Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterases (PDEs) regulate intracellular cyclic nucleotide metabolism and, thus, contraction and relaxation of smooth musculature. The aim of the present study was to evaluate the functional effects of isoenzyme-selective inhibitors and their effects on cyclic nucleotide levels in the human detrusor smooth muscle. In addition, the functional relevance of the cAMP versus the cGMP pathways in the regulation of the detrusor smooth muscle tone was assessed. Relaxant responses to various PDE inhibitors, forskolin and sodium nitroprusside (SNP) were investigated in vitro using a standard organ bath setup. Cyclic nucleotide levels were measured after incubation with the same substances using cAMP and cGMP radioimmunoassays (RIAs). Significant relaxant responses were only induced by non-selective PDE inhibition, the PDE I inhibitor vinpocetine and the adenylate cyclase activator forskolin. Relaxant responses to these substances were paralleled by increases in cyclic nucleotide levels. Our data suggest that the cAMP pathway and calcium/calmodulin-stimulated PDE (PDE I) may be of functional importance in the regulation of the human detrusor smooth muscle tone in vitro.
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PMID:Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. 883 79

Pharmacodynamic interactions in vitro between different types of airway smooth muscle relaxants were systematically and quantitatively evaluated by using a new methodological technique. Relaxant concentration-effect curves for terbutaline, theophylline, cromakalim, sodium nitroprusside and isradipine were obtained in isolated guinea-pig trachea contracted by histamine (1 microM). The effects of three different fixed concentrations of each airway smooth muscle relaxant were initially attained and concentration-effect curves for combinations with increasing concentrations of either one of the other relaxants were produced. Based on pharmacodynamic parameters obtained by non-linear regression analysis of experimental data for the relaxants alone theoretical concentration-effect curves for predicted additive interaction were constructed by using the isobolic method. Synergistic (over-additive) interaction was defined as existing when data points and derived pharmacodynamic parameters obtained with combinations of the relaxants showed statistically significant deviation from the predicted additive interaction curve and its functional parameters. Significant synergistic interaction with terbutaline was found for both theophylline (70 or 200 microM), cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (30 or 100 nM) and isradipine (1, 3 or 10 nM). Theophylline showed synergistic interaction with cromakalim (0.1, 0.3 or 1 microM), sodium nitroprusside (10 nM) and isradipine (1, 3 or 10 nM). Interactions between cromakalim and sodium nitroprusside (10, 30 or 100 nM) were also synergistic, whereas cromakalim and isradipine (1, 3 or 10 nM) produced only additive interaction. Possible mechanisms underlying the interactions are discussed on basis of existing knowledge with special regards to phosphodiesterase isoenzymes, K+ and Ca2+ channels.
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PMID:In vitro studies on the interactions of beta2-adrenoceptor agonists, methylxanthines, Ca2+-channel blockers, K+-channel openers and other airway smooth muscle relaxants in isolated guinea-pig trachea. 919 72

1. The effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) on tension, levels of cyclic GMP and cyclic AMP were investigated in guinea-pig trachea. We especially studied the combined effect of YC-1 with exogenous or endogenous nitric oxide on these parameters. 2. YC-1 at the concentration 3 or 10 microM, which caused only minor effect by itself, elicited concentration-dependent potentiation of sodium nitroprusside (SNP)-induced tracheal relaxation. This relaxation of YC-1 with SNP was reversed by ODQ. 3. Relaxant responses to electric field stimulation (EFS) in the presence of indomethacin, atropine, guanethidine, alpha-chymotrypsin and histamine were also markedly increased by YC-1 (10 microM). In the presence of L-NAME or ODQ, the relaxant effects to EFS were attenuated and the following addition of YC-1 did not further enhance relaxation. 4. YC-1 (10 microM) or SNP (0.3 microM) alone did not induce significant elevation of cyclic GMP levels in the presence of IBMX, whereas simultaneous application of both compounds markedly elevated the cyclic GMP accumulation. In contrast, the cyclic AMP levels were not altered even at the combination of YC-1 and SNP. Additionally, YC-1 also affected cyclic GMP metabolism, since it inhibited the activity of phosphodiesterase type V in human platelets. 5. YC-1 (30 microM) did not scavenge superoxide anion and had no effect on the removal of superoxide anion by superoxide dismutase in a xanthine/xanthine oxidase system. 6. In conclusion, these results indicate that although YC-1 elicits negligible relaxation of guinea-pig trachea by itself, it can potentiate the relaxant responses of exogenous or endogenous NO. This synergistic response of YC-1 is via the elevation of cyclic GMP contents.
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PMID:YC-1 potentiates nitric oxide-induced relaxation in guinea-pig trachea. 1051 35

An experimental study was done to examine a potential role of phosphodiesterase (PDE) inhibitors in the treatment of diabetic erectile dysfunction. Relaxant effect of specific PDE inhibitors were measured in strips of corpus cavernosum smooth muscle taken from control and diabetic groups. Diabetes mellitus was induced in New Zealand white rabbits using alloxan. Penises excised from diabetic rabbits 8 weeks after the induction of diabetes mellitus. In the organ bath strips from control and diabetic rabbit corpus cavernosum were precontracted and increasing doses of several PDE inhibitors were added. In the precontracted rabbit cavernous tissue, sulmazole and zaprinast specific PDE V inhibitors were equally potent and efficacious in vitro but amrinone, a specific PDE III inhibitor, exhibits low relaxant effects. All PDE inhibitors tested showed a similar relaxation effect on corpus cavernosum smooth muscle from control and 8-week diabetic rabbits. The present study provides the possibility of using selective PDE III and V inhibitors in the treatment of diabetic impotence.
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PMID:Effects of the specific phosphodiesterase inhibitors on alloxan-induced diabetic rabbit cavernous tissue in vitro. 1131 37

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes are key proteins regulating intracellular cyclic nucleotide turnover and thus smooth muscle tension. Several in vitro studies have indicated that the cyclic GMP and cyclic AMP-mediated signaling may play a role in the control of human ureteral muscle. The aim of the present study was to evaluate the functional effects of PDE5 inhibitors sildenafil (Sil), vardenafil (Var) and tadalafil (Tad), as well as nitric oxide (NO)-donating agent sodium nitroprusside (SNP) and non-selective muscarinic antagonist butylscopolamine (BSC) on the tension induced by KCl and the turnover of cyclic nucleotides in isolated human ureteral smooth muscle. In vitro relaxant responses of human ureteral smooth muscle to the PDE5 inhibitors mentioned above were investigated using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by means of specific radioimmunoassay following incubation of the tissue with Sil, Var, Tad and SNP. The tension induced by KCl of the ureteral tissue was dose dependently reversed by the drugs with the following rank order of efficacy: SNP > Var >or= Sil > Tad > BSC. R(max) values ranged from 25 +/- 9% (SNP) to 5 +/- 3% (BSC). Relaxant responses were paralleled by threefold to fourfold increase in tissue levels of cGMP. Our results indicate that PDE5 inhibitors can reverse the tension of isolated human ureteral smooth muscle via cGMP-mediated pathways. Nevertheless, further studies are indicated in order to evaluate as to whether there might be a use for PDE5 inhibitors in the treatment of ureteral stone disease.
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PMID:In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. 1710 58