A dual and conflicting role for imiquimod in inflammation: A TLR7 agonist and a cAMP phosphodiesterase inhibitor

SummaryRidogrel, a combined thromboxane receptor antagonist and thromboxane synthase inhibitor (1), inhibits platelet aggregation. Following stimulation with arachidonic acid, cAMP-levels are increased in human platelets preincubated with ridogrel, this is due to the known reorientation of the metabolism of the formed endoperoxides towards adenylate cyclase stimulating prostaglandins.Pretreatment of resting platelets with UDCG-212, a cAMP-phosphodiesterase inhibitor (2), also inhibits platelet aggregation induced by arachidonic acid, concomitant with an increase in cAMP levels, due to an inhibition of its breakdown. Under basal conditions, cAMP also is increased.By combining the two drugs, a more than additive action was observed on platelet aggregation and on both resting and stimulated platelet cAMP content. The appropriate combination may result in a more effective antiplatelet strategy.

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Microwave-Assisted Synthesis of cAMP Phosphodiesterase Inhibitor 8-Hydroxy-6,7-dimethoxy-3-hydroxymethylisocoumarin.

ChemInform ◽

10.1002/chin.200741201 ◽

2007 ◽

Vol 38 (41) ◽

Author(s):

Aamer Saeed

Keyword(s):

Phosphodiesterase Inhibitor ◽

Microwave Assisted Synthesis ◽

Camp Phosphodiesterase ◽

Microwave Assisted

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Vasodilator responses to adenosine and hyperemia are mediated by A1 and A2 receptors in the cat vascular bed

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00394.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. R1696-R1709 ◽

Cited By ~ 5

Author(s):

Trinity J. Bivalacqua ◽

Hunter C. Champion ◽

David G. Lambert ◽

Philip J. Kadowitz

Keyword(s):

Nitric Oxide ◽

Reactive Hyperemia ◽

Phosphodiesterase Inhibitor ◽

Receptor Antagonists ◽

Camp Phosphodiesterase ◽

Nitric Oxide Synthase Inhibitor ◽

Vascular Bed ◽

S Period ◽

Synthase Inhibitor ◽

Oxide Synthase

Hemodynamic responses to adenosine, the A1 receptor agonists N 6-cyclopentyladenosine (CPA) and adenosine amine congener (ADAC), and the A2 receptor agonist 5′-( N-cyclopropyl)-carboxamido-adenosine (CPCA) were investigated in the hindquarter vascular bed of the cat under constant-flow conditions. Injections of adenosine, CPA, ADAC, CPCA, ATP, and adenosine 5′- O-(3-thiotriphosphate) (ATPγS) into the perfusion circuit induced dose-related decreases in perfusion pressure. Vasodilator responses to the A1 agonists were reduced by the A1 receptor antagonists KW-3902 and CGS-15943, whereas responses to CPCA were reduced by the A2 antagonist KF-17837. Vasodilator responses to adenosine were reduced by KW-3902, CGS-15943, and by KF-17837, suggesting a role for both A1 and A2 receptors. Vasodilator responses to ATP and the nonhydrolyzable ATP analog ATPγS were not attenuated by CGS-15943 or KF-17837. After treatment with the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester, the cyclooxygenase inhibitor sodium meclofenamate, or the ATP-dependent K+ (K[Formula: see text]) channel antagonists U-37883A or glibenclamide, responses to adenosine and ATP were not altered. Responses to adenosine, CPA, and CPCA were increased in duration by rolipram, a type 4 cAMP phosphodiesterase inhibitor, but were not altered by zaprinast, a type 5 cGMP phosphodiesterase inhibitor. When blood flow was interrupted for a 30-s period, the magnitude and duration of the reactive vasodilator response were reduced by A1 and A2 receptor antagonists. These data suggest that vasodilator responses to adenosine and the A1and A2 agonists studied are not dependent on the release of cyclooxygenase products, nitric oxide, or the opening of K[Formula: see text] channels in the regional vascular bed of the cat. The present data suggest a role for cAMP in mediating responses to adenosine and suggest that vasodilator responses to adenosine and to reactive hyperemia are mediated in part by A1 and A2 receptors in the hindquarter vascular bed of the cat.

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Evaluation of alprazolam-induced behavioural effects: diffefences with chlordiazepoxide after interaction with desipramine and rolipram, a camp phosphodiesterase inhibitor

Pharmacological Research ◽

10.1016/s1043-6618(89)80049-0 ◽

1989 ◽

Vol 21 ◽

pp. 53-54 ◽

Cited By ~ 2

Author(s):

G. Cannizzaro ◽

M. Gagliano ◽

S. La Rocca ◽

V. Novara ◽

A. Flugy

Keyword(s):

Phosphodiesterase Inhibitor ◽

Camp Phosphodiesterase ◽

Behavioural Effects

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Cilostazol, a selective cAMP phosphodiesterase inhibitor, dilates retinal arterioles and increases retinal and choroidal blood flow in rats

European Journal of Pharmacology ◽

10.1016/s0014-2999(98)00015-6 ◽

1998 ◽

Vol 344 (1) ◽

pp. 49-52 ◽

Cited By ~ 19

Author(s):

Harumi Hotta ◽

Hideki Ito ◽

Fusako Kagitani ◽

Akio Sato

Keyword(s):

Blood Flow ◽

Phosphodiesterase Inhibitor ◽

Choroidal Blood Flow ◽

Camp Phosphodiesterase ◽

Retinal Arterioles

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Differential Effects of cGMP Produced by Soluble and Particulate Guanylyl Cyclase on Mouse Ventricular Myocytes

Experimental Biology and Medicine ◽

10.1177/153537020523000403 ◽

2005 ◽

Vol 230 (4) ◽

pp. 242-250 ◽

Cited By ~ 53

Author(s):

Jun Su ◽

Peter M. Scholz ◽

Harvey R. Weiss

Keyword(s):

Guanylyl Cyclase ◽

Kinase Inhibitor ◽

Ventricular Myocytes ◽

Phosphodiesterase Inhibitor ◽

Soluble Guanylyl Cyclase ◽

Major Effect ◽

Nitric Oxide Donor ◽

Similar Degree ◽

Camp Phosphodiesterase ◽

Functional Changes

Particulate guanylyl cyclase (pGC) and soluble guanylyl cyclase (sGC) are cGMP-generation systems distributed in different intracellular locations. Our aim was to test the hypothesis that the functional effects of cGMP produced by pGC and sGC on contraction and Ca2+ transients would differ in ventricular myocytes. We measured myocyte shortening from adult mice using a video edge-detector and investigated the functional changes after stimulating pGC with C-type natriuretic peptide (CNP; 10–8 M and 10–7 M) or sGC with S-nitroso-N-acetyl-penicillamine (SNAP; nitric oxide donor; 10–6 M and 10–5 M). Significant concentration-dependent decreases in percentage shortening (PCS), maximal rate of shortening (RSmax), and relaxation (RRmax) were produced by CNP. To a similar degree, SNAP concentration-dependently reduced PCS, RSmax, and RRmax. The addition of Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine (cGMP-dependent protein kinase inhibitor; 5 × 10–6 M) or erythro-9-(2-hydroxy-3-nonyl) adenine (cGMP-stimulated cAMP phosphodiesterase inhibitor; 10–5 M) reduced the responses induced by CNP or SNAP, suggesting that their actions were through cGMP-mediated pathways. While SNAP significantly increased intracellular cGMP concentration by 57%, CNP had little effect on cGMP production. We also found that CNP markedly decreased the amplitude of Ca2+ transients while SNAP had little effect, suggesting the cGMP generated by sGC may decrease myofilament Ca2+ sensitivity. The small amount of cGMP generated by pGC had a major effect in reducing Ca2+ level. This study suggested the existence of compartmentalization for cGMP in ventricular myocytes.

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Initiation of meiosis and sporulation in Saccharomyces cerevisiae does not require a decrease in cyclic AMP.

Molecular and Cellular Biology ◽

10.1128/mcb.7.6.2141 ◽

1987 ◽

Vol 7 (6) ◽

pp. 2141-2147 ◽

Cited By ~ 8

Author(s):

Z Olempska-Beer ◽

E Freese

Keyword(s):

Saccharomyces Cerevisiae ◽

Carbon Source ◽

Cyclic Amp ◽

Phosphodiesterase Inhibitor ◽

Intracellular Camp ◽

Glucose Medium ◽

Camp Concentration ◽

Ishikawa Cell ◽

Camp Phosphodiesterase ◽

Low Level

Meiosis and sporulation of Saccharomyces cerevisiae are initiated in a guanine auxotroph by guanine deprivation (E. Bautz Freese, Z. Olempska-Beer, A. Hartig, and E. Freese, Dev. Biol. 102:438-451, 1984). We used this condition to examine a hypothesis (K. Matsumoto, I. Uno, and T. Ishikawa, Cell 32:417-423, 1983) that initiation of meiosis requires a low level of cAMP. We found that, after guanine deprivation, the intracellular concentration of cAMP transiently decreased not more than 20% and not at all if the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was added to the medium. Under these conditions, at least 76% of the cells sporulated in the absence of IBMX, and almost 100% sporulated in its presence. The sporulating cells continually excreted cAMP and utilized the gluconeogenic carbon source. The cells failed to sporulate efficiently and to form four-spored asci if simultaneously deprived of guanine and carbon. After guanine deprivation in glucose medium, sporulation remained suppressed and intracellular cAMP was unchanged. We conclude that, under conditions of guanine starvation, cAMP deficiency is not required for initiation of meiosis and sporulation, cAMP is produced in excess and excreted to the medium, the cells sporulate better if the cAMP concentration is increased by addition of IBMX, the cells require a gluconeogenic carbon source for complete and efficient sporulation, and suppression of sporulation by glucose is not mediated by cAMP.

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Sodium fluoride mimics effects of both agonists and antagonists on intact human platelets by simultaneous modulation of phospholipase C and adenylate cyclase activity

Blood ◽

10.1182/blood.v69.3.859.bloodjournal693859 ◽

1987 ◽

Vol 69 (3) ◽

pp. 859-866

Author(s):

J Kienast ◽

J Arnout ◽

G Pfliegler ◽

H Deckmyn ◽

B Hoet ◽

...

Keyword(s):

Adenylate Cyclase ◽

Phospholipase C ◽

Sodium Fluoride ◽

Inositol Phosphates ◽

Atp Release ◽

Phosphodiesterase Inhibitor ◽

Human Platelets ◽

Camp Phosphodiesterase ◽

Induced Aggregation ◽

Camp Levels

Using intact human platelets, we studied the effect of sodium fluoride (NaF) on platelet aggregation and release reaction and correlated the functional changes to intracellular events specific for either agonist- induced or antagonist-induced platelet responses. At lower concentrations, with a peak activity between 30 and 40 mmol/L, NaF induced aggregation and release of adenosine 5′-triphosphate (ATP) that was associated with increased formation of inositol phosphates, a rise in cytosolic free Ca2+, and phosphorylation of 20-kd and 40-kd proteins. At NaF concentrations greater than 40 mmol/L, aggregation and ATP release decreased dose-dependently in parallel with a decrease in Ca2+ mobilization, whereas neither inositol phosphate formation nor 40- kd protein phosphorylation was reduced. At these concentrations, NaF caused a dose-dependent transient rise in platelet cyclic adenosine 3′,5′-monophosphate (cAMP) levels that was sufficient to account for the observed reduction in Ca2+ mobilization, aggregation, and ATP release. Stimulated cAMP levels started declining rapidly within 30 seconds of addition of NaF, however. Similarly, prostacyclin (PGI2)- induced cAMP accumulation was temporarily enhanced but subsequently suppressed by NaF, suggesting either stimulation of a cAMP phosphodiesterase or delayed inhibition of adenylate cyclase. Evidence for the latter was provided by the finding that NaF pretreatment of platelets resulted in partial inhibition of PGI2-stimulated cAMP formation in the presence of the cAMP phosphodiesterase inhibitor 3- isobutyl-1-methyl-xanthine (MIX). We conclude that NaF exerts a dual (stimulatory and inhibitory) effect on adenylate cyclase in intact platelets that is accompanied by simultaneous activation of a phosphoinositide-specific phospholipase C; in addition, a cAMP phosphodiesterase may be activated.

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Proadrenomedullin NH2-terminal 20 peptide has direct vasodilator activity in the cat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.4.r1047 ◽

1997 ◽

Vol 272 (4) ◽

pp. R1047-R1054 ◽

Cited By ~ 2

Author(s):

H. C. Champion ◽

W. A. Murphy ◽

D. H. Coy ◽

P. J. Kadowitz

Keyword(s):

Phosphodiesterase Inhibitor ◽

Sympathetic Nerves ◽

Adrenergic Nerve ◽

Camp Phosphodiesterase ◽

Cyclic Monophosphate ◽

Vascular Bed ◽

Vasodilator Activity ◽

Calcitonin Gene ◽

Cgrp Receptor Antagonist ◽

Oxide Synthase

The mechanism by which proadrenomedullin NH2-terminal 20 peptide (PAMP) decreases vascular resistance was investigated in the hindlimb vascular bed in the cat. Injections of PAMP, a shortened form of the peptide PAMP-(12-20), and adrenomedullin (ADM) into the hindlimb perfusion circuit elicit dose-related decreases in perfusion pressure. The order of potency was ADM > PAMP > PAMP-(12-20), and the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) had no effect on vasodilator responses to PAMP or ADM. Vasodilator responses to PAMP were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor Rolipram, whereas inhibitors of nitric oxide synthase and guanosine 3',5'-cyclic monophosphate phosphodiesterase had no effect. Vasodilator responses to PAMP were not altered by treatment with alpha-receptor or adrenergic nerve terminal blocking agents and were similar in innervated and denervated hindlimb preparations. Responses to PAMP were similar when vasoconstrictor tone was increased by stimulation of the sympathetic nerves or infusion of phenylephrine and were not altered by the passage of time. These data suggest that PAMP dilates the hindlimb vascular bed by a direct cAMP-dependent mechanism and that inhibition of norepinephrine release plays little if any role in mediating responses to the peptide in the regional vascular bed of the cat.

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