Relaxation of guinea‐pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside

Turner, Nicholas C.; Lamb, Janine; Worby, Angela; Murray, Kenneth

doi:10.1111/j.1476-5381.1994.tb14850.x

Cited by 19 publications

(23 citation statements)

References 19 publications

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“…There are a number of possible explanations for this difference in the effects of sodium nitroprusside and zaprinast. First, a component of the sodium nitroprusside response may be attributed to cAMP accumulation secondary to PDE3 inhibition as reported in other tissues (Turner et al 1994); second, the expression of the functional response of a PDE5 inhibitor is limited by the level of the basal activity of coupled guanylyl cyclase; and third, zaprinast poorly penetrates whole cell preparations (Nicholson and Shahid 1994). Our results with sodium nitroprusside give support to the potential clinical interest of nitroglycerin in obstetrics recently shown by Mercier et al (1996) and Riley et al (1996).…”

Section: Discussionsupporting

confidence: 82%

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Bardou¹,

Cortijo

Loustalot

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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This study was aimed at evaluating the in vitro effects of phosphodiesterase inhibitors and beta2-adrenoceptor agonists on spontaneous contractions of human term myometrium. Rolipram, RP 73401 (3-cyclopentyloxy-N-(3,5(-dichloro-4-pyridil)-4-methoxybenzamide) and Ro 20-1724 (1-4-(3-butoxy-4-methoxybenzyl)-2-imidozolidinone) (phosphodiesterase 4 inhibitors) inhibited spontaneous myometrial contractions (Emax approximately 100%; pD2 of 6.80+/-0.28, 6.84+/-0.32 and 6.31+/-0.03, respectively). Salbutamol and formoterol were less effective (Emax=40+/-6% and 35+/-12%, respectively) than phosphodiesterase 4 inhibitors to reduce myometrial contractility. Inhibitors of phosphodiesterase 3 (milrinone and siguazodan) and 5 (zaprinast) were marginally effective. Rolipram (10-30 nM) and siguazodan (0.1 microM) potentiated the response to salbutamol (Emax=75+/-12%, 88+/-8% and 73+/-12% and pD2=6.51+/-0.20, 6.93+/-0.29 and 6.48+/-0.16, respectively). Sodium nitroprusside (pD2=6.76+/-0.29) and theophylline (pD2=5.15+/-0.22) were effective inhibitors of myometrial contractions. Chromatographic separation of phosphodiesterase isoenzymes demonstrated that phosphodiesterase 4 is predominant but other phosphodiesterase isoenzymes were also identified. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta2-adrenoceptor agonists have potential interest as tocolytic agents.

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Section: Discussionsupporting

confidence: 82%

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Bardou¹,

Cortijo

Loustalot

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Despite the fact that PDE IV is present in smooth muscle cells, selective inhibitors of PDE IV have not been shown to have marked vasodilator potential. Recently, it was suggested that PDE IV inhibitors are bronchodilators but PDE III inhibitors are only weakly active (Cortijo et al, 1993;Turner et al, 1994). In the present study, the marked enhancement of the relaxant activity of rolipram in carbachol-precontracted guinea-pig trachea by isoliquiritigenin, indicates that isoliquiritigenin combined with PDE IV inhibition (rolipram) might offer greater bronchodilator potential.…”

Section: Discussionsupporting

confidence: 47%

Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta

Sun

Kuo

1995

British J Pharmacology

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1 The vasorelaxant activity of isoliquiritigenin, isolated from Dalbergia odorifera T., was investigated in the phenylephrine-precontracted rat aorta by measuring tension, guanylate and adenylate cyclase activities, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 2 Isoliquiritigenin concentration-dependently relaxed rat aorta contracted with phenylephrine, KCl, U-46619, endothelin and 5-hydroxytryptamine, with ECvs of 7.4 ± 1.6, 10.5 ± 2.3, 14.3 ± 3.3, 11.8 ± 2.0 and 13.6 ± 3.7 IM, respectively. 3 Isoliquiritigenin caused endothelium-independent relaxation of phenylephrine-precontracted rat aortic rings. Neither N0-monomethyl-L-arginine (L-NMMA) (an inhibitor of the L-arginine-NO pathway) nor oxyhaemoglobin (which binds NO) modified the relaxant effect of isoliquiritigenin. The relaxant action of isoliquiritigenin also persisted in intact aorta in the presence of indomethacin or glibenclamide. However, methylene blue, an inhibitor of soluble guanylate cyclase, abolished relaxation induced by isoliquiritigenin. 4 Incubation of rat aorta with isoliquiritigenin not only increased aortic cyclic GMP content but also caused small increases in aortic cyclic AMP content, and greatly potentiated the increases in cyclic AMP observed in the presence of forskolin. The maximum increase in cyclic GMP (Kukovetz et al., 1981;Ignarro & Kadowitz, 1985).Cyclic GMP has been assumed to mediate vascular relaxation by stimulating the phosphorylation of critical protein substrates by cyclic GMP-dependent protein kinase (Waldman & Murad, 1987). In most tissues, the concentration and the action of cyclic GMP are regulated by guanylate cyclase and cyclic nucleotide phosphodiesterases (PDEs) (Schulz et al., 1991 (Ko et al., 1993;Yu et al., 1992;. During random screening tests, we found that isoliquiritigenin (Figure 1), isolated from Dalbergia odorifera T., mercially available, which exerts anti-tumour promoting and anti-platelet activity (Yamamoto et al., 1991). In the present study, the vasorelaxant activity of isoliquiritigenin was studied in the precontracted rat aorta. Methods Rat aortic contractionWistar rats of either sex (250-300 g) were killed by a blow to the head. The thoracic aorta was isolated and excess fat and connective tissue were removed. Vessels were cut into rings of about 5 mm in length and mounted in organ baths containing 5 ml Krebs solution of the following composition (mM): NaCl 118.4, KCl 4.7, CaC12 1.9, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25.0 and glucose 11.7. The tissue bath solution was maintained at 37'C and gassed with 95% 02: 5% CO2 mixture. Two stainless steel hooks were inserted into the aortic lumen, one was fixed while the other was connected to a transducer. Aortic segments were equilibrated in the medium for 90 min with three changes of Krebs solution and maintained under an optimal tension of 1 g before specific experimental protocols were initiated. Contractions were recorded isometrically via a force-displacement transducer connected to...

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“…PDE III is inhibited by cGMP and, therefore, stimulation of cells with agents that stimulate guanylyl cyclase may result in an increase in cAMP via inhibition of cAMP hydrolysis by PDE III. Thus, in guinea-pig trachea sodium nitroprusside, which increases cGMP, enhances the increase in cAMP induced by rolipram [48].…”

Section: Regulation Of Pdesmentioning

confidence: 85%

Cyclic nucleotides and phosphodiesterases and airway function

Barnes¹

1995

Eur Respir J

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Regulation of PDE expression in health and disease is now under investigation. Several selective PDE inhibitors have recently been developed, and experimental studies indicate that PDE IV inhibitors may be useful as anti-inflammatory treatments in asthma. Clinical trials in asthma are now in progress.Eur Respir J., 1995, 8, 457-462. The cyclic nucleotides cyclic 3'5'adenosine monophosphate (cAMP) and cyclic 3',5'guanosine monophosphate (cGMP) are important second messengers and play a key role in the regulation of cell activity. In the airways, these nucleotides regulate the smooth muscle tone, mediator secretion and activation of inflammatory cells. The intracellular concentration of cyclic nucleotides is determined by stimulation of surface receptors and intracellular breakdown of cyclic nucleotides by phosphodiesterases (PDEs). Five distinct isoenzyme families have now been distinguished, based on substrate specificity and the development of selective inhibitors [1,2], and molecular cloning studies have revealed that several additional families exist [3] (table 1). Theophylline as a PDE inhibitorIt is widely held that the bronchodilator effect of theophylline is due to inhibition of PDE, thereby leading to an increase in intracellular concentrations ( fig. 1). Theophylline is a nonselective PDE inhibitor, but the degree of inhibition is small at concentrations of theophylline which are therapeutically relevant. Thus, total therapeutic concentrations of theophylline inhibit PDE activity in human lung extracts by only 5-10% [4]. There is no evidence that airway smooth muscle or inflammatory cells concentrate theophylline to achieve higher intracellular than circulating concentrations. Furthermore, inhibition of PDE should lead to synergistic interaction with β-agonists, but this has not been convincingly demonstrated. However, this might be explained by the recent observations that relaxation of airway smooth muscle by β-agonists may involve direct coupling of β-receptors via a stimulatory G-protein to the opening of potassium channels, without the involvement of cAMP [5,6]. SERIES 'THEOPHYLLINE AND PHOSPHODIESTERASES INHIBITORS' Edited by M. Aubier and P.J. BarnesDept of Thoracic Medicine, National Heart and Lung Institute, London, UK.

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Relaxation of guinea‐pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside

Cited by 19 publications

References 19 publications

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Pharmacological and biochemical study on the effects of selective phosphodiesterase inhibitors on human term myometrium

Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta

Cyclic nucleotides and phosphodiesterases and airway function

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