Different spasmolytic effects of smooth muscle relaxants on the guinea-pig esophageal muscularis mucosae contracted by carbachol or high potassium in vitro

At least two laboratories have independently reported the synthesis of benzofuroindole compounds having potential therapeutic implications in many disease states including those that involve smooth muscle hyperactivity. Through a series ofin vitroscreenings, they demonstrated the efficacy (and selectivity) of these compounds to potentiate large conductance calcium- (Ca2+-) activated K+(BKCa) channels, by far, the most characterized of all Ca2+-dependent K+channels. Interestingly, promising benzofuroindole derivatives such as compound 7 (10H-benzo[4,5]furo[3,2-b]indole) and compound 22 (4-chloro-7-trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid) both exhibited high bladder (versus aorta) selectivity, making them attractive alternative treatments for bladder overactivity. In recent reports, compound 22 (LDD175 or TBIC) also showed inhibition of ileum and uterine contractions, indicating multiple target tissues, which is not surprising as BKCachannels are ubiquitously expressed in the animal and human tissues. In this paper, the authors discuss the value of benzofuroindole compounds and the challenges that need to be overcome if they were considered as smooth muscle relaxants.

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Tumour necrosis factor-α induces hyperreactivity in tracheal smooth muscle of the guinea-pig in vitro

CrossRef Listing of Deleted DOIs ◽

10.1183/09031936.98.12010045 ◽

1998 ◽

Vol 12 (1) ◽

pp. 45-49 ◽

Cited By ~ 35

Author(s):

H-J. Pennings ◽

K. Kramer ◽

A. Bast ◽

W.A. Buurman ◽

E.F.M. Wouters

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Tracheal Smooth Muscle ◽

Factor I ◽

Necrosis Factor

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Effect of airway inflammation on smooth muscle shortening and contractility in guinea pig trachealis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.265.6.l549 ◽

1993 ◽

Vol 265 (6) ◽

pp. L549-L554 ◽

Cited By ~ 4

Author(s):

R. W. Mitchell ◽

I. M. Ndukwu ◽

K. Arbetter ◽

J. Solway ◽

A. R. Leff

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Neurogenic Inflammation ◽

Isometric Force ◽

Electrical Field Stimulation ◽

Shortening Velocity ◽

Lever System ◽

Force Velocity

We studied the effect of either 1) immunogenic inflammation caused by aerosolized ovalbumin or 2) neurogenic inflammation caused by aerosolized capsaicin in vivo on guinea pig tracheal smooth muscle (TSM) contractility in vitro. Force-velocity relationships were determined for nine epithelium-intact TSM strips from ovalbumin-sensitized (OAS) vs. seven sham-sensitized controls and TSM strips for seven animals treated with capsaicin aerosol (Cap-Aer) vs. eight sham controls. Muscle strips were tethered to an electromagnetic lever system, which allowed isotonic shortening when load clamps [from 0 to maximal isometric force (Po)] were applied at specific times after onset of contraction. Contractions were elicited by supramaximal electrical field stimulation (60 Hz, 10-s duration, 18 V). Optimal length for each muscle was determined during equilibration. Maximal shortening velocity (Vmax) was increased in TSM from OAS (1.72 +/- 0.46 mm/s) compared with sham-sensitized animals (0.90 +/- 0.15 mm/s, P < 0.05); Vmax for TSM from Cap-Aer (0.88 +/- 0.11 mm/s) was not different from control TSM (1.13 +/- 0.08 mm/s, P = NS). Similarly, maximal shortening (delta max) was augmented in TSM from OAS (1.01 +/- 0.15 mm) compared with sham-sensitized animals (0.72 +/- 0.14 mm, P < 0.05); delta max for TSM from Cap-Aer animals (0.65 +/- 0.11 mm) was not different from saline aerosol controls (0.71 +/- 0.15 mm, P = NS). We demonstrate Vmax and delta max are augmented in TSM after ovalbumin sensitization; in contrast, neurogenic inflammation caused by capsaicin has no effect on isolated TSM contractility in vitro. These data suggest that airway hyperresponsiveness in vivo that occurs in association with immunogenic or neurogenic inflammation may result from different effects of these types of inflammation on airway smooth muscle.

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THE EFFECTS OF GR32191, A NEW THROMBOXANE RECEPTOR BLOCKING DRUG,ON PLATELETS AND VASCULAR SMOOTH MUSCLE IN VITRO

10.1055/s-0038-1643754 ◽

1987 ◽

Author(s):

P Lumley ◽

E W Collington ◽

P Hallett ◽

E J Hornby ◽

p PA Humphrey ◽

...

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Vascular Smooth Muscle ◽

Inhibitory Activity ◽

Whole Blood ◽

Blocking Drug ◽

Receptor Blocking ◽

Thromboxane Receptor ◽

Induced Aggregation

The effect of a new thromboxane receptor blocking drug GR32191 ([1R-[1α(Z),2β,3β,5α]]-(+)-7-[5-[[(1,1"-biphenyl)-4-yl]methoxy] -3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoic acid,hydrochloride) has been examined upon platelets and vascular smooth muscle. In human platelet-rich plasma (PRP), aggregation to thromboxane(Tx) A2, PGH2, arachidonic acid, collagen andU-46619 was antagonised by GR32191 (IC50 range 2-36 nM).Primary aggregation (PRP treated with aspirin 10 pM) to ADP, 5-HT and adrenaline were unaffected by concentrations of GR32191 up to 10 pM. In human PRP, U-46619-induced aggregation and 5-HT release were antagonised by GR32191(10-100 nM). In contrast, in theabsence of aspirin, ADP-induced 5-HT release,but not aggregation, was antagonised by the compound implicating a role for TXA2 in the release process. In human PRP GR32191 (up to 30μM) did not itself induce aggregation or, in the presence of EGTA (4 mM), induce detectable shape change. Up to 10 μM GR32191 was without effect upon the inhibitory activity of PGI2 or PGD2 and at 1μMhad no significant inhibitory activity upon fatty acid cyclooxygenase, thromboxane synthase, prostacyclin synthase, 12-lipoxygenase orphosphodiesterase. The effect of GR32191was quantified further in human platelets suspended in whole blood or physiological salt solution. Aggregation to U-46619 was antagonised byGR32191 with a pA2 (slope of the Schild regression) of 8.2 (1.3) in whole blood and 8.8 (1.3) in resuspended platelets. The compound competitively and specifically antagonised the contractions of strips of human isolatedpulmonary blood vessels and rat and guinea-pig aortic strips produced by U-46619 with pA2 (slope) values of 8.2 (1.1), 7.9 (0.9) and 8.7(0.9) respectively. In contrast contractions induced by KC1 and 5-HT (rat) orKC1and histamine (guinea-pig) were unaffectedbyconcentrations of GR32191 up to 30 μM.Thus GR32191 is a potent and specific thromboxane receptor blocking drug on platelets and vascular smooth muscle in vitro. It is orally active and long lasting in man (Thomas, M et al.,this meeting).

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