Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two groups of Sprague-Dawley rats, Harlan (H) and Charles River (CR), were discovered in that the medullary thick ascending limb (MAL) had a profoundly different adenylate cyclase response to arginine vasopressin (AVP). Using these two groups of rats, we studied the correlation between AVP action on the MAL and maximal urinary concentration. AVP (10(-6) M) significantly stimulated adenylate cyclase in MAL of H rats (7.4 +/- 0.9 to 43.8 +/- 4.6 fmol cAMP formed X 30 min-1 X mm-1, P less than 0.001) but not in CR rats (10.3 +/- 1.4 to 12.7 +/- 2.0 fmol cAMP formed X 30 min-1 X mm-1, NS). In contrast, AVP significantly stimulated adenylate cyclase of cortical, outer and inner medullary collecting tubules from both H and CR rats. Glucagon (10(-6) M) significantly stimulated adenylate cyclase of MAL from both H and CR rats. After 48 h of fluid deprivation, urinary osmolality was significantly higher (P less than 0.001) in the H (4,504 +/- 399 mosmol/kg H2O, n = 14) than CR (2,840 +/- 176 mosmol/kg H2O, n = rats. This observation was not attributable to differences in creatinine clearance (CR, 1.30 +/- 0.24; H, 1.24 +/- 0.03 ml/min, NS, n = 4) or plasma AVP (CR, 12.75 +/- 1.44; H, 12.38 +/- 1.17 pg/ml, NS, n = 6) levels. These results therefore suggest that the action of AVP on the MAL, in addition to the effect on collecting tubules, is involved in maximal urinary concentration in rats.
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PMID:Role of arginine vasopressin in medullary thick ascending limb on maximal urinary concentration. 374 Feb 73

To evaluate the possible role of microtubules in the cellular action of vasopressin on the mammalian kidney, the effects of microtubule-disrupting agents were studied in vivo and in vitro. In vivo studies were done in rats in mild to moderate water diuresis induced by drinking 5% glucose. Microtubule-disrupting alkaloids, colchicine (0.1 mg/day) or vinblastine (0.08 mg/day), given intraperitoneally, did not change water and solute excretion itself, but blocked or markedly inhibited the antidiuretic response (increase in urine osmolality and decrease in urine flow) to exogenous vasopressin. Total solute excretion was unaffected by these two alkaloids and there were no substantial changes in excretion of sodium, potassium, or creatinine. Lumicolchicine, a derivative of colchicine that does not interact with microtubules, did not alter the antidiuretic response to exogenous vasopressin. Activities of adenylate cyclase in the renal medullary plasma membrane, and cyclic AMP phosphodiesterase and protein kinase in renal medullary cytosol, were not influenced by 10(-5)-10(-4) M colchicine or vinblastine in vitro. Studies on the subcellular distribution of microtubular protein (assessed as [(3)H]colchicine-binding protein) in renal medulla shows that this protein is contained predominantly in the cytosol. Particulate fractions, including plasma membrane, contain only a minute amount (less than 6%) of the colchicine-binding activity. The results suggest that the integrity of cytoplasmic microtubules in cells of the distal nephron is required for the antidiuretic action of vasopressin, probably in the sites distal to cyclic AMP generation in the mammalian kidney.
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PMID:Effects of colchicine and vinblastine on the cellular action of vasopressin in mammalian kidney. A possible role of microtubules. 436 87

Receptors for parathyroid hormone (PTH) in the renal tubule are coupled to adenylate cyclase stimulation. PTH causes a rise in urinary cAMP by leakage from adenylate cyclase stimulation. PTH causes a rise in urinary cAMP by leakage from cells of the proximal convoluted tubule. The effects of alpha-adrenergic agonists and antagonists on the urinary cAMP response to PTH were investigated in anaesthetized rats in vivo. Injection of PTH (15 u/kg i.v.) produced an increase in urinary cAMP from 1.7 (s.e.m. = 0.3, n = 6) to 7.47 (s.e.m. = 0.7, n = 6) nmol cAMP/mumol creatinine in 30 min urine samples. Infusion of the alpha 2-adrenoceptor agonist clonidine at 1 microgram/kg per min caused a decrease in the cAMP response to PTH to 3.6 (s.e.m. = 0.5, n = 12) nmol cAMP/mumol creatinine. Infusion of the alpha 2-selective catecholamine alpha-methylnoradrenaline (1 microgram/kg per min) caused a similar reduction in urinary cAMP response to that observed with clonidine. The alpha-adrenoceptor antagonist phentolamine (100 micrograms/kg per min) enhanced the cAMP response to PTH and reversed the decreased response caused by clonidine. These results demonstrate the presence of alpha-receptors in the rat proximal convoluted tubule which oppose the actions of PTH in vivo.
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PMID:Demonstration of proximal tubular alpha-adrenoceptors in vivo. 615 30

We investigated the effects of uraemia and haemodialysis on the basal activity of adenylate cyclase and the cyclic-AMP content of human platelets in patients with end-stage renal insufficiency, patients receiving maintenance haemodialysis, and as controls healthy voluntary subjects. Basal adenylate cyclase activity in terminal renal disease (creatinine clearance less than 15 ml/min/1.73 m2) was 824 +/- SEM 57, in comparison to the healthy subjects with 453 +/-SEM 28 (P less than 0.001). We also found significant elevation (P less than 0 . 001) of platelet cAMP levels as compared to the controls. Basal adenylate cyclase activity and platelet cAMP levels were approximately normal in the dialysed patients. These results show that uraemic toxins adversely affect the platelet AC-cAMP system, possibly causing impaired platelet aggregation and the bleeding diathesis of uraemia.
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PMID:Adenylate cyclase activity and cAMP content of human platelets in uraemia. 629 33

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

Urinary c-AMP and c-GMP levels were measured in male and female F344/DuCrj rats during dietary treatment with 2% sodium o-phenylphenate (OPP-Na) for 136 days. At the end of the experiment, levels of the cyclic nucleotides in the plasma, kidney and liver, and of adenylate cyclase in the kidney and liver were also determined. Urinary c-AMP/creatinine in males decreased immediately after the start of OPP-Na treatment and recovered to the normal level within 1 wk. Such a biphasic change recurred intermittently until the end of the experiment. In the case of treated females, urinary c-AMP/creatinine also showed a decrease and recovery in 1 wk but no subsequent decrease was observed. As urinary c-GMP/creatinine in treated males was higher than that in control males, low c-AMP/c-GMP ratios persisted throughout the experiment. Although there was no significant difference of c-AMP or c-GMP levels in the liver or kidney between control and treated animals, c-AMP/c-GMP ratios in these tissues from treated rats decreased slightly. The c-AMP levels in plasma from treated males were significantly lower than those in the male controls, but no significant difference was observed between treated and control females. In the presence of activators (sodium fluoride, glucagon, epinephrine), adenylate cyclase activity in liver and kidney homogenates from treated rats was only about 70% of the control activity, except with the female kidney enzyme. This observed inhibition in treated rats suggests that the decreased excretion of urinary c-AMP in treated rats was not due to a decrease in renal clearance but to reduced production of c-AMP.
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PMID:Altered levels of cyclic nucleotides in F344 rats fed sodium o-phenylphenate. 632 89

Predicting the course of parathormone (PTH)-elicited bone turnover in both humans and experimental rat models with moderate chronic uremia, using only standard clinical chemistry analyses, is often difficult. Consequently, rat bone from 1 + 2/3 nephrectomized animals, after 230 days of progressive renal failure, was examined for PTH-stimulated adenylate cyclase (AC) and phospholipase C (PL-C) activities. Correlations to biological parameters related to the function of bone and kidney were made. Reduced renal function was demonstrated by increased serum creatinine; circulating 1,25 dihydroxyvitamin D3 below detection level; diminished renal PTH-elicited AC activity; and decreased urinary cAMP excretion. PTH-activated renal PL-C was also reduced. However, no significant differences were seen in urine creatinine, calcium, phosphate, and hydroxyproline, nor in serum PTH, alkaline phosphatase, calcium, and phosphate. Notwithstanding, renal osteodystrophy developed as estimated by increased plasticity of the long bones, as well as reduction of the diaphyseal (Dd) and inner femoral mid-shaft (Di) diameters. Femoral cancellous bone exhibited a substantial elevation of both eroded surface (ES) and osteoid surface (OS) as well as a marked reduction in trabecular bone volume (TBV). Calvarial PTH-activated AC was enhanced, whereas corresponding PL-C was markedly reduced. PTH-enhanced AC correlated positively with ES and negatively with Di, respectively. PTH-enhanced PL-C, however, correlated positively with bone calcium content and negatively with ES. Our results indicate that bone modeling and remodeling are to a large extent related to PTH-elicited signaling systems, and cannot easily be predicted by standard clinical chemistry analyses.
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PMID:Surgically induced uremia in rats. II: Osseous PTH-susceptible signaling systems as predictors of bone resorption. 782 Jul 79

Iliac crest biopsies of normals, uremic patients and subjects with primary hyperparathyroidism (pHPT) were investigated. It appeared that serum 1,25- and 24,25-(OH)2-D3 correlated inversely with basal adenylate cyclase (AC) activity and relative PTH-stimulated AC, respectively. Net PTH-elicited AC (dPTH-AC) activation hence reflected individual vitamin D status. The combination variable serum PTH (s-PTH) x dPTH-AC x [H+] correlated well with resorption surface (RS) in both normals, patients with pHPT or subjects with uremia, while s-PTH, dPTH-AC activity or pH as single variables were only marginally related to RS. For all subjects analyzed, osteoid volume (OV) correlated positively with serum alkaline phosphatase but negatively with serum 1,25-(OH)2-D3. OV showed no correlation with dPTH-AC, while the relationship between OV and s-PTH was strong, suggesting that PTH stimulates osteoid deposition via some signalling pathway other than cAMP. In normals, OV was inversely proportional to s-PTH, due to homologous desensitization of this signalling system. Furthermore, s-PTH was negatively correlated with urine cAMP due to homologous desensitization of the effect of PTH on the kidney 25-(OH)-D3 1 alpha-hydroxylase. This phenomenon was absent in uremic patients. Evaluation of variables by artificial intelligence showed that the prototype uremic patient exhibited serum creatinine > 900 microM, RS > 0.12, pH between 7.15 and 7.34 and s-PTH x dPTH-AC x [H+] between 0.5 and 3.7 units with the distinguishability index 'very good' (< 5% overlap) towards normals. Average similarity of uremic patients with the prototype for normal subjects was only 22%. Cluster analysis of all the variables was conducted for comparison and yielded less clinically relevant information. Hence, emulation done by the expert system was superior and clearly indicates that present treatment modalities restore normal bone turnover only to a minor degree or not at all.
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PMID:PTH-stimulated adenylate cyclase activity and bone histomorphometry in iliac crest biopsies in the evaluation of uremic patients: a pilot study with the use of artificial intelligence. 816 16

Renal osteodystrophy with increased bone resorption is a major clinical problem in patients with chronic renal failure. Previous reports have shown that treatment with 24,25-dihydroxy vitamin D3 (24,25(OH)2D3) may result in decreased bone resorption. The present study addresses basic mechanisms for the action of 24,25(OH)2D3 in bone of patients with elevated serum parathyroid hormone (PTH) levels due to chronic renal disease. Twenty-four patients 56 +/- 17 years old (mean +/- SE) with chronic kidney disease in the predialytic state (serum creatinine > 150 mumol/l) and elevated serum midregion PTH > 1.2 micrograms/l were randomly assigned to oral treatment with either 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) (0.25-0.50 microgram/day), 24,25(OH)2D3 (daily dose of 15 micrograms), or a combination of the two vitamin D3 analogs. The control group received calcium carbonate (maximal dosage of 1 g x 3). Selected variables in serum and urine as well as hormone sensitive adenylate cyclase (AC) in iliac crest biopsies were assessed before treatment and during follow-up after two and six months. Serum levels of 1,25(OH)2D3 and 24,25(OH)2D3 were significantly (P < 0.05) increased after two and six months in the respective treatment groups. Net bone PTH-enhanced AC (PTH-AC) fell abruptly (P < 0.01) after two months of treatment and was nearly abolished (P < 0.01) after six months with 24,25(OH)2D3 given alone or in combination with 1,25(OH)2D3. An inverse relationship (r = -0.57, P < 0.05, n = 48) between net PTH-AC in bone and serum levels of 24,25(OH)2D3 was demonstrated. In all groups, serum total calcium (s-Ca) was maintained within normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:24,25-dihydroxy vitamin D3 treatment inhibits parathyroid-stimulated adenylate cyclase in iliac crest biopsies from uremic patients. 833 29

Previously we demonstrated that bone resorption in uremic patients appears to be related to increased serum parathyroid hormone (PTH) and to osseous PTH-stimulated adenylate cyclase (AC), the latter being inversely correlated to serum 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]. In this study, we continue to examine the possible modulatory role of vitamin D3 analogs on the progression of the uremic condition. Four groups of predialytic uremic patients received oral administrations of CaCO3 (control), 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] (0.25-0.50 microgram/day), 24,25(OH)2D3 (15 micrograms/day) or a combination of the two vitamin D3 analogs for 6 months. In the treatment groups receiving single or combined therapy, respectively, the low pretrial serum levels of 1,25(OH)2D3 were raised (p < 0.05) within upper normal range, while the serum levels of 24,25(OH)2D3 were increased (p < 0.05) to twice the average physiological level. Neither regimens alone resulted in significant changes in serum levels of calcium of PTH. 1,25(OH)2D3 moderately hampered bone formation by reducing serum alkaline phosphatase (ALP) by some 15%. 24,25(OH)2D3 significantly decreased (p < 0.01) bone PTH-AC up to 98% after 2 and 6 months. However, no correlation was found between serum 24,25(OH)2D3 and the bone turnover parameters serum ALP, serum osteocalcin and urine hydroxyproline/creatinine ratio. These parameters were all positively correlated (p < 0.05) to serum PTH, indicating an on-going bone turnover. These biochemical events strongly indicate that 24,25(OH)2D3 may retard the PTH-dependent progression in bone demineralization occurring in uremic patients. This effect is apparently not reduced by concomitant 1,25(OH)2D3 administration.
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PMID:Alterations in serum and urine parameters reflecting bone turnover in uremic patients during treatment with 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3. 837 28


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