NO does not mediate inhibitory neural responses in sheep airway and bronchial vascular smooth muscle

1998 ◽  
Vol 84 (3) ◽  
pp. 809-814 ◽  
Author(s):  
Elisabeth M. Baile ◽  
Karen McKay ◽  
Lu Wang ◽  
Tony R. Bai ◽  
Peter D. Paré
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Vagal Stimulation ◽  
Smooth Muscle Contraction ◽  
Neural Responses ◽  
Endogenous Nitric Oxide ◽  
Synthase Inhibitor ◽  
Trachealis Muscle

Endogenous nitric oxide (NO) influences acetylcholine-induced bronchovascular dilation in sheep and is a mediator of the airway smooth muscle inhibitory nonadrenergic, noncholinergic neural response in several species. This study was designed to determine the importance of NO as a neurally derived modulator of ovine airway and bronchial vascular smooth muscle. We measured the response of pulmonary resistance (Rl) and bronchial blood flow (Q˙br) to vagal stimulation in 14 anesthetized, ventilated, open-chest sheep during the following conditions: 1) control; 2) infusion of the α-agonist phenylephrine to reduce baseline Q˙br by the same amount as would be produced by infusion of N ω-nitro-l-arginine (l-NNA), a NO synthase inhibitor; 3) infusion ofl-NNA (10−2 M); and 4) after administration of atropine (1.5 mg/kg). The results showed that vagal stimulation produced an increase in Rl andQ˙br in periods 1, 2, and 3( P < 0.01) that was not affected byl-NNA. After atropine was administered, there was no increase inQ˙br or Rl. In vitro experiments on trachealis smooth muscle contracted with carbachol showed no effect ofl-NNA on neural relaxation but showed a complete blockade with propranolol ( P < 0.01). In conclusion, the vagally induced airway smooth muscle contraction and bronchial vascular dilation are not influenced by NO, and the sheep’s trachealis muscle, unlike that in several other species, does not have inhibitory nonadrenergic, noncholinergic innervation.

In vivo loads on airway smooth muscle: the role of noncontractile airway structures

1992 ◽  
Vol 70 (4) ◽  
pp. 602-606 ◽  
Author(s):  
Philip Robinson ◽  
Mitsushi Okazawa ◽  
Tony Bai ◽  
Peter Paré
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Activation ◽  
Muscle Length ◽  
Tracheal Cartilage ◽  
Elastic Load ◽  
Muscle Shortening ◽  
Trachealis Muscle

The degree of airway smooth muscle contraction and shortening that occurs in vivo is modified by many factors, including those that influence the degree of muscle activation, the resting muscle length, and the loads against which the muscle contracts. Canine trachealis muscle will shorten up to 70% of starting length from optimal length in vitro but will only shorten by around 30% in vivo. This limitation of shortening may be a result of the muscle shortening against an elastic load such as could be applied by tracheal cartilage. Limitation of airway smooth muscle shortening in smaller airways may be the result of contraction against an elastic load, such as could be applied by lung parenchymal recoil. Measurement of the elastic loads applied by the tracheal cartilage to the trachealis muscle and by lung parenchymal recoil to smooth muscle of smaller airways were performed in canine preparations. In both experiments the calculated elastic loads applied by the cartilage and the parenchymal recoil explained in part the limitation of maximal active shortening and airway narrowing observed. We conclude that the elastic loads provided by surrounding structures are important in determining the degree of airway smooth muscle shortening and the resultant airway narrowing.Key words: elastic loads, tracheal cartilage, airway smooth muscle shortening.

Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O3 inhalation

1988 ◽  
Vol 65 (1) ◽  
pp. 57-64 ◽  
Author(s):  
G. L. Jones ◽  
P. M. O'Byrne ◽  
M. Pashley ◽  
R. Serio ◽  
J. Jury ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Potassium Chloride ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Electrical Field ◽  
Trachealis Muscle

Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

Catecholamine release: mechanism of mercury-induced vascular smooth muscle contraction

1975 ◽  
Vol 229 (1) ◽  
pp. 8-12 ◽  
Author(s):  
HS Solomon ◽  
NK Hollenberg
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Electromagnetic Flowmeter ◽  
Smooth Muscle Contraction ◽  
Release Mechanism ◽  
Adrenergic Blockade ◽  
Mercuric Ion ◽  
Anesthetized Dogs

The mechanism by which mercuric ion (HgCl2) induces contraction of vascular smooth muscle was defined in the kidney of anesthetized dogs and in rabbit aortic strips. In vivo, HgCl2 injected into the renal artery induced a dose-related reduction in renal blood flow (electromagnetic flowmeter) and glomerular filtration rate (creatinine clearance). An intra-arterial infusion of phenoxybenzamine (POB) significantly reduced the vascular response to HgCl2 (P less than 0.001). In vitro, alpha-adrenergic blockade with phentolamine and POB prevented mercury-induced contraction, whereas agents that block serotonin, histamine, acetylcholine, and angiotensin did not do so. Norepinephrine receptor "protection" from phenoxybenzamine blockade sustained the response to HgCl2. Reserpine pretreatment produced a parallel reduction in the response of the aorta to tyramine and mercury. The results are consistent with an indirect action of mercuric ion via release of endogenous catecholamines.

Role of platelets in contraction of canine tracheal muscle elicited by PAF in vitro

1988 ◽  
Vol 65 (2) ◽  
pp. 914-920 ◽  
Author(s):  
K. J. Popovich ◽  
G. Sheldon ◽  
M. Mack ◽  
N. M. Munoz ◽  
P. Denberg ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Airway Epithelium ◽  
Platelet Activating Factor ◽  
Smooth Muscle Contraction ◽  
Tracheal Smooth Muscle ◽  
Serotonin Antagonist

To elucidate mechanisms of platelet-activating factor (PAF)-induced contraction, we studied the effect of PAF on 203 canine tracheal smooth muscle (TSM) strips from 45 dogs in vitro in the presence and absence of platelets. PAF (10(-11) to 10(-7) M) alone caused no contraction of TSM even in the presence of airway epithelium. In the presence of 2 x 10(5) platelets/microliter, PAF was an extremely potent contractile agonist (threshold 10(-11) M). This response was inhibited by the PAF antagonist, CV-3988 (10(-6) M), and reversed by the serotonin antagonist, methysergide (EC50 = 3.7 +/- 0.79 x 10(-9) M). Neither atropine nor chlorpheniramine (10(-9) to 10(-6) M) attenuated the response to PAF + platelets. In the presence of platelets, 10(-7) M PAF caused an increase in perfusate concentration of serotonin from 0.93 +/- 0.037 x 10(-8) to 1.7 +/- 0.046 x 10(-8) M (P less than 0.001). Tachyphylaxis, previously demonstrated to be irreversible, was shown to be a platelet-dependent phenomenon; contraction could be repeated in the same TSM after addition of fresh platelets. We demonstrate that PAF-induced contraction of canine TSM is caused by the release of cellular intermediates such as serotonin from platelets. We also demonstrate the site of PAF-induced tachyphylaxis in airway smooth muscle contraction.

Mechanism for substance P-induced relaxation of precontracted airway smooth muscle during development

1999 ◽  
Vol 276 (1) ◽  
pp. L51-L56 ◽  
Author(s):  
Maroun J. Mhanna ◽  
Ismail A. Dreshaj ◽  
Musa A. Haxhiu ◽  
Richard J. Martin
Keyword(s):  
Smooth Muscle ◽  
Substance P ◽  
Airway Smooth Muscle ◽  
Sensory Nerve ◽  
Smooth Muscle Contraction ◽  
Relaxant Effect ◽  
Postnatal Maturation ◽  
Relaxant Response ◽  
Tracheobronchial System ◽  
Synthase Inhibitor

Release of substance P (SP) from sensory nerve endings of the tracheobronchial system modulates airway smooth muscle contraction and may cause relaxation of precontracted airways. We sought to elucidate the effect of postnatal maturation on SP-induced relaxation of precontracted airways and determine the roles of endogenously generated nitric oxide (NO) and prostaglandins (PGs). Cylindrical airway segments were isolated from the midtrachea of rats at four different ages, 1, 2, and 4 wk and 3 mo, and contracted to 50–75% of the maximum response induced by bethanechol. SP was then administered in the absence and presence of the NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME), the PG inhibitor indomethacin, or both. Relaxation of airways with SP decreased significantly with advancing postnatal age. SP-induced tracheal relaxation was consistently attenuated by pretreatment withl-NAME, indomethacin, or both. In a different group of animals,l-NAME significantly attenuated the relaxant response of airways to PGE2 exposure, but indomethacin had no significant effect on the relaxant response to exogenous NO. We conclude that SP induces a relaxant effect on precontracted airway smooth muscle, which decreases with advancing age and is mediated via SP-induced release of NO and/or PG.

scholarly journals Regulation of PKC Autophosphorylation by Calponin in Contractile Vascular Smooth Muscle Tissue

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Hak Rim Kim ◽  
Cynthia Gallant ◽  
Kathleen G. Morgan
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Smooth Muscle Tissue ◽  
Hydrophobic Site ◽  
Regulatory Phosphorylation ◽  
Motif Site ◽  
Key Enzyme

Protein kinase C (PKC) is a key enzyme involved in agonist-induced smooth muscle contraction. In some cases, regulatory phosphorylation of PKC is required for full activation of the enzyme. However, this issue has largely been ignored with respect to PKC-dependent regulation of contractile vascular smooth muscle (VSM) contractility. The first event in PKC regulation is a transphosphorylation by PDK at a conserved threonine in the activation loop of PKC, followed by the subsequent autophosphorylation at the turn motif and hydrophobic motif sites. In the present study, we determined whether phosphorylation of PKC is a regulated process in VSM and also investigated a potential role of calponin in the regulation of PKC. We found that calponin increases the level of in vitro PKCαphosphorylation at the PDK and hydrophobic sites, but not the turn motif site. In vascular tissues, phosphorylation of the PKC hydrophobic site, but not turn motif site, as well as phosphorylation of PDK at S241 increased in response to phenylephrine. Calponin knockdown inhibits autophosphorylation of cellular PKC in response to phenylephrine, confirming results with recombinant PKC. Thus these results show that autophosphorylation of PKC is regulated in dVSM and calponin is necessary for autophosphorylation of PKC in VSM.

Effects of the β-Receptor Antagonists Propranolol, Oxprenolol and Labetalol on Human Vascular Smooth-Muscle Contraction

1978 ◽  
Vol 55 (3) ◽  
pp. 235-240
Author(s):  
R. F. W. Moulds ◽  
R. A. Jauernig ◽  
J. D. Hobson ◽  
J. Shaw
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Barium Chloride ◽  
Smooth Muscle Contraction ◽  
Hypotensive Activity ◽  
Inhibitory Effects ◽  
Vascular Effects ◽  
High Concentrations ◽  
Β Receptor

1. Spiral strips of human digital arteries have been studied in vitro to investigate whether dl-propranolol, d-propranolol, oxprenolol and labetalol have peripheral vascular effects in man. 2. Labetalol was a potent inhibitor of contractile responses to noradrenaline, but had less effect on responses to 5-hydroxytryptamine and barium chloride. 3. dl-and d-propranolol were equally effective inhibitors of responses to barium chloride. They were only weak antagonists of noradrenaline responses, but stronger, non-competitive antagonists of 5-hydroxytryptamine responses. 4. Oxprenolol was only a weak inhibitor of the responses to both noradrenaline and 5-hydroxytryptamine and had little effect on responses to barium chloride. 5. It is concluded that labetalol has specific α-adrenoreceptor-blocking properties, which are probably relevant to its therapeutic action in man. Propranolol has non-specific inhibitory effects on vascular smooth muscle, which might contribute to its hypotensive activity at high concentrations, but oxprenolol has only slight peripheral effects that are probably therapeutically insignificant.

Abstract MP30: Small Molecule Inhibitor Of Chloride Channel Tmem16a Blocks Vascular Smooth Muscle Contraction And Lowers Blood Pressure In Spontaneously Hypertensive Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Onur Cil ◽  
Maria C Jordan ◽  
Henry R Askew Page ◽  
Pyone Myat Thwe ◽  
Samuel N Baldwin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Spontaneously Hypertensive Rats ◽  
Antihypertensive Drugs ◽  
Smooth Muscle Contraction ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Cardiovascular Morbidity And Mortality ◽  
Vascular Smooth Muscle Contraction

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. TM inh -23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM inh -23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 μM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM inh -23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM inh -23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM inh -23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM inh -23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.

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