Studies with Two New Phosphodiesterase Inhibitors (ICI 58,301 and ICI 63,197) on Anaphylaxis in Guinea Pigs, Mice and Rats

Davies, G. E.; Evans, David P.

doi:10.1159/000231064

Cited by 21 publications

(5 citation statements)

References 10 publications

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“…Both compounds inhibit anaphylactic bronchospasm (Hoshino et al, 1989;Underwood et al, 1992) and, microvascular leakage (Eda et al, 1987;Ortiz et al, 1992). Ibudilast (Nagai et al, 1983) and other PDE IV inhibitors (Davies & Evans, 1973) also reduce passive cutaneous anaphylaxis. Surprisingly, ibudilast had no effect on PAF-induced accumulation of eosinophils in the airways of guinea-pigs, whereas another PDE inhibitor, benzafentrine (AH-21-132) reduced cell numbers (Sanjar et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Souness¹,

Villamil²,

Scott³

et al. 1994

British J Pharmacology

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1 The possible role of cyclic AMP phosphodiesterase (PDE) in the inhibitory actions of ibudilast on tracheal smooth muscle contractility and eosinophil thromboxane generation was investigated. 2 Ibudilast was a non-selective inhibitor of partially purified cyclic nucleotide PDE isoenzymes from pig aorta and bovine tracheal smooth muscle, exhibiting only moderate potency against bovine tracheal PDE IV (IC0 = 12 ± 4 AM, n = 3). Similar or slightly lower potencies were displayed against PDEs I, II, III and V. In contrast, rolipram exhibited selectivity for PDE IV (3 0.5 AM, n = 3).3 Ibudilast (IC50 = 0.87 ± 0.37 AM, n = 3), like rolipram (IC = 0.20 0.04 AM, n = 3), was a more potent inhibitor of membrane-bound PDE IV from guinea-pig eosinophils than of partially purified PDE IV from bovine tracheal smooth muscle. The potency of ibudilast increased when the eosinophil enzyme was solubilised with deoxycholate and NaCl (IC50 = 0.11 ± 0.05 JAM, n = 3) or exposed to vanadate/glutathione complex (V/GSH) (ICo=0.11 ± 0.02 JM, n = 3). The potency of rolipram was also increased by solubilization (IC50 = 0.012 0.003, n = 3) or V/GSH (IC,0 = 0.012 ± 0.003, n = 3). 4 In intact eosinophils, ibudilast (0.032 jiM-20 JM) potentiated isoprenaline-induced cyclic AMP accumulation in a concentration-dependent manner, being approximately 20 fold less potent than rolipram. Little or no effect on basal cyclic AMP levels was observed with either compound. The cyclic AMP-dependent protein kinase activity ratio was significantly increased following incubation of eosinophils with either ibudilast (20 AM) or rolipram (20 gM) in the absence or presence of isoprenaline. 5Leukotriene B4 (300 nM)-induced thromboxane generation from guinea-pig eosinophils was inhibited by ibudilast (IC50 = 11.3 ± 3.7 AM, n = 5) and rolipram (IC,0 = 0.280 ± 0.067 AM, n = 5) in a concentration-dependent manner. 6 Ibudilast (10 nM-I AM), whilst generally less potent than rolipram (1 nM-AM), produced concentration-dependent relaxation of spasmogen (methacholine, histamine, LTD4)-induced tone in the guineapig isolated tracheal strip. Ibudilast was less potent in reversing the methacholine (IC50 = 1.95 ± 0.40 JM, n = 6)-induced contraction than those of histamine (IC50 = 0.18 ± 0.70 AM, n =6) or leukotriene D4 (LTD4, IC50 = 0.12 ± 0.05 JM, n = 6). Rolipram also exhibited a similar pattern of activity, although the difference in potency against methacholine (IC50 = 0.1 ± 0.01 JAM, n = 6) compared with the other two spasmogens, histamine (IC50 = 0.034 ± 0.017 JM, n = 7) and LTD4 (IC50 = 0.026 ± 0.008 AM, n = 7), was not as great.7 These results demonstrate that ibudilast, like rolipram, has several biological actions on the eosinophil and airways smooth muscle which may be attributed to inhibition of cyclic AMP PDE. These actions may account, at least in part, for the recently reported anti-asthma effects of ibudilast.

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Section: Discussionmentioning

confidence: 99%

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Souness¹,

Villamil²,

Scott³

et al. 1994

British J Pharmacology

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“…In vivo, PDE IV inhibitors suppress microvascular leakage (Raeburn Author for correspondence. & Karlsson, 1993), eosinophil accumulation (Underwood et al, 1993), passive cutaneous anaphylaxis (Davies & Evans, 1973) and anaphylactic bronchospasm (Underwood et al, 1993). As well as their anti-inflammatory effects, PDE IV inhibitors relax airways smooth muscle and exhibit bronchodilator activity in vivo (Harris et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP‐specific phosphodiesterase: comparison with rolipram

Souness¹,

Maslen²,

Webber³

et al. 1995

British J Pharmacology

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1. We have investigated the inhibitory potency of RP 73401, a novel, highly selective and potent inhibitor of cyclic AMP-specific phosphodiesterase (PDE IV), against partially-purified PDE isoenzymes from smooth muscle and the particulate PDE IV from guinea-pig eosinophils. The inhibitory effects of RP 73401 on the generation of superoxide (.O2-), major basic protein (MBP) and eosinophil cationic protein (ECP) from guinea-pig eosinophils have also been studied. 2. RP 73401 potently inhibited partially-purified cyclic AMP-specific phosphodiesterase (PDE IV) from pig aortic smooth muscle (IC50 = 1.2 nM); it was similarly potent against the particulate PDE IV from guinea-pig peritoneal eosinophils (IC50 = 0.7 nM). It displayed at least a 19000 fold selectivity for PDE IV compared to its potencies against other PDE isoenzymes. Rolipram was approximately 2600 fold less potent than RP 73401 against pig aortic smooth muscle PDE IV (IC50 = 3162 nM) and about 250 times less potent against eosinophil PDE IV (IC50 = 186 nM). 3. Solubilization of the eosinophil particulate PDE IV increased the potency of rolipram 10 fold but did not markedly affect the potency of RP 73401. A similar (10 fold) increase in the PDE IV inhibitory potency of rolipram, but not RP 73401, was observed when eosinophil membranes were exposed to vanadate/glutathione complex (V/GSH). 4. Reverse transcription polymerase chain reaction (RT-PCR), using primer pairs designed against specific sequences in four distinct rat PDE IV subtype cDNA clones (PDE IVA-D), showed only mRNA for PDE IVD in guinea-pig eosinophils. PDE IVD was also the predominant subtype expressed in pig aortic smooth muscle cells. 5. RP 73401 (Kiapp = 0.4 nM) was 4 fold more potent than (+/-)-rolipram (Kiapp = 1.7 nM) in displacing[3H]-(+/-)-rolipram from guinea-pig brain membranes.6. In intact eosinophils, RP 73401 potentiated isoprenaline-induced cyclic AMP accumulation(EC50 = 79 nM). RP 73401 also inhibited leukotriene B4-induced generation of *02- (IC50 = 25 nM), and the release of major basic protein (ICo = 115 nM) and eosinophil cationic protein (IC50 = 7 nM). Rolipram was 3-14 times less potent than RP 73401.7. Thus RP 73401 is a very potent and selective PDE IV inhibitor which suppresses eosinophil function suggesting that it may be a useful agent for the treatment of inflammatory diseases such as asthma. The greatly different inhibitory potencies of rolipram against PDE IV from smooth muscle and eosinophils(in contrast to the invariable effects of RP 73401) are unlikely to be attributable to diverse PDE IV subtypes but suggest distinct interactions of the two inhibitors with the enzyme.

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“…Comparing structurally similar PDE inhibitors to caffeine, we found differential effects on the percentage of UVB-induced apoptotic sunburn cells. The selective PDE2 inhibitor, EHNA hydrochloride [15] , significantly increased the percentage of UVB-induced apoptotic sunburn cells compared with caffeine and control while the selective PDE4 inhibitor, ICI 63,197 [16] , significantly decreased the percentage. PDEs hydrolyze cyclic nucleotides and, due differences in affinities, PDE2 inhibitors, specifically EHNA hydrochloride, have been shown to mainly increase cGMP signaling whereas PDE4 inhibitors have been shown to increase cAMP signaling.…”

Section: Introductionmentioning

confidence: 90%

PDE2 Is a Novel Target for Attenuating Tumor Formation in a Mouse Model of UVB-Induced Skin Carcinogenesis

et al. 2014

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Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 µmole or 0.8 µmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 µmole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer.

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Studies with Two New Phosphodiesterase Inhibitors (ICI 58,301 and ICI 63,197) on Anaphylaxis in Guinea Pigs, Mice and Rats

Cited by 21 publications

References 10 publications

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone

Suppression of eosinophil function by RP 73401, a potent and selective inhibitor of cyclic AMP‐specific phosphodiesterase: comparison with rolipram

PDE2 Is a Novel Target for Attenuating Tumor Formation in a Mouse Model of UVB-Induced Skin Carcinogenesis

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