cholinergic hyperresponsiveness can be frequently demonstrated. These observations have provided support for the beta blockade theory of asthma, advanced in the late 1960s by Andor Szentivanyi's experiments involving sensitized rodents. However, in addition to asthma, aberrations in autonomic nervous system function have been noted in other individuals including cystic fibrosis patients and their parents, patients with emphysema and bronchitis, and in patients (allergic rhinitis and atopic dermatitis) who have demonstrable IgE antibody responses to a variety of antigens. Thus, although these defects are not specific for asthma, it is noteworthy that these conditions share many clinical features; the ultimate phenotypic expression of these abnormalities may depend on both genetic and environmental factors that have yet to be defined.

Attention deficit disorder and allergy: A neurochemical model of the relation between the illnesses.

Empirical studies suggest that allergies play an etiological role in a small subgroup of children who suffer from attention deficit-hyperactivity disorder (ADHD). Research indicates that allergic reactions results in cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness in the autonomic nervous system. Evidence is reviewed that similar imbalances in central nervous system cholinergic/adrenergic activity play a causal role in manic and depressive behaviors. It is hypothesized that allergic reactions engender cholinergic/adrenergic activity imbalances in the central nervous system, leading to poorly regulated arousal levels and ADHD behaviors in some children.

Effect of forskolin on beta-adrenergic hyporesponsiveness in skin.

beta-Adrenergic receptor hyporesponsiveness has been observed in psoriasis and after exposure of epidermis to phorbol esters. It was the purpose of our studies to determine if forskolin, which is known to act synergistically with receptor agonists in elevating endogenous levels of cyclic AMP, could return these responses to those seen under control conditions. It was observed that topical application of phorbol ester to mouse ears in vivo led to a significant reduction in isoproterenol stimulation of cyclic AMP in vitro. Low doses of forskolin (10(-7) M) were able to enhance isoproterenol's effect under these conditions. Similarly, human keratinocyte cell cultures treated with phorbol esters and human psoriatic epidermis in vitro were both hyporesponsive to isoproterenol. Again, pretreatment of these samples with forskolin restored the beta-agonist stimulation to control values. These data indicate that forskolin is still able to act synergistically with beta-agonists in hyporesponsive systems and suggest that forskolin may be a useful probe in defining the mechanism of this decreased responsiveness both in phorbol-ester-treated skin and in psoriasis.

Elevated mononuclear leukocyte phosphodiesterase in allergic dogs with and without airway hyperresponsiveness

To investigate if mononuclear leukocyte beta-adrenergic hyporesponsiveness of Basenji greyhound (BG) dogs is associated with atopy or nonspecific airway hyperresponsiveness, we examined the relationship between mononuclear leukocyte cAMP phosphodiesterase levels, airway responsiveness to methacholine, and intradermal allergen responses in 17 BG dogs, five unrelated purebred Basenjis, and five greyhounds. BG dogs were hyperresponsive to aerosols of methacholine compared to Basenjis and greyhounds. Both BG dogs and Basenjis were allergic and had increased leukocyte cAMP phosphodiesterase activity compared to greyhounds. We concluded that the leukocyte abnormality is not associated with airway hyperresponsiveness. The leukocyte abnormality is either associated with the allergic state, with some hereditary trait that BG dogs acquired from the Basenji ancestry, or the leukocyte abnormality is necessary but not sufficient for the development of airway hyperresponsiveness.

Potassium tolerance and bronchial reactivity in asthmatic and nonasthmatic atopic subjects.

Abnormal autonomic nervous system responsiveness may contribute to the pathogenesis of allergic diseases. Therefore, we measured the beta-adrenergic systemic (metabolic) responsiveness by means of acute potassium load in 10 normal healthy subjects and in 19 patients with allergic asthma and/or rhinitis. Ten allergic patients showed a greater potassium increment, as in normal subjects, when potassium was infused in the presence of propranolol. There was no difference between asthmatic and rhinitic patients. We then examined the relation between the response to potassium tolerance and the nonspecific, nonpharmacological bronchial reactivity in response to inhalation of ultrasonically nebulized distilled water. Some allergic patients showed bronchial hyperreactivity, while others did not show a difference compared with the controls; there was no significant difference between asthmatics and rhinitics, and there was no relation between nonspecific bronchial reactivity and potassium load tolerance. These findings suggest that systemic beta-adrenergic hyporesponsiveness may be present only in some allergic patients. There is no demonstrable relation among atopic state, nonspecific, nonpharmacological bronchial reactivity, and systemic beta-adrenergic hyporesponsiveness.

Adrenoceptors: molecular nature and role in atopic diseases.

Since Szentivanyi proposed the idea that asthma and other atopic diseases are due to a beta adrenergic defect there has been much interest in the role of the adrenergic receptors in allergy. The radioactive ligand binding techniques developed within the last few years have greatly increased our knowledge concerning the molecular nature of the adrenoceptors and the events following receptor stimulation. The adrenoceptors have shown to be very dynamic structures. Their number and affinity may be altered due to various physiological and pharmacological stimuli. Their role in the pathogenesis of atopic diseases has not been definitely settled, but there seem to be a true beta adrenergic hyporesponsiveness and alpha hyperresponsiveness in asthma. This article briefly describes the radioligand binding technique and summarizes our present knowledge of the nature of the alpha and beta adrenoceptors and their possible role in atopic diseases.

Abnormal beta adrenergic responsiveness in allergic subjects: Analysis of isoproterenol-induced cardiovascular and plasma cyclic adenosine monophosphate responses

Beta adrenergic responses were compared between normal control subjects and patients with allergic asthma or allergic rhinitis and a group of asymptomatic individuals with positive immediate hypersensitivity skin tests. Two responses to infused isoproterenol were monitored: increases in pulse pressure and plasma cyclic adenosine monophosphate (cyclic AMP). Although the normal control subjects responded with increases in pulse pressure of greater magnitude than the other groups in response to infused isoproterenol, the differences in responsiveness were more apparent when the concentration of isoproterenol required to increase the pulse pressure ≧22 mm Hg was compared. The 25 control subjects required 8.04 ± 0.48 ng/kg/min isoproterenol, whereas the 17 asthmatic patients required 14.25 ± 1.21 (p < 0.0001), the eight subjects with allergic rhinitis required 12.75 ± 1.58 (p < 0.0005), and the seven asymptomatic subjects with positive skin tests needed 11.1 ± 1.26 (p < 0.01). Comparison of baseline plasma cyclic AMP levels of the groups revealed no apparent differences. However, the normal controls responded to isoproterenol with larger increases in plasma cyclic AMP than the other groups at both 6 and 9 ng/kg/min. Furthermore, significantly fewer of the subjects with asthma, rhinitis, or positive skin tests demonstrated an increase in plasma cyclic AMP ≧ 50% above baseline as compared with controls. Thus, as reflected in both cardiovascular and cyclic AMP responses to infused isoproterenol, allergic asthmatic subjects are hyporesponsive as compared with normal controls. However, a comparable degree of diminished responsiveness is seen in subjects with allergic rhinitis or in asymptomatic individuals with positive skin tests. Therefore beta adrenergic hyporesponsiveness appears to be related with the atopic state rather than with asthma.