Phosphodiesterase Inhibitors: A Chemogenomic View

SummaryHuman monocytes in vitro respond to various agents (immune complexes, lectins, endotoxin, the divalent ionophore A 23187, 12-0-tetradecanoyl-phorbol 13-acetate [TPA], purified protein derivative [PPD] of Bacille Calmette-Guerin) with an increased synthesis of the protein component of thromboplastin. The effect of cyclic AMP and cyclic GMP on this response has been studied. Dibutyryl-cyclic AMP, prostaglandin E1 and the phosphodiesterase inhibitors 3-butyl-1-methyl-xanthine (MIX) and rac -4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 201724), separately and in combination have a pronounced inhibitory effect on the response to immune complexes and PPD, and a moderate effect on the response to endotoxin and lectins. The effect on TPA response and on the response to A 23187 was slight. Dibutyryl-cyclic GMP (1 mM) gave a slight inhibition of the TPA arid IC response, but had essentially no effect on the response to other inducers. The intracellular cAMP level increased when monocytes were incubated with IC, TPA or A 23187 followed by a decrease to basal levels within 1-2 hr, whereas lectin (PHA) and PPD did not induce such changes. The cAMP response to endotoxin varied. Stimulation with IC induced an increase in monocyte cGMP levels, whereas the other stimulants did not cause such changes.

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Stimulation of Ca(2+)-dependent exocytosis of the sperm acrosome by cAMP acting downstream of phospholipase A2

Reproduction ◽

10.1530/reprod/118.1.57 ◽

2000 ◽

pp. 57-68 ◽

Cited By ~ 11

Author(s):

J Garde ◽

ER Roldan

Keyword(s):

Arachidonic Acid ◽

Phospholipase A2 ◽

Phospholipase C ◽

Phosphodiesterase Inhibitors ◽

Dibutyryl Camp ◽

Camp Phosphodiesterase ◽

Ram Sperm ◽

Camp Formation ◽

Stimulation Of

Spermatozoa undergo exocytosis in response to agonists that induce Ca2+ influx and, in turn, activation of phosphoinositidase C, phospholipase C, phospholipase A2, and cAMP formation. Since the role of cAMP downstream of Ca2+ influx is unknown, this study investigated whether cAMP modulates phospholipase C or phospholipase A2 using a ram sperm model stimulated with A23187 and Ca2+. Exposure to dibutyryl-cAMP, phosphodiesterase inhibitors or forskolin resulted in enhancement of exocytosis. However, the effect was not due to stimulation of phospholipase C or phospholipase A2: in spermatozoa prelabelled with [3H]palmitic acid or [14C]arachidonic acid, these reagents did not enhance [3H]diacylglycerol formation or [14C]arachidonic acid release. Spermatozoa were treated with the phospholipase A2 inhibitor aristolochic acid, and dibutyryl-cAMP to test whether cAMP acts downstream of phospholipase A2. Under these conditions, exocytosis did not occur in response to A23187 and Ca2+. However, inclusion of dibutyryl-cAMP and the phospholipase A2 metabolite lysophosphatidylcholine did result in exocytosis (at an extent similar to that seen when cells were treated with A23187/Ca2+ and without the inhibitor). Inclusion of lysophosphatidylcholine alone, without dibutyryl-cAMP, enhanced exocytosis to a lesser extent, demonstrating that cAMP requires a phospholipase A2 metabolite to stimulate the final stages of exocytosis. These results indicate that cAMP may act downstream of phospholipase A2, exerting a regulatory role in the exocytosis triggered by physiological agonists.

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β-Adrenoceptor responsiveness in intact leukocytes from adults and newborn infants; effect of phosphodiesterase inhibitors

Scandinavian Journal of Clinical and Laboratory Investigation ◽

10.3109/00365519009089149 ◽

1990 ◽

Vol 50 (2) ◽

pp. 169-175 ◽

Cited By ~ 3

Author(s):

N. Foged ◽

H. Bertelsen ◽

T. Johansen

Keyword(s):

Newborn Infants ◽

Phosphodiesterase Inhibitors

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Faculty Opinions recommendation of Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13685.471180 ◽

2006 ◽

Author(s):

Alain Vuylsteke

Keyword(s):

Pulmonary Hypertension ◽

Phosphodiesterase Inhibitors ◽

Type Iii ◽

Effective Combination ◽

Acute Pulmonary Hypertension

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Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

Current Pharmaceutical Design ◽

10.2174/1381612826666200403172736 ◽

2020 ◽

Vol 26 (30) ◽

pp. 3633-3651 ◽

Cited By ~ 2

Author(s):

Javier Blanco-Rivero ◽

Fabiano E. Xavier

Keyword(s):

Nitric Oxide ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Therapeutic Potential ◽

Treatment Strategies ◽

Phosphodiesterase Inhibitors ◽

Developed Countries ◽

Major Health Problem ◽

Pde Inhibitors ◽

Pharmaceutical Industries

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

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