Effects of salmeterol on muscarinic inhibition of adenylyl cyclase in bovine trachealis cells.

The goal was to assess whether salmeterol, a potent and long-acting beta-2-adrenergic agonist used in the treatment of asthma, also has non-beta-2-adrenergic effects on the stimulation or inhibition of adenylyl cyclase activity. Salmeterol (100 nM) maximally stimulated cAMP accumulation in enzyme dispersed bovine trachealis cells and this was entirely inhibited by propranolol, as expected for beta-adrenergic stimulation. However, the same concentration of salmeterol also antagonized carbachol inhibition of cAMP accumulation and altered binding of carbachol to muscarinic receptors. These effects of salmeterol were sensitive to washing of the cells and this was not consistent with a beta-2-adrenergic mechanism. The findings suggested that the maximal, beta-2-adrenergic stimulation of cAMP accumulation by salmeterol was accompanied by a non-beta-2-adrenergic interaction of salmeterol with muscarinic receptors that attenuated muscarinic inhibition of adenylyl cyclase.

Aspirin sensitivity: the role for aspirin challenge and desensitization in postmyocardial infarction patients.

Aspirin is one of the world's most commonly used medications and its use benefits many diverse conditions. Adverse reactions, however, are relatively common as well. Hypersensitivity to aspirin can be manifested as acute asthma, urticaria and/or angioedema, or a systemic anaphylactoid reaction. We report 3 cases in whom aspirin was indicated for secondary prophylaxis of myocardial infarction but in whom a remote history of an untoward reaction to it prevented its initial use. These patients all underwent further evaluation of their pulmonary and allergic history and all 3 were challenged with aspirin. Two patients were found not to be sensitive and started on aspirin, the other had a classic asthmatic reaction to the drug and was successfully desensitized to aspirin allowing for its use.

Necrotizing tracheobronchitis with progressive airflow obstruction associated with paraneoplastic pemphigus.

Paraneoplastic pemphigus (PNP) is an autoimmune disease associated with leukemia and non-Hodgkin's lymphoma. A patient with stage IVB poorly differentiated lymphocytic lymphoma developed characteristic upper and lower airway involvement with profound mucocutaneous erosion and tracheobronchial epithelial desquamation. Immunofluorescence testing confirmed autoantibody deposition along the basement membrane of bronchial epithelium. Disruption of the cellular adhesion mechanisms, including desmosomes, hemidesmosomes, and possibly the integrin subunits, is presumed to have led to disruption and desquamation of the tracheobronchial epithelial barrier, severe obstruction of the airways and hypoxia, and possibly bacterial superinfection. As far as can be determined, the feature of airflow obstruction occurring in association with PNP has not been described. Physicians should be aware that these complications of PNP may rapidly lead to hypoxic respiratory failure and death.

Muscarinic receptor reserve for inhibition of cAMP accumulation in bovine trachealis cells.

In airway smooth muscle, muscarinic agonists inhibit synthesis of adenosine 3',5'-cyclic monophosphate (cAMP). The goal was to characterize the relationship between agonist occupancy of muscarinic receptors and regulation of cAMP for bovine trachealis cells. For intact cells dispersed by enzyme, carbachol maximally inhibited 58 +/- 4% (mean +/- SE, n = 5) of isoproterenol-stimulated cAMP accumulation at low concentrations [log half-maximal effective concentration (EC50) = -8.34 +/- 0.16]. In radioligand binding experiments, carbachol competed for [3H]quinuclidinyl benzilate (n = 7) and [N-methyl-3H]scopolamine (n = 3) binding sites on intact cells with both low (log KL = -4.26 +/- 0.06 and -4.50 +/- 0.20, respectively) and high affinities (log KH = -5.91 +/- 0.24 and -6.39 +/- 0.19, respectively). In separate experiments, a fraction of the muscarinic receptors on intact cells were inactivated with either phenoxybenzamine (POB) or propylbenzylcholine mustard (PBCM). We compared equally effective concentrations of carbachol before and after partial inactivation of receptors, and the calculated equilibrium dissociation constants for agonist (log KA = -4.36 +/- 0.42 to -3.20 +/- 0.40 for POB; log KA = -4.27 +/- 0.45 for PBCM) were much greater than the half-maximally effective concentration of carbachol in control cells (log EC50 = -8.34 +/- 0.16). Based on these equilibrium dissociation constants, we calculated that maximum responses (EC95) to carbachol were obtained by occupancy of 0.8% of the receptors coupled to cAMP regulation. We concluded that muscarinic inhibition of cAMP accumulation is characterized by a muscarinic receptor reserve.

Muscarinic regulation of cyclic AMP in bovine trachealis cells.

The goal of this study was to characterize the receptors and coupling mechanisms mediating muscarinic inhibition of adenylyl cyclase activity in bovine tracheal smooth muscle. In radioligand binding experiments, methoctramine and AF-DX 116 competed for approximately 85% of the 3H-quinuclidynyl benzilate (3H-QNB) binding sites on intact cells with high affinities (-log KI of 7.73 +/- 0.16 and 6.67 +/- 0.31, respectively) characteristic of binding to M2 receptors. The antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) bound the receptors on intact cells with an affinity (-log KI = 7.76 +/- 0.21) characteristic of binding at M2 receptors. In experiments measuring 3',5'-cyclic adenosine monophosphate (cAMP) accumulation, methoctramine, AF-DX 116, and 4-DAMP antagonized the inhibitory effect of carbachol on isoproterenol-stimulated cAMP accumulation with potencies consistent with mediation by M2 muscarinic receptors (-log Kb of 8.01 +/- 0.22 to 7.58 +/- 0.25 for methoctramine; 7.43 +/- 0.36 to 7.02 +/- 0.30 for AF-DX 116; and 7.60 +/- 0.21 for 4-DAMP). In other experiments, 24 +/- 3% of the inhibitory effect of carbachol was not reversed by 60 min exposure to atropine. Moreover, pertussis toxin (10, 250, and 1,000 ng/ml) decreased only a portion of the inhibitory effect of carbachol (8 +/- 19%, 32 +/- 10%, and 33 +/- 8%, respectively) on cAMP accumulation. These findings indicated that M2 receptors were coupled to adenylyl cyclase in trachealis cells, but that coupling mechanisms in addition to those of pertussis toxin-sensitive guanine nucleotide binding proteins were involved. Since the inhibitory effect of carbachol (10(-8) M) on isoproterenol-stimulated cAMP accumulation was decreased from 20 +/- 4% to -1 +/- 5% (n = 6) by okadaic acid (1 microM), protein phosphatases may regulate the processes coupling muscarinic receptors to adenylyl cyclase.

Tracheoarterial fistula: an unusual complication of tracheostomy.

The tracheoarterial fistula is an unusual but devastating complication of tracheostomy. It occurs with a frequency of approximately 0.7%, and it is uniformly fatal if not recognized and surgically corrected. Mucosal damage from the tracheal cannula, pressure necrosis from high cuff pressure, or mucosal trauma from an improperly positioned cannula tip results in erosion through the tracheal wall into the vascular structures that lie in the pretracheal space. Bleeding from this complication almost always occurs late (> 48 hours postprocedure). It is often preceded by sentinel hemoptysis. A paucity of signs and symptoms that precede or are associated with this complication require a high index of clinical suspicion to make the diagnosis. In addition to bleeding, other potential clues include a low-lying tracheostomy tube, pulsation of the tracheostomy tube, and the presence of infection, hypotension, malnutrition, and corticosteroid use. Unfortunately, there are no consistently useful diagnostic tools for tracheoarterial fistula. Fiberoptic bronchoscopy and angiography have been performed with mixed results. Should no other cause be found to explain the hemorrhage from or around the tracheostomy, or from disease distal to the primary carina, the patient must be taken to the operating room for a more definitive examination and possible vascular repair. Management is divided into acute stabilization and support, with protection of the airway and restoration of circulating blood volume, followed by definitive repair should the patient survive. Measures to prevent tracheal damage by the tracheostomy tube, such as proper surgical technique and proper inflation of the tracheostomy tube cuff, may go a long way to avoid this potentially lethal complication. Early consideration of this entity may be what saves the life of its victim.