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 papaverine on renal function and renin release was investigated in dogs in vivo and in vitro. Intrarenal arterial infusion of 0.1 mg/kg/min of papaverine for 10 minutes caused a significant rise in renal blood flow, a significant decrease in renal vascular resistance, clearance and extraction ratio of creatinine and PAH and in the amount of filtered sodium, without altering arterial blood pressure. There was a significant increase in sodium excretion and in the excreted percentage of filtered sodium (TRFNa). Renin activity (PRA) of arterial blood and renal venous blood, veno-arterious PRA-difference and renin secretion increased significantly after papaverine infusion. In order to eliminate the effect of hemodynamic changes on renin secretion, the effect of papaverine (10(-5), 10(-4)M) was investigated in vitro in surviving canine kidney cortex slices. Papaverine caused a significant increase in renin release and in tissue cAMP concentration. This supports the assumption that the increase in renin secretion might be due to a direct effect on the juxtaglomerular apparatus, by blocking phosphodiesterase activity and by increasing the renal cAMP level.
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PMID:Effect of papaverine on renin release in dogs in vivo and in vitro. 75 46

To evaluate organ recovery during mechanical assistance, respiratory, hepatic and renal function parameters of 40 patients who underwent bridge-to-transplant procedures were reviewed retrospectively. Mechanical circulatory support was indicated if the hemodynamic and clinical status deteriorated despite pharmacotherapy with catecholamines, vasodilators, and intravenous use of the phosphodiesterase inhibitor enoximone. Sequelae of cardiogenic shock such as renal, hepatic and respiratory insufficiency were not considered a contraindication for mechanical support. The analysis of preimplant data such as serum creatinine, liver enzymes and pulmonary gas exchange did not identify any predictive indicator of irreversible organ damage. Functional recovery of preexisting respiratory, hepatic and renal dysfunction was found in 91%, 90%, and 85%, respectively. Subsequent transplantation, however, was affected by the number of failing organs prior to mechanical support. Of 17 patients with isolated organ failure prior to assist, 14 (82%) were transplanted. By contrast, 9 (75%) of 12 with combined failure of two organs, and only 6 (54%) of 11 patients with clinical patterns of three failing organ systems received transplants. In all patients who underwent successful transplantation, transplantability was associated with rapid organ recovery within 10 to 15 days after initiating mechanical assistance.
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PMID:Recovery of end-organ failure during mechanical circulatory support. 138 32

Mechanisms responsible for the reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) in response to acute infusions of amphotericin B were investigated in vivo in rats. The influence of salt status and the roles of adenosine, cyclic AMP, and calcium influx were examined. Amphotericin B was infused into the renal artery in seven groups of rats at 0.025 mg/kg of body weight per min for 15 min. RBF and GFR were measured over 15 min before, during, and after the infusion. Control rats were maintained on a normal salt diet; a second group of rats received a salt-depleted diet, and a third group received a high-salt intake. Four other groups were kept on a normal diet and received theophylline (0.5 mumol/kg/min into the renal artery, intra-arterially [i.a.]), dibutyryl cyclic AMP (85 micrograms/min, i.a.), the 5'-nucleotidase inhibitor adenosine alpha,beta-methylene diphosphate (4 mg/kg, intramuscularly), or diltiazem (20 micrograms/kg/min, i.a.). Control rats had a prompt 50% decrease in RBF in response to amphotericin B. This was sustained over the 15-min infusion period and was accompanied by a decrease in creatinine clearance (CLCR) (from 0.83 +/- 0.08 to 0.40 +/- 0.09 ml/min; P less than 0.05). On stopping the infusion, RBF returned quickly to baseline but CLCR continued to decrease further (to 0.35 +/- 0.07 ml/min; P less than 0.05). Salt loading, theophylline, and diltiazem administration prevented the decreases in both RBF and CLCR. Both RBF and CLCR responses in the remaining groups were not significantly different from those in controls. The results of this study reveal a protective effect of salt loading and theophylline against amphotericin B nephrotoxicity in the rat but deny a role for adenosine in mediating these effects. They further suggest that theophylline inhibits the acute responses by a mechanism unrelated to either adenosine receptor blockade or phosphodiesterase inhibition and that calcium influx into the cells is probably responsible for the acute changes in RBF and GFR in response to amphotericin B.
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PMID:Mechanisms of amphotericin B-induced decrease in glomerular filtration rate in rats. 166 54

To determine vasopressin (VP)-potentiating effect of chlorpropamide (CPMD), we studied the effect of CPMD in vivo and in vitro in kidneys and in specific tubule segments of rats with hypothalamic diabetes insipidus, homozygotes of the Brattleboro strain (DI rats). Rats on ad lib. water intake were treated with CPMD (20 mg/100 g body wt s.c. daily) for 7 d. While on ad lib. water intake, the urine flow, urine osmolality, urinary excretion of Na +, K +, creatinine, or total solute excretion did not change. However, corticopapillary gradient of solutes was significantly increased in CPMD-treated rats. Higher tissue osmolality was due to significantly increased concentration of Na +, and to a lesser degree urea, in the medulla and papilla of CPMD-treated rats. Consequently, the osmotic gradient between urine and papillary tissue of CPMD-treated rats (delta = 385 +/- 47 mosM) was significantly (P less than 0.001) higher compared with controls (delta = 150 +/- 26 mosM). Minimum urine osmolality after water loading was higher in CPMD-treated DI rats than in controls. Oxidation of [14C]lactate to 14CO2 coupled to NaCl cotransport was measured in thick medullary ascending limb of Henle's loop (MAL) microdissected from control and CPMD-treated rats. The rate of 14CO2 production was higher (delta + 113% +/- 20; P less than 0.01) in CPMD-treated MAL compared with controls, but 14CO2 production in the presence of 10(-3) M furosemide did not differ between MAL from control and from CPMD-treated rats. These observations suggest that CPMD treatment enhances NaCl transport in MAL. Cyclic AMP metabolism was analyzed in microdissected MAL and in medullary collecting tubule (MCT). MCT from control and from CPMD-treated rats did not differ in the basal or VP-stimulated accumulated of cAMP. The increase in cAMP content elicited by 10(-6) M VP in MAL from CPMD-treated rats (delta + 12.0 +/- 1.8 fmol cAMP/mm) was significantly (P less than 0.02) higher compared with MAL from control rats (delta + 5.1 +/- 1.0 fmol cAMP/mm). Preincubation of MAL dissected from Sprague-Dawley rats with 10(-4) M CPMD in vitro increased cAMP accumulation in the presence of VP, but no such enhancement was found in preincubated MCT. Adenylate cyclase activity, basal or stimulated by VP, 5'guanylimidodiphosphate, or by NaF, assayed in isotonic medium did not differ between MAL or MCT from control rats and MAL or MCT from CPMD-treated rats. When assayed in hypertonic medium (800 mosM), the adenylate cyclase activity in the presence of 10(-6) M VP was significantly higher in MAL of CPMD-treated rats. MAL and MCT from control and CPMD-treated rats did not differ in the activities of cAMP phosphodiesterase. The rate of [(14)C]prostaglandin E2 by medullary and papillary microsomes was not different between the control and CPMD-treated rats; likewise, there was no difference in accumulation of immunoreactive prostaglandin E2 in the medium of in vitro incubated medullary or papillary slices prepared from control and CPMD-treated rats. Based on the findings recounted above, we propose a hypothesis that CPMD administration enhances the antidiuretic effect of VP, primarily by increasing medullary and papillary tonicity dye to increased NaCl reabsorption in MAL. There is no evidence that CPMD sensitizes collecting tubules to the action of VP, at least at the camp-generation step. Therefore, increased antidiuretic response to VP in the kidneys of CPMD-treated DI rats is due to enhanced osmotic driving force for water reabsorption (lumen-to-interstitium osmotic gradient) in collecting tubules, rather than due to increased VP-dependent water permeability of tubular epithelium.
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PMID:Chlorpropamide action on renal concentrating mechanism in rats with hypothalamic diabetes insipidus. 631 59

Atrial natriuretic factor (ANF) has been demonstrated to be effective in the treatment of acute renal failure (ARF) in both rat and humans. The biological effects of ANF are presumed to be mediated by the generation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). Therefore, the current investigation examined whether zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, would be effective in the treatment of established acute renal failure in the rat. Acute renal failure was induced by 60 minutes of bilateral renal artery clamping. Twenty-four hours after the ischemic insult, rats received either vehicle (5% Dextrose), zaprinast (0.03 or 0.3 mg/kg/min) or ANF24 (0.2 micrograms/kg/min) intravenously for four hours. Renal function, as measured by daily serum creatinine (days 1 to 7) and day 2 inulin clearances, was dramatically improved by zaprinast but not ANF treatment. Forty-eight hours post-renal ischemia, glomerular filtration rate (GFR) was 0.14 +/- 0.04 (ml/min/100 g body wt) in the vehicle and 0.94 +/- 0.29 in the zaprinast treated animals. To evaluate the mechanism by which zaprinast accelerated renal recovery, we measured regional blood flow in the postischemic rat kidneys during drug treatment with a laser doppler flowmeter. Both high and low dose zaprinast significantly increased cortical (17%) and outer medullary blood flow (40% and 60%), an effect not seen with ANF. In summary, zaprinast is effective in the treatment of established ischemic ARF. The mechanism by which zaprinast accelerates renal recovery is due to its unique ability to stimulate regional renal blood flow and increase intracellular cGMP in the setting of tissue ischemia.
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PMID:Zaprinast accelerates recovery from established acute renal failure in the rat. 764 25

Lipid peroxidation is one of the most important expression of oxidative stress induced by oxygen-derived free radicals. Here we evaluate the behavior of malondialdehyde (MDA) in the serum and urine from patients with chronic pancreatic diseases, with respect to patients with extra-pancreatic digestive diseases and glomerulonephritis. Serum and urinary phospholipase A2 (PLA2) activity was also determined, since this enzyme contributes to damage of plasma membranes. MDA and PLA2 levels increased in the sera from most of the patients with pancreatic and extra-pancreatic digestive diseases. In glomerulonephritis, pathological MDA levels (36%), but not PLA2 levels, were found. Serum MDA correlated with gamma-glutamyl transpeptidase (GGT), while PLA2 correlated with alanine-phosphodiesterase (ALP), GGT, alanine-aminotransferase (ALT) and creatinine. In urine, MDA and PLA2 behaved differently from the corresponding serum values. MDA increased in some patients with pancreatic cancer, extra-pancreatic diseases and glomerulonephritis. PLA2 levels did not significantly vary between groups. Urinary MDA correlated with some indicators of renal tubular damage [urinary ribonuclease, beta-2-microglobulin (B-2-M) and N-acetyl-glucosaminidase (NGA)] and with serum bilirubin. Urinary PLA2 correlated only with ribonuclease (RNase). We conclude that serum MDA increases aspecifically in pancreatic and extra-pancreatic diseases, probably reflecting an aspecific phlogistic phenomenon; PLA2, although sharing a similar pattern with MDA, seems mainly related to hepato-biliary damage. Urinary MDA reflects the presence of renal tubular damage, which may be the cause or a consequence of lipid peroxidation; little variations in PLA2 are recorded in urine, and mainly reflect the presence of impaired tubular function.
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PMID:Lipid peroxidation and renal tubular damage in chronic pancreatic diseases: is there any relationship? 793 Sep 60

Microalbuminuria is characteristic in diabetic nephropathy and is thought to be influenced by renal hemodynamics, especially by the metabolism of prostaglandins (PGs) in glomruli. To reduce urinary albumin excretion in patients with non-insulin-dependent diabetes mellitus (NIDDM), we administered 100 mg of cilostazol, a phosphodiesterase inhibitor, daily for 3 months. The urinary albumin index (UAI: microgram albumin/mg creatinine) decreased significantly after 3 months of administering cilostazol. Urinary excretions of thromboxane B2 (TXB2), a stable metabolite of thromboxane A2, decreased significantly after treatment. However, it had no effects on urinary excretions of PGE2 and 6-keto PGF1 alpha (6KF), a stable metabolite of prostacyclin. The ratio 6KF/TXB2 has been known to reflect the renal metabolism of PGs. In this study, urinary 6KF/TXB2 ratio increased significantly in parallel with a significant reduction of UAI. Cilostazol had no adverse effects on the control of blood glucose and lipids. In conclusion, cilostazol has a beneficial effect on UAI in patients with NIDDM by reducing renal production of TXB2., which increases 6KF/TXB2 ratio.
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PMID:Effects of cilostazol, a phosphodiesterase inhibitor, on urinary excretion of albumin and prostaglandins in non-insulin-dependent diabetic patients. 813 17

Renal failure after cardiac surgery using cardiopulmonary bypass (CPB) is well understood for infants, children and adults. The perioperative risk factors after CPB for immature kidneys in newborns are not well known. This retrospective study investigates perioperative risk factors for renal insufficiency in neonates. I) Preoperative: Age; weight, performed angiography, amount of dye used in angiography, renal disease and creatinine. II) Intraoperative: Duration of operation, duration of MAP < 40 mmHg, use of deep hypothermia, in-out fluid balance, duration of CPB, duration of circulatory arrest and cross-clamp time. III) Postoperative: Creatinine, use of catecholamines, use of nitroglycerine (NG) or phosphodiesterase inhibitors (PDI) and additional antibiotics. From Jan. 1990 to Dec. 1994 50 neonates underwent cardiac surgery using CPB (n = 23 transposition of the great arteries; n = 4 pulmonary atresia; n = 6 critical pulmonary stenosis; n = 5 hypoplastic left heart syndrome; n = 3 Ebstein's anomaly; n = 2 interrupted arch with hypoplastic left ventricle; n = 2 single ventricle; n = 1 each: double outlet right ventricle, tricuspid atresia, critical aortic stenosis, rhabdo-myosarkoma, corrected transposition of the great arteries.) Thirty-one patients entered the study. Depending on the postoperative creatinine level two groups (group I: creatinine <1 mg/dl and group II: >1 mg/dl) were created. The diureses between the two groups did not differ. Comparing the patients of group I vs. group II, patients of group I were younger (mean age: 7.7 d. vs. 11.4 d), lighter (mean weight: 3260 g vs. 3430 g), less had angiography (44% vs. 77%), received more dye (mean amount: 14 ml vs. 7 ml), the duration of MAP < 40 mmHg while on CPB was longer (mean duration 3 min vs. 21 min), more patients were operated on using deep hypothermia (55% vs. 27%), the postoperative in-out-fluid balance was more positive (mean balance +413 ml vs. +221 ml), received postop. more frequently high doses of catocholamines and less common NG or PDI, but more often additional antibiotics. The duration of circulatory arrest (mean time: 60 min vs. 55 min) and cross clamp time (mean time: 68 min vs. 65 min) seems not to be a risk factor and vasodilators given simultaneously with catecholamines may have preventive effects on postoperative renal insufficiency. Immature kidneys may play an outstanding role in the susceptibility of damaging factors. Further investigation with a larger number of patients allowing to obtain statistical significant risk factors are required.
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PMID:Renal insufficiency in neonates after cardiac surgery. 883 54

Acute endotoxemic renal failure involves renal vasoconstriction, which presumably occurs despite increased nitric oxide (NO) generation by inducible NO synthase in the kidney. The present study examined the hypothesis that the renal vasoconstriction during endotoxemia occurs in part because of desensitization of soluble guanylate cyclase (sGC). Endotoxic shock was induced in male B6/129F2/J mice by an intraperitoneal injection of Escherichia coli lipopolysaccharide. The endotoxemia resulted in shock and renal failure as evidenced by a decrease in mean arterial pressure and an increase in serum creatinine and urea nitrogen. Serum NO increased in a time-dependent manner, reaching the highest levels at 24 h, in parallel with induction of inducible NO synthase protein in the renal cortex. In renal cortical slices obtained from endotoxemic mice, cyclic guanosine monophosphate (cGMP) increased significantly at 6 h and 15 h as compared with control but normalized at 24 h after injection of lipopolysaccharide. Incubation of renal cortical slices in the presence of a phosphodiesterase inhibitor isobutylmethylxantine did not alter the pattern of changes in cGMP. Incubation of renal cortical slices with 2 mM sodium nitroprusside resulted in a similar accumulation of cGMP in slices taken from control and endotoxemic mice at 6 h and 15 h. However, in slices from 24-h endotoxemic mice, accumulation of cGMP in response to sodium nitroprusside was significantly lower. This lower stimulability of sGC was not paralleled by a decrease in its abundance in renal cortex on immunoblot. Taken together, these results demonstrate a desensitization of sGC in renal cortex during endotoxemia, which may contribute to the associated renal vasoconstriction.
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PMID:Desensitization of soluble guanylate cyclase in renal cortex during endotoxemia in mice. 1105 91

1. The effect of the immunosuppressant drug, cyclosporin A (CsA), on the nitric oxide (NO)-cyclic GMP pathway was examined in spontaneous hypertensive rats (SHR). 2. CsA (50 mg kg(-1)) treatment for 14 days induced typical CsA nephrotoxicity, which was characterized by morphological changes in the glomerulus and proximal tubule as well as an abnormality of creatinine clearance, FENa and BUN. 3. CsA significantly decreased both NOS activity in the kidney and NOx contents in urine, but significantly increased cyclic GMP content in the kidney. 4. A marked change in two kinds of enzyme, which contribute towards the increase in cyclic GMP in tissue, namely, a decrease in cyclic GMP-phosphodiesterase activity and increase in guanylate cyclase activity, was observed in the kidney treated with CsA. 5. In the isolated perfused kidney, a decreased in perfusion pressure induced by SNP in the kidney isolated from CsA group was significantly greater than that of control. 6. There seem to exist a reciprocal mechanism to maintain cyclic GMP content via both a decrease in cyclic GMP degradation and an increase in synthesis of cyclic GMP in the kidney treated with CsA. This mechanism is likely to be playing an important role to regulate the homeostasis in the kidney with CsA nephrotoxicity.
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PMID:Reciprocal regulation of cyclic GMP content by cyclic GMP-phosphodiesterase and guanylate cyclase in SHR with CsA-induced nephrotoxicity. 1168 47


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