Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes

Nicholson, C. D.; Challiss, R. A. John; Shahid, Mohammed

doi:10.1016/0165-6147(91)90484-a

Cited by 436 publications

(244 citation statements)

References 30 publications

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“…Moreover, taking into account that PDE-IV inhibitors are currently under evaluation as anti-inflammatory agents [36], our results with RO 20-1724 and salmeterol suggest new possibilities to control the histotoxic properties of neutrophil-derived oxidants at sites of airway inflammation. Finally, the co-operation between salmeterol and PGE 2 to suppress the neutrophil oxidative response provides an example of the possibility of pharmacologically amplifying natural systems (PGE 2 ) devoted to downregulation of neutrophil reactivity.…”

Section: Neutrophilsmentioning

confidence: 78%

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Ottonello

Morone

Dapino

et al. 1996

Clinical and Experimental Immunology

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SUMMARYHuman neutrophils, plated in fibronectin-coated wells and stimulated with N-formyl-methionyl-leucylphenylalanine (fMLP), were found to undergo a massive and prolonged respiratory burst, as measured by monitoring superoxide production. The 2 -agonist salmeterol inhibited the respiratory burst in a dose-dependent manner. In contrast, salbutamol was ineffective. Moreover, the neutrophil respiratory burst was partially suppressed by prostaglandin E 2 (PGE 2 ) and the phosphodiesterase type IV (PDE-IV) inhibitor RO 20-1724. When salmeterol was used in combination with PGE 2 or RO 20-1724, additive inhibitory effects were observed. The inhibitory activity of salmeterol was not reversed in the presence of the -blocker propranolol, and did not correlate with its ability of increasing cyclic AMP (cAMP) levels. Finally, the compounds used did not affect neutrophil adherence to fibronectin-coated wells. The results suggest that salmeterol is capable of down-regulating the neutrophil oxidative response to fMLP, also of co-operating with PGE 2 and PDE-IV inhibitor RO 20-1724 in a manner not related to its 2 -receptor binding activity. In other words, salmeterol displays neutrophil-directed effects, susceptible to be amplified by natural mediators such as PGE 2 or PDE-IV inhibitors, consistent with possible anti-inflammatory properties of the drug.

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Section: Neutrophilsmentioning

confidence: 78%

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Ottonello

Morone

Dapino

et al. 1996

Clinical and Experimental Immunology

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“…These relate to the pharmacological effects arising from the elevation of cGMP levels in tissues other than the corpus cavernosum, in particular, the retina and smooth muscle (Table 2). 4 Safety pharmacology studies were unremarkable.…”

Section: Introductionmentioning

confidence: 99%

Preclinical safety profile of sildenafil

et al. 2004

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Sildenafil citrate, marketed as Viagra s , for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively. Plasma analyses were conducted to determine the exposure to sildenafil. We found species-specific effects in dogs (Beagle pain syndrome), mice (marked intestinal dilatation) and rats (adaptive reversible hepatocellular hypertrophy associated with secondary thyroid hypertrophy). All these effects in rodents and dogs have no relevance to humans. Morphometric thickness measurements of the retinal layers carried out in response to clinical observations of visual disturbances in humans indicated no difference between treated and control rats and dogs after up to 24 months of treatment. There was no evidence of histopathologic damage to any structures of the visual pathway. Sildenafil had no effects on fertility, no teratogenic potential, was not genotoxic and has no carcinogenic potential. In rats and dogs, safety ratios were 40:1 and 28:1, respectively, in terms of exposure over 24 h (AUC 24 h ) and 19:1 and 8:1, respectively, in terms of peak plasma concentration (C max ). These safety ratios illustrate the separation between exposure to sildenafil of animals at large nontoxic doses and the much smaller human therapeutic exposure. This profile highlights the very low risk of human toxicity for sildenafil. The favourable results of the nonclinical safety evaluation of sildenafil in established animal models have been confirmed by many years of clinical experience during the development and marketing of sildenafil.

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“…POE III (a cAMP-preferring enzyme) is deficient in the brain, and the majority of cAMP hydrolysis is via the POE IV isozyme, where it is an important regulator of neuronal excitability and activity (Nemoz et a!., 1989;Challiss and Nicholson, 1990). In this regard, selective POE IV inhibitors (i.e., denbufylline and rolipram) possess a variety of CNS effects, including anti-ischemic, antidepressant, and nootropic activity (Angersbach, 1991;Nicholson et a!., 1991).…”

mentioning

confidence: 99%

“…In peripheral arteries (e.g., rat and bovine aorta), membrane-bound and cytosolic POE III and POE IV catalyze cAMP hydrolysis (Nicholson et a!., 1991;Ivorra et a!., 1992;Komas et a!., 1993). A variety of PDE III inhibitors produce complete, endothelium independent relaxation in precontracted rat aorta (Komas et ai., 1991) and potentiate the vasorelaxant effects of isoprenaline (Lindgren et ai., 1990).…”

mentioning

confidence: 99%

Identification, Characterization, and Functional Role of Phosphodiesterase Type IV in Cerebral Vessels: Effects of Selective Phosphodiesterase Inhibitors

Willette

Shiloh

Sauermelch

et al. 1997

J Cereb Blood Flow Metab

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Summary:The role of the phosphodiesterase type IV iso zyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE) Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. The family of phosphodiesterase (POE) isozymes is responsible for the intracellular hydrolysis of cAMP and cOMPo Some members of the seven POE gene families differ in their structure, substrate speci ficity, sensitivity to selective inhibitors, and tissue dis- Abbreviations used: DEAE, diethylaminoethanol; EC50s, con centrations producing 50% relaxation; EDT A, ethylenediaminetetra acetic acid; IC50s, concentrations producing 50% inhibition; PDE, phosphodiesterase; SAH, subarachnoid hemorrhage. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hy drolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cere bral vasospasm associated with subarachnoid hemorrhage.

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Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes

Cited by 436 publications

References 30 publications

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Preclinical safety profile of sildenafil

Identification, Characterization, and Functional Role of Phosphodiesterase Type IV in Cerebral Vessels: Effects of Selective Phosphodiesterase Inhibitors

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