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Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska
Correspondence and requests for reprints should be addressed to M. L. Toews, Ph.D., 985800 University of Nebraska Medical Center, Omaha, NE 68198-5800. E-mail: mtoews{at}unmc.edu
Dr. Liggett's data on ß2-receptor–induced upregulation of the muscarinic receptor–modulated phospholipase C (PLC) signaling pathway suggest the opportunity for combination therapy targeted at preventing the development or blocking the effects of an adaptive change in a second pathway, one of the hypothetical combination approaches mentioned in Dr. Toews's earlier talk (Session 1). Dr. Liggett was asked about the molecular mechanisms involved. He explained that in the ß-receptor knockout animals, PLC mRNA goes down along with the decrease in protein and activity, indicating a transcriptional mechanism, perhaps a cAMP-mediated mechanism. He expressed some doubts about the safety of targeting this change for therapy because of the central role of PLC in many cellular processes.
Dr. Liggett was asked about effects of the PLC changes on the resting membrane potential, as opposed to the ligand-activated changes; the known ß-receptor coupling to potassium channels might drive very large calcium responses that would be difficult to surmount. He responded that one mouse with massive ß-receptor overexpression became completely resistant to constriction, suggesting that it had sufficient relaxant response to overcome even maximal contractile input.
It was proposed that it might be possible to find a partial ß-receptor agonist that would avoid this adaptive change. Dr. Liggett agreed, but suggested that if the effect is cAMP mediated, even partial agonists may generate enough cAMP to drive this adaptive response. He suggested that a drug to prevent this adaptive response might need to be a "conformation-selective" agonist, as Dr. Toews had mentioned, to selectively stabilize the ß2-receptor in a conformation that does not induce the adaptive changes in PLC.
Asked whether his results might theoretically be different in a patient with asthma during an acute attack, Dr. Liggett replied that if the patient had not been taking a ß-agonist, these adaptive changes would not have occurred and the patient should be able to respond well. Such a patient who was taking an anticholinergic agent rather than a ß-agonist would not have a decreased ß-receptor response (because the adaptive change is unidirectional). Predicting the effect in patients receiving long-term ß-agonist therapy would be more difficult, but it is known that these patients generally respond to emergency ß-agonist.
Dr. Belmonte's talk addressed muscarinic acetylcholine (ACh) receptor function in airway disease. A discussant cited evidence for extraneuronal production of ACh, including production by airway epithelial cells and macrophages, saying that there is little or no innervation of small airways in spite of their high expression of muscarinic receptors. Taken together, the discussant noted, these findings suggest that it may be the extraneuronal ACh rather than nerve cell–released ACh that is important in chronic obstructive pulmonary disease (COPD). Dr. Belmonte agreed that this could be a component of the benefit of anticholinergic agents. She mentioned that various other groups are exploring muscarinic receptors on immune and inflammatory cells, not with the idea that anticholinergics will be effective antiinflammatory agents but rather that this effect may contribute to their clinical benefit. However, another discussant disagreed with the first, claiming that in fact small airways are highly ACh innervated, perhaps even more than large airways.
It was suggested that the very tight binding and hence slow dissociation of tiotropium is perhaps a more important component of its unique benefit than is its once-per-day administration. The suggestion was that, because the release of ACh is pulsatile, the transient high concentrations with each pulse might overcome ipratropium (even though ipratropium appears effective in blocking typical doses of administered ACh). Dr. Belmonte agreed that the reversible competitive binding of ipratropium might make it less effective than tiotropium, whose tighter binding might allow it to effectively block even the transiently high pulsatile concentrations of released ACh.
A discussant asked why there seem to be only small effects of muscarinic agents on sputum/mucus production in animals and humans, given that these agents have been shown to be good inhibitors in isolated cell studies. The discussant acknowledged the debate about whether or not it would be clinically useful to inhibit mucus/sputum production but felt that it would be beneficial. Dr. Belmonte indicated that she thought the problem was likely to be mainly with getting the drug to the mucus glands. It was then suggested that the need is for better delivery of drugs to the mucus glands. Dr. Belmonte pointed out that this problem is somewhat inherent in the way effective anticholinergic drugs were developed, because they were made to be highly hydrophilic to prevent their systemic absorption and consequent unwanted side effects on the heart and other tissues. These properties likely also keep them from reaching mucus glands.
A clinician pointed out that most patients with COPD are taking ipratropium–albuterol or similar combinations as well as nebulizers with ipratropium. The concern was raised as to whether additional toxicity would likely occur if ipratropium were similarly used in patients taking the newer long-acting tiotropium (although preliminary clinical studies suggest few side effects). Dr. Belmonte suggested that the short residence time of tiotropium on the M2-receptor (where it does not bind so tightly) would allow it to be cleared more effectively from sites of potential toxicity, such as the heart. There might be a brief spike in some unwanted effect, but it would likely be short in duration.
After her talk on combination therapy with ß2-agonists and anticholinergics, Dr. Fryer was asked what is known about the role of muscarinic receptors in the peripheral or pulmonary vasculature. She indicated that there are muscarinic receptors in the vasculature, and with new evidence that both epithelial and endothelial cells can produce ACh, this is a potentially important question to pursue.
Dr. Fryer was asked whether differential desensitization of M2- versus M3-receptors might make for more subtype-selective effects, or whether blocking both subtypes is always best. She responded that blocking both is probably best, and she referred the desensitization issue to Dr. Belmonte. Dr. Belmonte indicated that the M3-receptor is clearly resistant to desensitization and that only about 10% of these receptors are needed for maximal responses because of receptor reserve. She indicated that very little is known about desensitization of the M2-receptors in vivo and that even results in cell culture systems are quite variable. It was suggested that downregulation of the M2-receptors might also decrease the magnitude of the M3-receptor effects. Dr. Fryer somewhat disagreed, citing data that there do not appear to be changes in M3-receptors in any of the relevant diseases, and that these are the primary receptors that are involved in the absence of ß-agonists. In the presence of ß-agonists, the M2-receptors would be able to counter the ß-agonist relaxation signals.
Dr. Fryer was asked what is known about the reversal or recovery from the M2-receptor deficit, and whether combinations with steroids or retinoids would be useful. She replied that the response is not irreversible, with recovery occurring over 1 to 2 days as inflammation decreases and major basic protein is cleared, although this has been demonstrated only for the ozone model. Dexamethasone is helpful, but apparently acts by effects on eosinophils to prevent them from associating with the nerves rather than by directly reversing the M2-receptor loss; she added that this is only a redistribution of eosinophils, not a decrease in total numbers. There may also be some beneficial effect on the receptors themselves, but these different sites of action are difficult to resolve. Another discussant commented that eosinophils are elevated in COPD exacerbations and that these exacerbations are somewhat asthma-like.
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FOOTNOTES |
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(Received in original form June 9, 2005; accepted in final form June 10, 2005)
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