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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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

1. Neuropeptide Y (NPY; 10(-10)-10(-7) mol l-1) reduced basal short-circuit current (Isc) in a concentration-dependent manner in the rat distal colon but was ineffective in the proximal colon. 2. The action of NPY was dependent upon the presence of Cl- and HCO3- anions and was blocked by prior treatment of the tissue with a Cl- channel blocker. The decrease in Isc was associated with an increase in mucosa-to-serosa fluxes of Na+, Rb+ (K+) and Cl-, whereas the serosa-to-mucosa flux of Cl- was decreased. 3. The size of the inhibitory NPY effect was linearly correlated with the height of the basal Isc, i.e. it inhibited 55% of basal secretory Isc. 4. The action of NPY was unaffected by indomethacin and tetrodotoxin, when given alone, but was abolished, when the basal Isc was decreased to values near zero by a combination of both inhibitors. This inhibition could be overcome by restoring basal Isc with prostaglandin E2, indicating that the effect of NPY is not mediated by nerves or prostaglandins, but that NPY is only effective, when anion secretion is stimulated by the spontaneous release of neurotransmitters and prostaglandins. 5. NPY inhibited the increase in Isc induced by veratridine and prostaglandin E2, but it had no effect on the Isc induced by direct stimulation of the adenylate cyclase with forskolin, or on Isc induced by stimulation of the Ca(2+)-pathway with carbachol. Inhibition of the response to veratridine or prostaglandin E2 by NPY showed the same dependence on the height of the ISC just prior to addition of NPY as seen in control conditions, i.e. NPY inhibited 55% of cyclic AMP-mediated secretion.6. These results suggest that the effect of NPY is mediated by an inhibition of cyclic AMP-stimulated secretion, which is stimulated in the rat distal colon by a continuous release of prostaglandins and neurotransmitters.
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PMID:The effect of neuropeptide Y on sodium, chloride and potassium transport across the rat distal colon. 758 5

To determine the role of anion transport in the forskolin-induced Cl- increase of scala media (SM), effects of forskolin on the EP (endocochlear potential) and Cl- activity (ACl) in SM were examined with double-barrelled Cl(-)-selective microelectrodes. The experiments were carried out on guinea pig cochleae, using a few anion transport inhibitors: IAA-94 for a Cl- channel blocker, bumetanide (BU) for an Na+/K+/2Cl- cotransport blocker, and SITS and DIDS for Cl-/HCO3- exchange blockers. The application of forskolin (200 microM) into scala vestibuli (SV) caused a 20 mEq increase of endolymphatic ACl and a 15 mV elevation of EP, and IAA-94 with forskolin completely abolished these responses. Although each application of BU, SITS or DIDS did not completely suppress EP elevation, the concurrent application of these inhibitors completely suppressed EP with endolymphatic ACl increase. The results indicate the involvement of Cl- channels, Na+/K+/2Cl- cotransport and Cl-/HCO3- exchange in forskolin-induced increase of ACl and EP. The role of adenylate cyclase activation and Cl- transport in endolymph homeostasis was discussed.
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PMID:Role of endolymphatic anion transport in forskolin-induced Cl- activity increase of scala media. 760 89

Adrenoceptor-mediated Cl- transport in cultured rabbit corneal endothelium was examined using a Cl(-)-sensitive fluorescent dye. The intracellular Cl- concentration ([Cl-]i) in the endothelial cells was estimated to be about 30 mM. Noradrenaline (0.001-0.1 mM) transiently decreased the [Cl-]i in a dose-dependent manner. Such a decrease in [Cl-]i was completely antagonized by pretreatment with the alpha-adrenoceptor antagonist phentolamine (0.1 mM). The selective alpha 2-adrenoceptor agonist UK 14304-18 (5-bromo-6-[(4H,5H-imidazol-2-yl)amino]quinoxaline, 0.1 mM) persistently decreased the [Cl-]i, but neither the alpha 1-adrenoceptor agonist phenylephrine (0.1 mM) nor the beta-adrenoceptor agonist isoproterenol (0.1 mM) had any effect. The alpha 2-adrenoceptor agonist/antagonist yohimbine (0.1 mM) persistently and more strongly decreased the [Cl-]i than UK 14304-18 did. The yohimbine-induced decrease in the [Cl-]i was not further altered by UK 14304-18 or phenylephrine, but partly reversed by noradrenaline, isoproterenol and an adenylate cyclase activator, forskolin (0.1 mM). The yohimbine-induced decrease in [Cl-]i was inhibited by the carbonic anhydrase inhibitor acetazolamide (1 mM), and Cl-/HCO3- exchange inhibitors, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, but not by the H(+)-ATPase inhibitor N,N'-dicylohexylcarbodiimide. The forskolin-induced recovery in [Cl-]i was inhibited by the Na+/K+/Cl- cotransport inhibitor bumetanide (0.1 mM), but not by the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenergic receptor-mediated Cl- transport in rabbit corneal endothelial cells. 765 Aug 65

Bioelectrical properties and anion secretion in cultured epithelia from different regions of rat and human male excurrent ducts were studied by measuring the short-circuit currents (ISC). In all regions of the rat excurrent duct, Cl- secretion accounts for over 90% of the basal ISC, although the magnitude varied in different regions. Cl- secretion was found to be mediated by a Cl-/HCO3- exchanger, an Na+/H+ exchanger, and an Na+/K+/2Cl- symport located on the basolateral side of the epithelial cells. Forskolin, an activator of adenylate cyclase, and ionomycin, a Ca2+ ionophore, were used to investigate the relative importance of cAMP and Ca2+ as intracellular messengers regulating Cl- secretion in different regions. It was found that in both species, the forskolin-evoked ISC response was larger in the proximal end (efferent duct/caput epididymidis [rat/human, respectively]) than in the distal end (cauda/corpus epididymidis). The response to ionomycin in the rat cauda epididymidis (distal end) was larger than that in the efferent duct (proximal end); on the other hand, no significant difference in the ionomycin-induced ISC was observed in the caput and the corpus regions from the human epididymis. Our results indicate that while the cAMP- and Ca(2+)-dependent pathways are both involved in regulating Cl- secretion in all regions along the male excurrent ducts in both species, a regional difference exists with respect to the relative importance of the two regulatory pathways involved in Cl- secretion along the male reproductive tract.
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PMID:Regional differences in bioelectrical properties and anion secretion in cultured epithelia from rat and human male excurrent ducts. 771 Nov 78

The role of somatostatin-14 in duodenal mucosal HCO3- secretion was investigated in anesthetized, indomethacin-treated guinea pigs. Net HCO3- output from the isolated, perfused (24 mM NaHCO3 + 130 mM NaCl) proximal duodenum was measured during intravenous infusion (alone or in combination) of somatostatin-14, carbachol, vasoactive intestinal peptide (VIP), and prostaglandin E2 (PGE2). In homogenates of duodenal enterocytes, the effect of these agents on adenylate cyclase activity was studied. Basal duodenal HCO3- secretion (3.5 +/- 0.2 mumol/cm/10 min) was reduced dose dependently by somatostatin-14 (10(-11) mol/kg, 10(-9) mol/kg, and 10(-7) mol/kg). Carbachol, VIP, and PGE2 (all 10(-8) mol/kg) increased basal duodenal HCO3- secretion two- to threefold. Somatostatin-14 (10(-7) mol/kg) abolished the stimulatory effect of carbachol and VIP, but not that of PGE2. Basal adenylate cyclase activity in isolated duodenal enterocytes (9.4 +/- 1.0 pmol cAMP/mg protein/min) was unaltered by somatostatin (10(-6) mol/liter) or carbachol (10(-3) mol/liter). VIP (10(-8) mol/liter) and PGE2 (10(-7) mol/liter) increased adenylate cyclase activity two- to threefold, and these effects were unchanged by somatostatin-14 (10(-6) mol/liter). In conclusion, somatostatin-14 inhibits basal and carbachol- and VIP-stimulated duodenal HCO3- secretion, and its mechanism of action is not via inhibition of adenylate cyclase activity in duodenal enterocytes.
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PMID:Effect of somatostatin-14 on duodenal mucosal bicarbonate secretion in guinea pigs. 789 65

We examined the regulation of the renal cortical basolateral Na-HCO3 cotransporter by G proteins. Na-HCO3 cotransporter activity was measured in highly purified rabbit renal cortical basolateral membranes (BLMV) as the difference in 22Na uptake in presence of HCO3- and gluconate. HCO(3-)-dependent 22Na uptake was significantly inhibited by 10 microM guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a G protein activator. In contrast, addition of 50 microM guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), an inhibitor of G protein, prevented the inhibition of the Na-HCO3 cotransporter activity by GTP gamma S. AlF4-, another G protein activator, also inhibited the activity of the Na-HCO3 cotransporter. This inhibitory effect of G protein on the Na-HCO3 cotransporter activity was not prevented by dideoxyadenosine, an adenylate cyclase inhibitor, or by the protein kinase A inhibitor, suggesting a direct effect of G protein on the cotransporter. To identify the G proteins that mediate the regulation of the Na-HCO3 cotransporter, purified BLMV were ADP ribosylated in presence of cholera toxin or pertussis toxin. Autoradiograms of BLMV incubated with [32P]NAD showed that cholera and pertussis toxins caused ADP ribosylation of 42- and 41-kDa G proteins, respectively. To determine whether the ADP ribosylation by cholera or pertussis toxin was associated with alterations of the Na-HCO3 cotransporter activity, we measured HCO(3-)-dependent 22Na uptake in BLMV treated with 20 micrograms/ml cholera toxin or with 100 ng/ml pertussis toxin. Na-HCO3 cotransporter activity was significantly decreased by both cholera and pertussis toxins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of renal cortical Na-HCO3 cotransporter. II. Role of G proteins. 790 Aug 46

The role of intracellular signal transduction mechanisms in regulating the motility and metabolism of rat spermatozoa in undiluted caudal epididymal fluid (CEF) was examined. Samples of CEF containing immotile spermatozoa were exposed to drugs and other agents that either stimulate signal transduction pathways or mimic the action of their second messengers. Under these conditions, sperm motility in 25-30 nl of CEF was stimulated by calcium ions (Ca2+), N2,2'-O-dibutyrylguanosine 3':5'-cyclic monophosphate (dibutyryl cGMP), cyclic adenosine 3':5'-monophosphate (cAMP), N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl cAMP), 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo cAMP), caffeine, theophylline and bicarbonate ions (HCO3-). Other agents such as magnesium ions (Mg2+), veratridine, phospholipase C (PLC), ionophore A23187, 1,2-dioctenoyl-sn-glycerol (DAG), phorbol 12-myristate 13-acetate, phospholipase A2 (PLA2), arachidonic acid, and melittin did not significantly influence motility. In the presence of radiolabelled energy substrates, untreated (immotile) spermatozoa in samples of CEF utilised D-[U-14C]glucose and [1-14C]acetate as exogenous energy sources for oxidative metabolism. No detectable 14C-lactate was produced, and none of the drugs altered the rate of glycolytic or oxidative metabolism. The findings suggest that the motility of rat caudal epididymal spermatozoa is regulated by Ca2+ and the guanylate cyclase and adenylate cyclase pathways, but not through the PLC and PLA2 pathways. Also, their metabolism of exogenous substrate was uncoupled from the induction of motility, and their oxidative capacity exceeded the rate of flux of glucose-carbon through the glycolytic pathway.
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PMID:Intracellular signal transduction mechanisms of rat epididymal spermatozoa and their relationship to motility and metabolism. 804 68

In a guinea-pig model we determined the intracellular events mediating the response of duodenal epithelial cells to vasoactive intestinal polypeptide (VIP) and prostaglandin (PG) E2. Intravenous administration of VIP (10(-9) to 10(-7) mol/kg) and PGE2 (10(-9) to 10(-6) mol/kg) dose-dependently increased duodenal epithelial bicarbonate secretion against an HCO3- concentration gradient, measured by a luminal perfusion technique, in anaesthetized guinea-pigs up to 4.5-fold. This secretion could be mimicked by intraduodenal dibutyryl cyclic adenosine monophosphate (dBcAMP; 10(-9) to 10(-7) mol/kg). Secretin (10(-9) mol/kg) and PGF 2 alpha (10(-9) to 10(-7) mol/kg), both given intravenously, were without effect or considerably less efficient. For VIP and PGE2, specific receptors coupled to adenylate cyclase could be demonstrated in homogenates of isolated duodenal epithelial cells. VIP and PGE2 stimulated adenylate cyclase activity up to sixfold, whereas PGF2 alpha and secretin were considerably less potent and efficient. VIP and PGE2 increased intracellular cyclic AMP levels up to fivefold and ninefold, respectively. This was followed by an increase in cytosolic protein kinase A activity. Bicarbonate secretion was maximal at 30 min. Examination of the subcellular distribution of protein kinase A showed a predominant cytosolic location. These data support the notion the PGE2 and VIP cause bicarbonate secretion by the serial activation of adenylate cyclase and protein kinase A in duodenal epithelial cells.
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PMID:Cyclic adenosine monophosphate is the second messenger of prostaglandin E2- and vasoactive intestinal polypeptide-stimulated active bicarbonate secretion by guinea-pig duodenum. 817 Dec 84

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


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