Tissue specificity of cAMP‐phosphodiesterase inhibitors: Rolipram, amrinone, milrinone, enoximone, piroximone, and imazodan
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Abstract The effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.Keywords:
Rolipram
Milrinone
Enoximone
Amrinone
IBMX
Phosphodiesterase 3
PDE10A
Rolipram
Phosphodiesterase 3
PDE10A
Cyclic adenosine monophosphate
Second messenger system
Cyclic guanosine monophosphate
Cyclic nucleotide phosphodiesterase
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Elevation of cAMP downregulates certain functions of inflammatory cells, including the release of TNF alpha and IL-1 beta by macrophages. Intracellular cAMP levels can be modulated pharmacologically by adding cell-permeable cAMP analogs, by stimulating adenylate cyclase or by inhibiting degradation of cAMP by cAMP-phosphodiesterases (cAMP-PDE). Multiple forms of cAMP-PDEs have been identified in various tissues and cells using both biochemical characterization and selective inhibitors. Therefore, we wanted to determine which of these different PDE isoforms was present in human monocytes and whether this isoform could regulate cytokine release from human monocytes by a mechanism similar to that seen with dbcAMP or PGE1. Our results demonstrate that selective inhibitors of type IV cAMP-PDE, such as rolipram and Ro20-1724, are clearly the most effective compounds at enhancing cAMP levels and inhibiting the release of TNF alpha and IL-1 beta in these cells. The type III cAMP-PDE-selective inhibitors C1930 and cilostamide and the nonselective PDE inhibitors IBMX and pentoxifylline were significantly less potent. In agreement with these data, cAMP-PDE activity in cytosolic extracts from human monocytes was also much more sensitive to inhibition by rolipram than by cilostamide. Additionally, rolipram dramatically reduced TNF alpha mRNA accumulation, which supports previous findings that cAMP regulates TNF alpha at the transcriptional level. Surprisingly, rolipram, rolipram, dbcAMP or PGE1 increased IL-1 beta was reduced, which indicates that cAMP can have both positive and negative effects on the regulation of IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)
Rolipram
PDE10A
IBMX
Phosphodiesterase 3
Phosphodiesterase inhibitor
Alpha (finance)
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In most cells, the steady-state level of cAMP ultimately depends on the rate of cAMP synthesis by adenylyl cyclase and the rate of cAMP hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). PDEs exist in multiple forms that have been grouped into seven families based on their substrate specificity, mode of regulation and kinetic properties. Selective inhibitors of many PDE families are now available. Examples are milrinone and trequinsin (PDE3); rolipram and Ro 20-1724 (PDE4); and zaprinast, sildenafil and didyridamole (PDE5). These inhibitors have proven to be valuable tools to investigate the role of PDEs in cell function. Representatives of most PDE families are present in the kidneys, and recent studies in this and other laboratories have provided evidence that some of them participate in the regulation of renin secretion. In particular, administration of selective PDE inhibitors has marked effects on renin secretion. For example, the PDE3 inhibitors milrinone and trequinsin increase resting renin in conscious rabbits and enhance the renin secretory response to beta-adrenergic stimulation. Milrinone also increases renin secretion in human subjects. The PDE4 inhibitors rolipram and Ro 20-1724 both increase renin secretion in rabbits and also enhance the renin response to beta-adrenergic stimulation. Studies in other laboratories have implicated other PDE families in the control of renin secretion. The aim of this review is to present current concepts concerning the PDEs and to discuss their role in the control of renin secretion by the kidneys.
Rolipram
Milrinone
Zaprinast
Phosphodiesterase 3
PDE10A
Ramipril
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Abstract The effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.
Rolipram
Milrinone
Enoximone
Amrinone
IBMX
Phosphodiesterase 3
PDE10A
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Rolipram
Cyclic nucleotide phosphodiesterase
PDE10A
Thymocyte
Phosphodiesterase 3
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Citations (39)
We observed the intracellular localization of low-Km cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDEIII) subclasses in human heart in comparison to that in human kidney by using comparable potencies of specific inhibitors. PDEIII was observed in not only soluble fraction but particulate fraction in human heart and kidney. Both soluble and particulate PDEIII from human heart selectively hydrolyzed cAMP with similar Km values of 0.36 and 0.40 microM, respectively. They were potently inhibited by amrinone, enoximone, and cyclic guanosine monophosphate (cGMP), but were weakly inhibited by rolipram with much the same IC50 values. Although several animals having soluble and particulate PDEIII possess two pharmacologically distinct subclasses of PDEIII, human heart has only one form, cGMP-sensitive PDEIII. In contrast to cardiac PDEIII, both soluble and particulate PDEIII from human kidney were not readily inhibited by amrinone, enoximone, and cGMP, but rather strongly inhibited by rolipram. Human kidney contains only cGMP-less sensitive form of PDEIII in soluble and particulate fractions. These results suggest that the intracellular distribution of PDEIII subclasses in human hearts are significantly different from those in the hearts of other animal species, and subclasses of PDEIII in humans hearts could not be distinguished by intracellular localization but by organ specificity.
Enoximone
Rolipram
Amrinone
Cyclic guanosine monophosphate
Phosphodiesterase inhibitor
Zaprinast
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We tested the hypothesis that cGMP stimulates renin release through inhibition of the cAMP-specific phosphodiesterase 3 (PDE3) in isolated rat juxtaglomerular (JG) cells. In addition, we assessed the involvement of PDE4 in JG-cell function. JG cells expressed PDE3A and PDE3B, and the PDE3 inhibitor trequinsin increased cellular cAMP content, enhanced forskolin-induced cAMP formation, and stimulated renin release from incubated and superfused JG cells. Trequinsin-mediated stimulation of renin release was inhibited by the permeable protein kinase A antagonist Rp-8-CPT-cAMPS. PDE4C was also expressed, and the PDE4 inhibitor rolipram enhanced cellular cAMP content. Dialysis of single JG cells with cAMP in whole-cell patch-clamp experiments led to concentration-dependent, biphasic changes in cell membrane capacitance (C(m)) with a marked increase in C(m) at 1 micromol/L, no net change at 10 micromol/L, and a decrease at 100 micromol/L cAMP. cGMP also had a dual effect on C(m) at 10-fold higher concentration compared with cAMP. Trequinsin, milrinone, and rolipram mimicked the effect of cAMP on C(m). Trequinsin, cAMP, and cGMP enhanced outward current 2- to 3-fold at positive membrane potentials. The effects of cAMP, cGMP, and trequinsin on C(m) and cell currents were abolished by inhibition of protein kinase A with Rp-cAMPs. We conclude that degradation of cAMP by PDE3 and PDE4 contributes to regulation of renin release from JG cells. Our data provide evidence at the cellular level that stimulation of renin release by cGMP involves inhibition of PDE3 resulting in enhanced cAMP formation and activation of the cAMP sensitive protein kinase.
Phosphodiesterase 3
Rolipram
PDE10A
IBMX
cGMP-dependent protein kinase
Phosphodiesterase inhibitor
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We have investigated the role played by cyclic nucleotide phosphodiesterases (EC 3.1.4.17) in the control of T-lymphocyte response to mitogenic agents by their ability to influence the cellular level of cAMP. The importance of this messenger as a negative regulator in this cell type is well established. Multiple isoenzymes of phosphodiesterase were fractionated from the cytosol of rat thymic lymphocytes by high performance liquid chromatography on an anion exchange column. In addition to the type II, III, IV isoforms that we have already described [Valette et al., Biochem. Biophys. Res. Commun. 169:864-872 (1990)], a phosphodiesterase fraction sharing several of the characteristics of type V, cGMP-binding phosphodiesterase, was detected. Non-isoform-selective inhibitors of phosphodiesterase such as dipyridamole, papaverine, and methyl-isobutylxanthine were able to totally prevent the proliferative response of thymocytes to stimulation by the mitogenic lectin concanavalin A. In contrast, the selective inhibitor of type IV phosphodiesterases rolipram induced a rather moderate inhibition of proliferation, not exceeding 60%; and the selective inhibitors of type III and type V phosphodiesterases, milrinone and M&B 22,948, respectively, displayed only marginal inhibitory effects. The association of the type III and IV phosphodiesterase inhibitors produced synergistic inhibition of proliferation, which could then be almost totally suppressed. These inhibitory effects on cell multiplication were reflected at the level of the cell cAMP content; only rolipram was able to induce a significant (approximately 50%) increase in cAMP, and this increase was potentiated by the presence of milrinone, reaching almost 100%. The type V phosphodiesterase selective inhibitor M&B 22,948 displayed similar properties to those of milrinone, which suggests that it indirectly inhibited the type III, cGMP-inhibitable isoenzyme, by inducing a cGMP rise. This hypothesis was supported by evidence of a significant raising effect of M&B 22,948 on cGMP level, and by the ability of a cGMP-elevating agent, sodium nitroprusside, to mimic the synergistic effects of milrinone associated with rolipram. Furthermore, 8-bromo-cGMP, a potent activator of cGMP-dependent protein kinase, which showed only weak inhibitory effects on thymic type III phosphodiesterase, failed to alter the effects of rolipram on the cell proliferation. These results allow us to delineate a role for types III, IV, and V phosphodiesterase in the control of cAMP level during the proliferative response of thymic lymphocytes. They also suggest that endogenously formed cGMP might participate in the regulation of cAMP level in the cells by means of the inhibition of the type III phosphodiesterase.(ABSTRACT TRUNCATED AT 400 WORDS)
Rolipram
Milrinone
IBMX
PDE10A
Cyclic nucleotide phosphodiesterase
Phosphodiesterase 3
Zaprinast
Second messenger system
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Rolipram
Phosphodiesterase 3
IBMX
Second messenger system
PDE10A
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Rolipram
PDE10A
Phosphodiesterase 3
Phosphodiesterase inhibitor
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Citations (26)