Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The effect of arginine vasopressin (AVP) on the low-conductance K+ channel in the apical membrane of rat cortical collecting duct (CCD) principal cells from animals on a control and high-K+ diet was studied using patch-clamp techniques. AVP stimulated apical low-conductance K+ channel activity in both control and high-K+ animals: application of 110-220 pM AVP induced a significant increase in the density of low-conductance K+ channels. In the presence of phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine), administration of 22 pM AVP also increased channel activity. The action of AVP on low-conductance K+ channel activity was mimicked by simultaneous application of forskolin and 3-isobutyl-1-methylxanthine. Exogenously applied N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dibutyryl-cAMP, 0.4-0.8 mM) also increased apical low-conductance K+ channel activity. Since channel open probability (Po) was almost saturated in the absence of AVP, the increase of channel activity induced by AVP, forskolin, and dibutyryl-cAMP resulted predominantly from stimulating previously silent K+ channels. We conclude that AVP induces an increase of low-conductance K+ channel activity of principal cells in rat CCD by the stimulation of cAMP-dependent protein kinase. The AVP-induced increase of low-conductance K+ channel activity can thus significantly contribute to the hormone-induced K+ secretion in the rat CCD.
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PMID:Vasopressin increases density of apical low-conductance K+ channels in rat CCD. 768 Dec 63

In rabbit renal cortical collecting tubule (CCT), perfused in vitro at 38 degrees C, ATP in concentrations of 10(-7) M and greater inhibits arginine vasopressin (AVP)-stimulated osmotic water permeability (Pf). The P1-purinergic receptor antagonist 8-phenyltheophylline did not attenuate the inhibitory action of ATP, and the poorly hydrolyzable ATP analogue, 5'-adenylylimidodiphosphate (AMP-PNP), mimicked the effect of ATP, arguing against an effect of ATP on a P1 receptor or the "P site." Purinergic receptor agonists inhibited AVP-stimulated Pf with the following rank order efficacy: ATP = ADP = UTP = AMP-PNP = alpha, beta-methylene-ATP > 2-methylthio-ATP >> AMP > adenosine, consistent with the pharmacology of a "nucleotide" receptor subtype. Pertussis toxin pretreatment attenuated the action of 10(-5) and 10(-6) MATP; however, 10(-4) MATP failed to inhibit the hydrosmotic action of forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate. Pretreatment with the phosphodiesterase inhibitor RO20-1724 or indomethacin did not inhibit the action of ATP. Staurosporin and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester significantly attenuated the inhibition of Pf by lower concentrations of ATP. These data suggest that ATP activates nucleotide receptors on the CCT, mobilizing intracellular Ca2+, which inhibits the hydrosmotic action of AVP.
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PMID:ATP inhibits the hydrosmotic effect of AVP in rabbit CCT: evidence for a nucleotide P2u receptor. 806 90

Insulin (Ins) decreases Na+ delivery in the final urine. To determine whether the loop of Henle participates in this reduction, the effects of Ins were tested on cortical (CTAL) and medullary thick ascending limbs (MTAL) of the mouse nephron, microperfused in vitro. In the MTAL, Ins increased the transepithelial potential difference (Vt) and the Na+ and Cl- net reabsorption fluxes (JNa and JCl, respectively) in a dose-dependent manner, the threshold being below 10(-9) M. At 10(-7) M, Ins reversibly increased JNa and JCl, leaving Mg2+ and Ca2+ fluxes (JMg and JCa, respectively) close to zero. In the CTAL, 10(-7) M Ins reversibly increased Vt, JNa, JCl, JMg, and JCa. In CTAL segments perfused under asymmetrical conditions, with a bath-to-lumen-directed NaCl gradient (lumen 50 mM NaCl, bath 150 mM NaCl), addition of 10(-7) M Ins to the bath resulted in a large increase in JMg and JCa. Thus the responses of CTAL and MTAL to Ins are in all ways similar to those already reported for the adenosine 3',5'-cyclic monophosphate (cAMP)-generating hormones acting on these nephron segments. When 10(-10) M arginine vasopressin (AVP) and 10(-7) M Ins were used in combination, previous addition of one hormone to the bath potentiated the response to the second hormone. In cAMP accumulation experiments, performed in the presence of a phosphodiesterase inhibitor, the amounts of cAMP formed with 10(-7) M Ins and 10(-10) M AVP (which elicit maximal physiological responses in these segments) were in the same range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin stimulates Na+, Cl-, Ca2+, and Mg2+ transports in TAL of mouse nephron: cross-potentiation with AVP. 821 94

To determine the molecular steps involved in the vasopressin-induced renal Na+ reabsorption, the patch-clamp technique was utilized to study the role of this hormone in the regulation of apical Na+ channels in renal epithelial A6 cells. Addition of arginine vasopressin (AVP) induced and/or enhanced Na+ channel activity within 5 min of addition under cell-attached conditions. The AVP-induced channel activity was a reflection of both an increase in the average apparent channel number (0.2-1.7) and the percent open time (2-56%). Addition of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, the adenosine 3',5'-cyclic monophosphate (cAMP) analogues, 8-(4-chlorophenylthio)-cAMP and 8-bromo-cAMP, or forskolin elicited a comparable effect to that of AVP. The induced channels had similar properties to Na+ channels previously reported, including a channel conductance of 9 pS, Na(+)-to-K+ selectivity of 3-5:1, and high amiloride sensitivity. The cAMP-dependent protein kinase A (PKA) in the presence of ATP induced and/or enhanced Na+ channel activity in excised inside-out patches with a change in average apparent channel number and percent open probability similar to those observed with either AVP or cAMP analogues in intact cells. Addition of activated pertussis toxin (100 ng/ml) completely blocked the AVP- or PKA-induced Na+ channel activity in excised inside-out patches, whereas incubation of intact cells with the toxin completely prevented the effect of both activators. The data indicate that AVP mediates its effect through a cAMP-dependent pathway involving PKA activation whose target is the G protein pathway that regulates apical epithelial Na+ channel activity.
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PMID:Vasopressin and protein kinase A activate G protein-sensitive epithelial Na+ channels. 839 79

These studies were conducted to determine whether the alpha 2-agonists epinephrine and dexmedetomidine inhibit osmotic water permeability (Pf) and urea permeability (Pu) in the rat inner medullary collecting duct (IMCD). Wistar rat IMCD segments were perfused via standard methods, and Pf and Pu were determined in separate studies. The control period was followed by adding 220 pM arginine vasopressin (AVP) or 10(-4) M dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP) to the bath. Epinephrine or dexmedetomidine, both at 1 microM, was then added to the bath, and this period was followed by adding 1 microM atipamezole, a selective alpha 2-antagonist. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was present in all experiments with DBcAMP. Epinephrine inhibited AVP- and DBcAMP-stimulated Pf by 90% and 80%, respectively. Dexmedetomidine inhibited AVP- and DBcAMP-stimulated Pf by 98% and 97%, respectively. Epinephrine inhibited AVP- and DBcAMP-stimulated Pu by 70% and 60%, respectively. Dexmedetomidine failed to affect Pu. Atipamezole reversed all inhibitory effects. These data confirm an alpha 2-mediated mechanism in the IMCD that modulates Pf and Pu, and they indicate that inhibition occurs via post-cAMP cellular events.
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PMID:Alpha 2-adrenergic-mediated inhibition of water and urea permeability in the rat IMCD. 876 Feb 56

Ionic reabsorption along the ascending limb of Henle's loop (TAL) is controlled by hormonal stimulation. Most of the hormones that affect this reabsorption regulate ionic transporter activity via cAMP, and some of these hormonal actions have been shown to be modulated by interstitial osmolarity. We studied the early effects of increasing extracellular urea concentration on the production of cAMP induced by arginine vasopressin (AVP) and forskolin in a suspension of medullary portions of TAL (MTAL) prepared from mouse kidney. The addition of urea, performed fifteen minutes before adenylyl cyclase stimulation, decreased both AVP- and forskolin-induced cAMP production. This effect, observed both in the presence and the absence of phosphodiesterase inhibition, was optimal with 300 mmol/liter urea. Addition of urea to the extracellular medium disturbed several cellular parameters, but the decrease in cAMP production appeared to be mediated by the activation of both the protein kinase A and a phosphatase rather than by the modifications in phospholipid metabolism. Since cAMP is the major cytosolic transductional factor in MTAL cells, urea present in the medullary interstitium may thus be considered as an important modulator of hormonal actions in this segment of the nephron.
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PMID:Extracellular urea concentration modulates cAMP production in the mouse MTAL. 880 68

1. Previous studies in our laboratory have shown that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro methods were used to compare the effects of denbufylline on HPA function with those of two other selective PDE-4 inhibitors, rolipram and BRL 61063 (1,3-dicyclopropylmethyl-8-amino-xanthine). For comparison, parallel measurements of the immunoreactive- (ir-) luteinising hormone (LH) were made where appropriate. 2. When injected intraperitoneally, rolipram (40 and 200 micrograms kg-1, P < 0.005), denbufylline (0.07-0.6 microgram kg-1, P < 0.05) and BRL 61063 (30 micrograms kg-1, P < 0.005) each produced marked rises in the serum ir-corticosterone concentrations. However, lower doses of rolipram (1.6 and 8 micrograms kg-1) and BRL 61063 (0.25-6 micrograms kg-1) were without effect (P > 0.05). By contrast, intracerebroventricular (i.c.v.) injection of rolipram (8 ng-1 micrograms kg-1) or denbufylline (50 ng-1 microgram kg-1) failed to influence the serum ir-corticosterone concentration. BRL 61063 (8-120 ng kg-1, i.c.v.) was also ineffective in this regard although at a higher dose (1 microgram kg-1, i.c.v.) it produced a small but significant (P < 0.05) increase in ir-corticosterone release. Denbufylline also increased the serum ir-LH concentration when given peripherally (0.2-0.6 microgram kg-1, i.p., P < 0.05) or centrally (100 ng kg-1, i.c.v., P < 0.05) but rolipram (1.6-200 micrograms kg-1, i.p. or 8 ng-1 microgram kg-1, i.c.v.) and BRL 61063 (0.25-30 micrograms kg-1, i.p. or 1 ng-1 microgram kg-1, i.c.v.) did not (P > 0.05). 3. In vitro rolipram (10 microM, P < 0.01), denbufylline (1 mM, P < 0.001) and BRL 61063 (1 and 10 microM, P < 0.05) stimulated the release of corticotrophin releasing hormone (ir-CRH-41) but lower concentrations of the drugs were without effect as also was BRL 61063 at 100 microM (P > 0.05); the rank order of potency was thus BRL 61063 > rolipram > denbufylline. The adenylyl cyclase activator forskolin (100 microM, P < 0.01) also stimulated the release of ir-CRH-41, producing effects which were additive with those of rolipram and denbufylline but not with those of BRL 61063. The secretory responses to forskolin (100 microM) were accompanied by a highly significant increase in the cyclic AMP content of the hypothalamic tissue (P < 0.005). Rolipram (10 microM) also significantly (P < 0.05) elevated the hypothalamic cyclic AMP but denbufylline (10 mM) and BRL 61063 (10 microM) did not. However, all three PDE-inhibitors potentiated the rise in cyclic AMP induced by forskolin (P < 0.05). None of the drugs tested, alone or in combination, modified the release of arginine vasopressin (ir-AVP) from the hypothalamus. 4. Rolipram (100 microM), denbufylline (100 microM) and BRL 61063 (100 microM) stimulated the release of corticotrophin (ir-ACTH) from pituitary tissue in vitro (P < 0.05) but in lower concentrations they were without significant effect. In addition, rolipram (10 microM, P < 0.05), denbufylline (0.1 microM, P < 0.05) and BRL 61063 (10 microM, P < 0.05) potentiated the significant (P < 0.05) rises in ir-ACTH secretion induced by forskolin (100 microM). Forskolin (100 microM) also produced a highly significant increase (P < 0.01) in the tissue cyclic AMP content which was further potentiated by rolipram (10 microM), denbufylline (10 microM) and BRL 61063 (10 microM) which, alone did not affect the cyclic AMP content of the tissue. 5. Since both denbufylline and BRL 61063 possess significant adenosine A1 receptor blocking activity, further studies examined the potential influence of these receptors on the secretion in vitro of CRH-41, AVP and ACTH. The release of ir-CRH-41 was increased significantly by adenosine deaminase (ADA, 5microml-1, P<0.05) and the A1-receptor antagonist, 1,3-dicyclopropyl-8-cyclopentylxanthine (DPCPX, 0.1-10nM, P<0.05). The responses to ADA were abolished by the A1 receptor agonist N6-cyclo-hexyladenosine (CHA, 100nM, P<0.05) which alone had no significant effect on ir-CRH-41 release. ADA (0.1-10microml-1) and DPCPX (1nM) had weak stimulant and inhibitory effects, respectively, on the release of ir-ACTH from the pituitary gland while CHA (0.1-10nM) was without effect. Ligand binding studies with [3H]-DPCPX as a probe demonstrated the presence of specific high affinity A1 binding sites in the hypothalamus (Kd=0.7nM; Bmax=367+/-32fmolmg-1 protein) and in the hippocampus (Kd=1nM; Bmax=1165 +/-145fmolmg-1 protein). In both tissues binding of the ligand was displaced by CHA (IC50=1nM (hypothalamus) and 2nM (hippocampus)), BRL 61063 (IC50=80nM (hypothalamus) and 100nM (hippocampus)) and denbufylline (IC50=5microM (hypothalamus) and 9microM(hippocampus)) but not by rolipram. 6.The results suggest that rolipram, denblufylline and BRL 61063 stimulate the HPA axis in the rat, acting at the levels of both the hypothalamus and the pituitary gland. Their actions may be explained, at least in part, by inhibition of PDE-4 but additional actions including blockade of hypothalamic adenosine A1 receptors by denbufylline and BRL 61063 cannot be excluded.
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PMID:Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by three selective type-4 phosphodiesterase inhibitors: in vitro and in vivo studies. 917 87

Adrenomedullin (AM) is a novel and potent vasodilator peptide originally isolated from human pheochromocytoma. The present study was designed to study whether AM is produced by and secreted from renal tubular cell lines and whether arginine vasopressin (AVP) affects AM secretion from these cell lines. Three renal tubular cell lines derived from different species (LLCPK1, MDCK, and MDBK) secrete AM-like immunoreactivity (AM-LI) into culture medium, the immunological and physicochemical properties of which are similar to that of synthetic human AM as evaluated by reverse-phase high-performance liquid chromatography. Among the three cell lines, AVP in combination with a phosphodiesterase inhibitor (isobutylmethylxanthine) stimulated AM-LI secretion most potently from MDCK cells in a time- and dose-dependent manner. In MDCK cells, a V2 receptor agonist (deamino-D-Arg8-vasopressin) dose-dependently stimulated AM-LI secretion in the same manner as AVP. Furthermore, the AVP-induced AM-LI secretion was blocked by a V2 receptor antagonist (OPC31260), but not by a V1 receptor antagonist (OPC21268). These data indicate that AM is secreted from renal tubular cell lines and that AVP stimulates AM secretion via V2 receptors, suggesting its autocrine/paracrine role in renal function.
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PMID:Secretion of adrenomedullin by renal tubular cell lines. 945 97

Activation of protein kinase C (PKC) stimulates adrenocorticotropin (ACTH) release synergistically in the presence of corticotropin releasing factor (CRF). We examined the effect of a cyclic nucleotide-specific phosphodiesterase inhibitor, 1-isoamyl-3-isobutylxanthine (IIX), on arginine vasopressin (AVP)-induced ACTH release and intracellular cAMP accumulation in normal rat anterior pituitary cells. IIX alone elevated intracellular cAMP accumulation. IIX potentiated AVP-induced ACTH release synergistically without further increase in cAMP accumulation, suggesting that synergistic ACTH release has an alternative mechanism other than the synergistic elevation of intracellular cAMP accumulation which has been reported. Phorbol 12-myristate-13-acetate (PMA) also induced synergistic ACTH release when incubated with IIX. IIX had no additional effect on ACTH response when incubated with maximal dose of CRF, forskolin or 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP). Moreover, the combination of PMA and 8-Br-cAMP produced synergistic ACTH response. In conclusion, the synergistic ACTH release from rat pituitary corticotrophs occurs at least in the presence of directly activating events of PKC and PKA as well as PKC-induced inhibition of phosphodiesterase activity.
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PMID:Mechanism involved in synergistic adrenocorticotropin response to activating protein kinase-A and -C in rat anterior pituitary cells. 1021 Feb 88

Characterisation of cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) in recombinant systems has highlighted regulatory properties indicative of distinct physiological roles for these enzymes. The present study investigated the role of PDEs in the adenosine 3'5'-monophosphate (cAMP) response to the hypothalamic neuropeptides corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) in acutely dispersed rat adenohypophysial cells. Ca(2+)-activated PDE (PDE1) and Ca(2+)-independent, rolipram-sensitive PDE (PDE4) accounted for close to 90% of cAMP-hydrolysing activity in the adenohypophysis. Messenger RNA transcripts of PDE1 (isotypes 1A and 1C) and PDE4 (isotypes B and D3) were detected by RT-PCR. The PDE blockers rolipram and IBMX enhanced cAMP accumulation induced by CRF or CRF and AVP. Vinpocetine, an inhibitor of low K(m) PDE1 isotypes, did not alter the response to CRF but enhanced the effect of the combined CRF/AVP stimulus. Thus, PDE4s terminate the cAMP response to moderate stimulation, while low-affinity PDE1 becomes important when the concentrations of CRF and AVP are characteristic of exposure to intensive stress.
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PMID:Functional plasticity of cyclic AMP hydrolysis in rat adenohypophysial corticotroph cells. 1188 89


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