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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured renal tubular cells (MDCK) have many of the biological properties of renal medullary tubular epithelial cells, including the ability to synthesize prostaglandin E2 (PGE2) as the major arachidonate metabolite. The hypothesis that adenosine 3',5'-cyclic monophosphate (cAMP) regulates prostaglandin synthesis in these cells was investigated by using cAMP, two degradation-resistant cAMP analogues [8-bromo-cAMP (8-BrcAMP) and N6,O2'-dibutyryl cAMP (DBcAMP)], and a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). These agents inhibited basal-, calcium ionophore (A23187)-, or bradykinin-stimulated PGE2 biosynthesis by MDCK cells. The observed inhibition was dose- and time-dependent and could be reversed after 30 min of incubation in the absence of inhibitor. IBMX dose-dependently increased intracellular and extracellular cAMP levels by severalfold, suggesting that it was inhibiting prostaglandin biosynthesis by increasing cellular cAMP levels. Vasopressin, which stimulated cAMP levels by less than two-fold, did not inhibit prostaglandin synthesis. 8-BrcAMP and N6,O2'-DBcAMP inhibited A23187- or bradykinin-stimulated release of [3H]arachidonate from prelabeled cells, suggesting that cAMP inhibited acylhydrolase activity. Moreover, 8-BrcAMP also inhibited the conversion of exogenous arachidonate to PGE2 in intact cells and in a subcellular fraction containing prostaglandin synthetase activity, suggesting that cAMP inhibited cyclooxygenase and/or PGE2 isomerase activity. cAMP thus appears to regulate prostaglandin biosynthesis in MDCK cells by modulating the activity of two or more of the enzymes involved in the biosynthetic process.
...
PMID:Inhibition of prostaglandin biosynthesis in renal (MDCK) cells by cAMP. 618 5

Methylisobutylxanthine (MIX) raised cAMP levels and inhibited prostacyclin synthesis and arachidonic acid release in endothelial cells from both pig aorta and human umbilical vein. These effects were reversible and dose dependent on MIX concentrations. Dibutyryl cAMP (3 mM) alone did not inhibit prostacyclin synthesis or arachidonic acid release. When added with MIX, dibutyryl cAMP did not enhance the inhibition elicited by MIX. MIX inhibited the formation of lysophospholipids, 1,2-diacylglycerol and phosphatidic acid in bradykinin-stimulated pig endothelial cells, suggesting that the inhibition of prostacyclin synthesis resulted from an apparent inhibition of both phospholipase A2 and phospholipase C. Other phosphodiesterase inhibitors, theophylline and mopidamole, also raised cAMP levels and inhibited arachidonic acid release. However, there was no correlation between cAMP levels and these inhibitions. Forskolin, an adenylate cyclase activator, elevated intracellular cAMP levels with no apparent inhibition on prostacyclin synthesis. We conclude that the inhibitory effect of MIX on phospholipase A2 and phospholipase C is probably through mechanisms other than the elevation of the cAMP level.
...
PMID:Inhibition of prostacyclin synthesis in endothelial cells by methylisobutylxanthine is not mediated through elevated cAMP level. 619 92

The papillary collecting duct (PCD) is considered to be of major importance in the final elaboration of the urine, but the metabolism of cyclic adenosine 3',5'-monophosphate (cAMP) has not yet been directly studied in the PCD. Therefore, in the present study we examined the basic properties of the cAMP system in isolated PCD microdissected from rat kidney. Vasopressin (VP) caused a marked (5- to 10-fold) stimulation of adenylate cyclase (AdC) but parathyroid hormone, calcitonin, isoproterenol, and bradykinin were without effect. A gradual increase in osmolality from 200 mosM had a biphasic effect on AdC, first enhancing (at 800 mosM) then inhibiting AdC activity at 2,000 mosM. cAMP-phosphodiesterase activity was inhibited as osmolality was increased from 200 to 800 mosM and the inhibition remained constant to 2,000 mosM. Incubation of intact PCD with VP resulted in a threefold increase in cAMP levels. As the osmolality of the incubation medium ws increased from 300 to 2,000 mosM, both basal and VP-stimulated cAMP levels continued to increase. Prostaglandin E2 (PGE2) (10(-5) M) alone (in the absence of vP) caused an increase in AdC activity, but the same dose of PGE2 had no effect on AdC activity stimulated by submaximal or maximal doses of VP. PGE2 (10(-5) M) caused a small increase in cAMP levels in intact PCD. On the other hand, PGE2 inhibited VP-stimulated cAMP levels by 50%. Incubation of PCD with PGE2 had no effect on cAMP-phosphodiesterase activity. The results demonstrate that osmolality in the physiologic range has a major influence on cAMP metabolism in the PCD and document an antagonism between PGE2 and VP at the level of cAMP accumulation in the PCD.
...
PMID:ADH-sensitive cAMP system in papillary collecting duct: effect of osmolality and PGE2. 626 88

The effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin were investigated using [125I]bovine serum albumin (125I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. On the other hand, 14,15-dihydroforskolin and 1,9-dideoxyforskolin, which are weak or inactive as activators of adenylate cyclase, did not have any significant effect on bradykinin and prostaglandin E1-induced plasma exudations. The phosphodiesterase inhibitors, ZK 62711, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. Papaverine had biphasic effects on the bradykinin-response and slight inhibitory effects on the prostaglandin E1-response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 microgram potentiated the bradykinin-induced plasma exudation, but had no effect at doses of 10 and 100 micrograms. 8-Bromo cyclic AMP at all doses significantly inhibited the prostaglandin E1-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin derive from activation of cyclic AMP-generating systems.
...
PMID:Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin. 631 36

Tiaramide hydrochloride (THC) is a benzothiazoline derivative with a remarkable antianaphylactic activity: in anaesthetized guinea-pig it shows protecting effects against histamine (H)- and bradykinin (Bk)-induced bronchoconstriction, preventing increase of lung resistance and decrease of dynamic compliance. At the same time THC inhibits formation of circulating thromboxane A2 brought about by H and Bk. THC is also able to antagonize the contractions induced by CaCl2 on isolated guinea-pig tracheal spirals and its mode of action seems to be of the competitive type. Furthermore THC abolishes the "tonic" phase of K+-induced contractions of guinea-pig taenia coli which are dependent on inward movement of calcium, whereas the "phasic" component of the contractions is left unaltered. THC is a very weak inhibitor of 3'-5' cyclic adenosine monophosphate phosphodiesterase which is affected only at very high dosage (10(-2) M). The calcium antagonistic activity of THC may explain both its bronchodilating and antianaphylactic properties.
...
PMID:New pharmacological aspects on the antiasthmatic activity of tiaramide-HCl. 689 Aug 32

The influence of interferon (IFN)-gamma on vasodilation was examined in bovine isolated mesenteric arteries. Arterial rings were incubated with IFN-gamma (100 U ml-1) for 20 hr and subsequently the response to vasodilators was determined isometrically in an organ bath. Treatment with IFN-gamma markedly inhibited endothelium-dependent relaxation to bradykinin and impaired vasodilation to nitroprusside, which was endothelium-independent. The decrease in relaxation was correlated with a decrease in bradykinin- and nitroprusside-induced cGMP production. Relaxation to the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine or zaprinast was not altered after IFN-gamma, which suggests that the IFN-gamma effect is specific for guanylate cyclase-activating agonists. Nitrite concentration in the incubation medium was increased after IFN-gamma, which indicates the induction of nitric oxide release during the incubation period. Inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine during the 20-hr incubation with IFN-gamma completely prevented the decrease in relaxation and cGMP elevation to nitroprusside. We conclude that IFN-gamma induces a marked increase in release of arterial-derived nitric oxide resulting in a desensitization of guanylate cyclase, which contributes to a decrease in relaxation to bradykinin and nitroprusside. These results may implicate the existence of an important adaptive process in the regulation of vascular tone during pathological situations associated with the induction of nitric oxide synthesis.
...
PMID:Induction of nitric oxide release by interferon-gamma inhibits vasodilation and cyclic GMP increase in bovine isolated mesenteric arteries. 750 93

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Analysis of responses to bradykinin in the pulmonary vascular bed of the cat. 751 46

Acute hypoxia causes pulmonary hypertension in the fetus and newborn that is contrasted by systemic hypotension or normotension. To better understand the role of nitric oxide (NO) in this specific pulmonary vascular response, we determined the acute effects of decreased oxygenation on NO production in ovine fetal pulmonary and systemic (mesenteric) endothelial cells. NO was assessed by measuring cGMP accumulation in fetal vascular smooth muscle (VSM) cells during co-culture incubations of endothelium and VSM (40 s) in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. Changes in cGMP were dependent on the endothelium and on NO synthase and guanylate cyclase activity. At high O2 (680 mm Hg), basal NO was detectable and NO increased 6- to 10-fold with bradykinin or A23187. In pulmonary endothelium, basal NO fell 58% at pO2 = 150 mm Hg and 51% at 40 mm Hg versus 680 mm Hg, while NO with bradykinin fell 56% and 63%, respectively. NO with A23187, however, was unchanged at 150 mm Hg, but it fell 56% at 40 mm Hg. In contrast, in systemic endothelium basal and stimulated NO production were not altered at lower O2. Findings were similar using pulmonary or systemic detector VSM cells, and exogenous L-arginine had no effect. Thus, decreased O2 acutely attenuates NO production specifically in fetal pulmonary endothelial cells. This process is not related to changes in O2 or L-arginine availability as substrates for NO synthase; alternatively, it may be partially mediated by specific effects of O2 on pulmonary endothelial cell calcium homeostasis.
...
PMID:Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. 752 86

Effects of bradykinin (BK) on the membrane conductance and level of cytoplasmic free Ca2+ in undifferentiated and differentiated neuroblastoma-glioma hybrid (NG108-15) cells were studied using the nystatin-perforated patch-clamp technique and fura-2 fluorometry. Under voltage clamp at -20 mV, undifferentiated cells responded to BK at > 10(-9) M, producing a biphasic current composed of an apamin-sensitive Ca(2+)-activated K+ outward current and non-specific cationic inward current. Both current components corresponding to a biphasic elevation of [Ca2+]i were completely prevented by an intracellular perfusion with EGTA (1 mM) under conventional whole cell recording condition. Undifferentiated cells revealed almost no voltage sensitive Ca2+ current. In NG108-15 cells differentiated with 8-Br-cyclic AMP (1 mM) or rolipram (1 mM), an inhibitor of type IV phosphodiesterase, BK concentration required for the non-specific cationic current with amplitude of > 100 pA was much greater than that of undifferentiated cells. This suggests that the differentiated cells decreased BK-sensitivity in induction of the non-specific cationic current. The non-specific cationic channel is suggested to play roles as a source of Ca2+ entry in undifferentiated NG108-15 cells.
...
PMID:Bradykinin-evoked non-specific cationic current in neuroblastoma-glioma hybrid (NG108-15) cells and its down-regulation through differentiation. 752 42

1. Bradykinin caused a transient reduction of about 25% in the cyclic AMP level in forskolin prestimulated DDT1 MF-2 smooth muscle cells (IC50: 36.4 +/- 4.9 nM) and a pronounced, sustained inhibition (40%) of the isoprenaline-stimulated cyclic AMP level (IC50: 37.5 +/- 1.1 nM). 2. The Ca2+ ionophore, ionomycin, mimicked both the bradykinin-induced transient reduction in the forskolin-stimulated cyclic AMP level and the sustained reduction in the isoprenaline-stimulated cyclic AMP level. 3. The Ca(2+)-dependent effect on cyclic AMP induced by bradykinin was mediated solely by Ca2+ release from internal stores, since inhibition of Ca2+ entry with LaCl3 did not reduce the response to bradykinin. 4. The involvement of calmodulin-dependent enzyme activities, protein kinase C or an inhibitory GTP binding protein in the bradykinin-induced responses was excluded since a calmodulin inhibitor, calmidazolium, a PKC inhibitor, staurosporine and pertussis toxin, respectively did not affect the decline in the cyclic AMP level. 5. Bradykinin enhanced the rate of cyclic AMP breakdown in intact cells, which effect was not mimicked by ionomycin. This suggested a Ca(2+)-independent activation of phosphodiesterase activity by bradykinin in DDT1 MF-2 cells. 6. The bradykinin B1 receptor agonist, desArg9-bradykinin, did not affect cyclic AMP formation in isoprenaline prestimulated cells, while the bradykinin B2 receptor antagonists, Hoe 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]-BK) and D-Arg[Hyp3, Thi5,8, D-Phe7]-BK completely abolished the bradykinin response in both forskolin and isoprenaline prestimulated cells. 7. Bradykinin caused an increase in intracellular Ca2+, which was antagonized by the bradykinin B2 receptor antagonists, Hoe 140 and D-Arg[Hyp3, Thi5,8, D-Phe7]-BK. The bradykinin B2 receptor agonist,desArg9-bradykinin, did not evoke a rise in cytoplasmic Ca2 .8. It is concluded, that stimulation of bradykinin B2 receptors causes a reduction in cellular cyclic AMP in DDT1, MF-2 cells. This decline in cyclic AMP is partly mediated by a Ca2+/calmodulin independent activation of phosphodiesterase activity. The increase in [Ca2+], mediated by bradykinin B2 receptors inhibited forskolin- and isoprenaline-activated adenylyl cyclase differently, most likely by interfering with different components of the adenylyl cyclase signalling pathway.
...
PMID:Ca(2+)-dependent and -independent mechanism of cyclic-AMP reduction: mediation by bradykinin B2 receptors. 758 24


<< Previous 1 2 3 4 5 6 7 Next >>

---