The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Ynuk Bossé - One of the best experts on this subject based on the ideXlab platform.
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The gain of smooth muscle's contractile capacity induced by tone on in vivo airway responsiveness in mice
Journal of applied physiology (Bethesda Md. : 1985), 2015Co-Authors: Audrey Lee-gosselin, David Gendron, Marie-renée Blanchet, David Marsolais, Ynuk BosséAbstract:Airway hyperresponsiveness to a Spasmogenic challenge such as methacholine, and an increased baseline tone measured by the reversibility of airway obstruction with a bronchodilator, are two common features of asthma. However, whether the increased tone influences the degree of airway responsiveness to a Spasmogen is unclear. Herein, we hypothesized that increased tone augments airway responsiveness in vivo by increasing the contractile capacity of airway smooth muscle (ASM). Anesthetized, tracheotomized, paralyzed, and mechanically ventilated mice were either exposed (experimental group) or not (control group) to tone for 20 min, which was elicited by nebulizing serial small doses of methacholine. Respiratory system resistance was monitored during this period and the peak response to a large cumulative dose of methacholine was then measured at the end of 20 min to assess and compare the level of airway responsiveness between groups. To confirm direct ASM involvement, the contractile capacity of excised murine tracheas was measured with and without preexposure to tone elicited by either methacholine or a thromboxane A2 mimetic (U46619). Distinct Spasmogens were tested because the Spasmogens liable for increased tone in asthma are likely to differ. The results indicate that preexposure to tone increases airway responsiveness in vivo by 126 ± 37% and increases the contractile capacity of excised tracheas ex vivo by 23 ± 4% for methacholine and 160 ± 63% for U46619. We conclude that an increased tone, regardless of whether it is elicited by a muscarinic agonist or a thromboxane A2 mimetic, may contribute to airway hyperresponsiveness by increasing the contractile capacity of ASM.
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bronchoprotective effect of simulated deep inspirations in tracheal smooth muscle
Journal of Applied Physiology, 2014Co-Authors: Ynuk Bossé, Christopher D Pascoe, Graham M Donovan, Chun Y Seow, Peter D PareAbstract:Deep inspirations (DIs) taken before an inhaled challenge with a Spasmogen limit airway responsiveness in nonasthmatic subjects. This phenomenon is called bronchoprotection and is severely impaired...
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asthmatic airway hyperresponsiveness the ants in the tree
Trends in Molecular Medicine, 2012Co-Authors: Ynuk BosséAbstract:Airways from asthmatics have a propensity to narrow excessively in response to Spasmogens (i.e., contractile agonists), a feature called airway hyperresponsiveness (AHR). AHR is an important contributor to asthma symptoms because the degree of responsiveness dictates the amount of airway narrowing that occurs in response to inflammation-derived Spasmogens produced endogenously following exposure to environmental triggers, such as allergens, viruses, or pollutants. The smooth muscle encircling the airways is responsible for responsiveness because it constricts the airway lumen when commanded to contract by Spasmogens. However, whether AHR seen in asthmatics is due to stronger muscle is equivocal. In this opinion article, I propose that environmental triggers and other inflammatory molecules released during asthma attacks contribute to AHR by increasing muscle force.
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Histamine And Endogenously Produced Spasmogenic Prostaglandins Increase The Strength Of Airway Smooth Muscle
Journal of Allergy and Clinical Immunology, 2012Co-Authors: Ynuk Bossé, Peter D PareAbstract:• Together, these results suggest that one of the reason why airway hyperresponsiveness is prevalent in asthmatics and more severe during exacerbations may be force adaptation. This is because many inflammation-derived Spasmogens are overexpressed in asthmatic airways, especially during asthma paroxysms. These Spasmogens may not only increase ASM tone, which is consistently observed in these patients, but also augment ASM’s ability to generate force via force adaptation. Abstract
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A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.
Respiratory Physiology & Neurobiology, 2011Co-Authors: Ynuk Bossé, Peter D Pare, David G. Chapman, Gregory G. King, Cheryl M. SalomeAbstract:Abstract Asthma is characterized by airway inflammation, with a consequent increase in Spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of Spasmogens in the airways, may “strengthen” the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed “force adaptation” [Bosse, Y., Chin, L.Y., Pare, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13–18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo . Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived Spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge.
Kenneth L. Byron - One of the best experts on this subject based on the ideXlab platform.
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Vascular KCNQ (Kv7) Potassium Channels as Common Signaling Intermediates and Therapeutic Targets in Cerebral Vasospasm
Journal of cardiovascular pharmacology, 2013Co-Authors: Bharath K. Mani, Lioubov I. Brueggemann, James O'dowd, Lalit Kumar, Masey Ross, Kenneth L. ByronAbstract:Cerebral vasospasm following subarachnoid hemorrhage (SAH) is characterized by prolonged severe constriction of the basilar artery, which often leads to ischemic brain damage. Locally elevated concentrations of Spasmogenic substances induce persistent depolarization of myocytes in the basilar artery, leading to continuous influx of calcium (Ca 2+ ) through voltage-sensitive Ca 2+ channels and myocyte contraction. Potassium (K + ) channel openers may have therapeutic utility to oppose membrane depolarization, dilate the arteries, and reduce ischemia. Here, we examined the involvement of vascular Kv7 K + channels in the pathogenesis of cerebral vasospasm and tested whether Kv7 channel openers are effective therapeutic agents in a rat model of SAH. Patch-clamp experiments revealed that three different Spasmogens (serotonin, endothelin and vasopressin) suppressed Kv7 currents and depolarized freshly isolated rat basilar artery myocytes. These effects were significantly reduced in the presence of a Kv7 channel opener, retigabine. Retigabine (10 μmol/L) also significantly blocked L-type Ca 2+ channels, reducing peak inward currents by >50%. In the presence of a selective Kv7 channel blocker, XE991, the Spasmogens did not produce additive constriction responses measured using pressure myography. Kv7 channel openers (retigabine or celecoxib) significantly attenuated basilar artery spasm in rats with experimentally-induced SAH. In conclusion, we identify Kv7 channels as common targets of vasoconstrictor Spasmogens and as candidates for therapeutic intervention for cerebral vasospasm.
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Activation of vascular KCNQ (Kv7) potassium channels reverses Spasmogen-induced constrictor responses in rat basilar artery.
British journal of pharmacology, 2011Co-Authors: Bharath K. Mani, Lioubov I. Brueggemann, Leanne L. Cribbs, Kenneth L. ByronAbstract:BACKGROUND AND PURPOSE Cerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (Spasmogens). We assessed the presence and function of KCNQ (Kv7) potassium channels in rat basilar artery myocytes, and determined the efficacy of Kv7 channel activators in relieving Spasmogen-induced basilar artery constriction. EXPERIMENTAL APPROACH Expression and function of Kv7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to Kv7 channel modulators were studied in intact artery segments using pressure myography. KEY RESULTS All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. Kv currents were attributed to Kv7 channel activity based on their voltage dependence of activation (V0.5∼−34 mV), lack of inactivation, enhancement by flupirtine (a selective Kv7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective Kv7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced Kv7 currents but also inhibited voltage-sensitive Ca2+ currents. In arteries pre-constricted with Spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca2+ channel blocker. CONCLUSIONS AND IMPLICATIONS Kv7 channels are important determinants of basilar artery contractile status. Targeting the Kv7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm. LINKED ARTICLES To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x
Bryce Weir - One of the best experts on this subject based on the ideXlab platform.
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Why Experimental Vasospasm Resolves
Stroke, 2001Co-Authors: Robert L Macdonald, Zhen-du Zhang, Bryce WeirAbstract:P112 It has been suggested that changes in the arterial wall contribute to the maintenance and resolution of vasospasm after subarachnoid hemorrhage (SAH). This study determined if such changes contribute to the resolution of vasosapsm after SAH, if vasospasm resolves because of loss of subarachnoid blood clot or if a combination of these mechanisms is involved. 27 monkeys underwent baseline angiography and unilateral (n = 17) or bilateral (n = 8) SAH. Animals with bilateral SAH underwent angiography 1, 3, 5 and 7 days later followed by euthanasia. Animals with unilateral SAH had angiography 7 days later. The clot then was removed in these animals and replaced with fresh clot (n = 7) or removed and not replaced (n = 5). The removed clot was placed on the left side (n = 12). Controls did not have clot removal (n = 5) and/or had fresh clot placed on the left on day 7 (n = 5). Angiography was repeated every 2 days until euthanasia on day 14. SAH caused significant middle cerebral artery vasospasm on day 7 that slowly resolved by day 14. Removal of clot on day 7 resulted in more rapid reversal of vasospasm suggesting that vasospasm depended on continued presence of subarachnoid clot rather than on or in addition to structural changes in the artery. Placing fresh clot on the right side on day 7 produced vasospasm that persisted without resolving suggesting that there is no preconditioning response in the artery that prevents or conributes to reversal of vasospasm. On the other hand, placing 7-day-old clot from the right onto the left caused significantly more rapid onset of severe vasospasm than placing fresh clot from animals 7 days after SAH, suggesting that breaking up the clot to replace it on the left increases release of Spasmogens or that there is a negative adaptive response that exacerbates vasospasm. In conclusion, vasospasm resolves because of loss of subarachnoid clot. There is no evidence for a preconditioning response in cerebral arteries that renders them less responsive to subarachnoid clot. Spasmogen release from clot 7 days after SAH may be reduced in this model so that breaking up the clot increases Spasmogen release resulting in rapid onset of severe vasospasm and/or that there is a negative adaptive response 7 days after SAH that worsens vasospasm.
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Phosphatidylcholine peroxidized by hemoglobin increases intracellular calcium in dog basilar artery smooth muscle cells.
Acta neurochirurgica. Supplement, 2001Co-Authors: Babak S. Jahromi, Robert L Macdonald, Taro Komuro, Linda S. Marton, Bryce WeirAbstract:Numerous studies in vitro and in vivo have identified hemoglobin as the primary Spasmogen underlying cerebral vasospasm following subarachnoid hemorrhage (SAH) [8]. Numerous cellular mechanisms, however, remain implicated in the pathogenesis of vasospasm, and the existence of other Spasmogen(s) is suggested by hemolysate fractionation studies [1, [9]. Lipid peroxides are attractive candidate Spasmogens as they are key structural components of cell membranes and are abundant in the subarachnoid space after SAH, are readily formed following exposure to reactive oxygen species [3] and can have wide-ranging biological effects depending upon their putative downstream target(s) in ensuing free-radical chain reactions. We hypothesized that hemoglobin promotes the peroxidation of phosphatidylcholine (PC) to phosphatidylcholine peroxide (PCOOH), and that PCOOH contributes to cerebral vasospasm by mobilizing intracellular calcium in vascular smooth muscle cells.
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Chapter 6 – Pharmacology
Cerebral Vasospasm, 2001Co-Authors: R. Loch Macdonald, Bryce WeirAbstract:Publisher Summary This chapter focuses on the pharmacology. An enormous volume of experimental evidence has accumulated with respect to the pharmacological basis for chronic vasospasm (VSP). Most generalizations must be interpreted with caution. The onset and resolution of human clinical VSP over many days, the gradual removal of thick clot, and an active repair response are seldom replicated in experimental studies. Pharmacological studies were performed on monkey, which had been surrounded by blood clot for seven days and these reactions were compared to those of the contralateral arteries. The ability of a compound to produce contraction of isolated arterial segments is only relevant to its potential as a mediator of clinical VSP if the slow-onset VSP arises from the slow liberation of a Spasmogen, which then reacts with a blood vessel that is approximately normal. A putative Spasmogen for chronic VSP should be liberated sometime after the hemorrhage and has a very prolonged duration of action or is liberated continuously during days and weeks. The prolonged nature of VSP may be partly because of the necrotic damage to the blood vessel wall resulting from ischemia. The resolution of VSP might therefore be due to tissue repair and not reversal of vasoconstriction.
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No Effect of Bilirubin on Electrical Properties of Isolated Cerebrovascular Smooth Muscle Cells
Cerebrovascular Diseases, 1992Co-Authors: N. Stockbridge, Gordana Maljkovic, Bryce WeirAbstract:An experimental model system, consisting of single isolated smooth muscle cells from the rat basilar artery, was developed to study the effects of Spasmogens thought to play a role in the pathophysiol
Peter D Pare - One of the best experts on this subject based on the ideXlab platform.
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bronchoprotective effect of simulated deep inspirations in tracheal smooth muscle
Journal of Applied Physiology, 2014Co-Authors: Ynuk Bossé, Christopher D Pascoe, Graham M Donovan, Chun Y Seow, Peter D PareAbstract:Deep inspirations (DIs) taken before an inhaled challenge with a Spasmogen limit airway responsiveness in nonasthmatic subjects. This phenomenon is called bronchoprotection and is severely impaired...
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Histamine And Endogenously Produced Spasmogenic Prostaglandins Increase The Strength Of Airway Smooth Muscle
Journal of Allergy and Clinical Immunology, 2012Co-Authors: Ynuk Bossé, Peter D PareAbstract:• Together, these results suggest that one of the reason why airway hyperresponsiveness is prevalent in asthmatics and more severe during exacerbations may be force adaptation. This is because many inflammation-derived Spasmogens are overexpressed in asthmatic airways, especially during asthma paroxysms. These Spasmogens may not only increase ASM tone, which is consistently observed in these patients, but also augment ASM’s ability to generate force via force adaptation. Abstract
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A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.
Respiratory Physiology & Neurobiology, 2011Co-Authors: Ynuk Bossé, Peter D Pare, David G. Chapman, Gregory G. King, Cheryl M. SalomeAbstract:Abstract Asthma is characterized by airway inflammation, with a consequent increase in Spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of Spasmogens in the airways, may “strengthen” the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed “force adaptation” [Bosse, Y., Chin, L.Y., Pare, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13–18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo . Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived Spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge.
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A 'Good' muscle in a 'Bad' environment: the importance of airway smooth muscle force adaptation to airway hyperresponsiveness.
Respiratory physiology & neurobiology, 2011Co-Authors: Ynuk Bossé, Peter D Pare, David G. Chapman, Gregory G. King, Cheryl M. SalomeAbstract:Asthma is characterized by airway inflammation, with a consequent increase in Spasmogens, and exaggerated airway narrowing in response to stimuli, termed airway hyperresponsiveness (AHR). The nature of any relationship between inflammation and AHR is less clear. Recent ex vivo data has suggested a novel mechanism by which inflammation may lead to AHR, in which increased basal ASM-tone, due to the presence of Spasmogens in the airways, may "strengthen" the ASM and ultimately lead to exaggerated airway narrowing. This phenomenon was termed "force adaptation" [Bossé, Y., Chin, L.Y., Paré, P.D., Seow, C.Y., 2009. Adaptation of airway smooth muscle to basal tone: relevance to airway hyperresponsiveness. Am. J. Respir. Cell Mol. Biol. 40, 13-18]. However, it is unknown whether the magnitude of the effect of force adaptation ex vivo could contribute to exaggerated airway narrowing in vivo. Our aim was to utilize a computational model of ASM shortening in order to quantify the potential effect of force adaptation on airway narrowing when all other mechanical factors were kept constant. The shortening in the model is dictated by a balance between physiological loads and ASM force-generating capacity at different lengths. The results suggest that the magnitude of the effect of force adaptation on ASM shortening would lead to substantially more airway narrowing during bronchial challenge at any given airway generation. We speculate that the increased basal ASM-tone in asthma, due to the presence of inflammation-derived Spasmogens, produces an increase in the force-generating capacity of ASM, predisposing to AHR during subsequent challenge.
Roy G. Goldie - One of the best experts on this subject based on the ideXlab platform.
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endothelins and asthma
Life Sciences, 1999Co-Authors: Roy G. Goldie, Peter J. HenryAbstract:In the decade since endothelin-1 (ET-1) and related endogenous peptides were first identified as vascular endothelium-derived Spasmogens, with potential pathophysiological roles in vascular diseases, there has been a significant accumulation of evidence pointing to mediator roles in obstructive respiratory diseases such as asthma. Critical pieces of evidence for this concept include the fact that ET-1 is an extremely potent Spasmogen in human and animal airway smooth muscle and that it is synthesised in and released from the bronchial epithelium. Importantly, symptomatic asthma involves a marked enhancement of these processes, whereas asthmatics treated with anti-inflammatory glucocorticoids exhibit reductions in these previously elevated indices. Despite this profile, a causal link between ET-1 and asthma has not been definitively established. This review attempts to bring together some of the evidence suggesting the potential mediator roles for ET-1 in this disease.
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The influence of post-mortem conditions on contractile and relaxant responsiveness of guinea-pig isolated tracheal smooth muscle
Naunyn-Schmiedeberg's Archives of Pharmacology, 1998Co-Authors: Janet M.h. Preuss, P. J. Rigby, Roy G. GoldieAbstract:Responsiveness to various contractile and relaxant agonists was assessed in tracheal preparations from guinea-pigs that had been incubated in situ at 4–37°C for 0–168h post-mortem. The potencies of histamine and acetylcholine were increased up to 168h at 4°C post-mortem and up to 24h post-mortem at 22°C. Histamine potency also increased with increasing post-mortem time at 37°C. After 48h at 22°C and 8h at 37°C, responses to all Spasmogens were abolished. Increases in histamine and acetylcholine potencies were similarly observed in tracheal tissue that had been removed at death and then incubated at 4°C in oxygenated Krebs-bicarbonate solution for 0–168h. The increased potency of these drugs may be explained by epithelial damage and/or loss of an epithelium-derived inhibitory factor (EpDIF). Both basal and Spasmogen-stimulated increases in intracellular phosphoinositides fell with increasing time and ambient temperature post-mortem, despite the fact that contraction in response to these agonists could still be evoked. This suggests the selective failure of this signal transduction pathway and the maintenance of responsiveness via other mechanisms. The potencies and maximum effects of relaxant agonists remained unaltered in tracheal tissue with increasing time post-mortem, suggesting little change in the function of the appropriate receptor-signal transduction processes. This study has therefore demonstrated that at 4°C, contractile and relaxant responses were preserved for up to 168h post-mortem, although the modulatory influence of the epithelium on histamine and acetylcholine responses was rapidly lost.
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Influence of age on epithelium-dependent responsiveness of guinea-pig and rat tracheal smooth muscle to Spasmogens.
European journal of pharmacology, 1992Co-Authors: Janet M.h. Preuss, Peter J. Henry, Roy G. GoldieAbstract:Abstract The current study describes the influence of age and of the presence of the epithelium on guinea-pig and rat tracheal airway smooth muscle sensitivity to the Spasmogens histamine, acetylcholine, carbochol and potassium. In guinea-pig trachea from animals aged 2–52 weeks the potency of each of these Spasmogens decreased with increased animal age. In contrast, no age-dependent changes in the potency of acetylcholine, carbachol or potassium were seen in rat trachea. Removal of the tracheal epithelium was associated with significant increases in the potencies of histamine and acetylcholine in guinea-pig trachea and of acetylcholine in rat trachea, but not of carbachol or potassium in either species. For histamine in guinea-pig trachea, the largest potency increase (4.6-fold) occurred in tissue from 6-week-old animals, with the smallest increases in tissue from the youngest (2 weeks) and the oldest (52 weeks) animals. Thus, although the sensitivity of airway smooth muscle to this Spasmogen fell between 2 and 12 weeks of age, the effect of epithelial removal on sensitivity to histamine was apparently increased during this period. Further studies are required to asses the reasons for increased histamine and acetylcholine potency in airway smooth muscle after epithelial ablation.
