Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biochemical problems of psoriasis are discussed, especially two modern hypothesis about the pathogenesis of this skin disease. 1. DHEA-deficiency leading to an increase of G-6-PDH inaugurated by Holzmann et al. 2. cAMP deficiency in psoriatic lesions as a cause of psoriasis hypothized by Voorhees and Duell. A synopsis of the physiology of the steroid hormone DHEA (synthesis, regulation, conjugation and excretion) is given. There are doubts that this hypothesis is correct. Recent findings have indicated, that there is no decrease of cAMP in the psoriatic lesion--in contrast there is an increase of this cyclic nucleotid. It means that this theory is also doubtfull. Treatment of an hypothetical decrease of cAMP by AMP is not possible, because this AMP will not penetrate in the cell and cannot be metabolized to cAMP.
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PMID:[Psoriasis: A general disease? Can psoriasis be explained biochemically?]. 19 71

At extremely low concentrations, in the picomole and the nanomole range, bradykinin produces contraction and relaxation of smooth muscle in the gastrointestinal and the urogenital tract. At the target organ, bradykinin interacts with discriminator proteins of the plasma membranes and triggers, via changes in certain membrane functions, its biological response:--The binding to the discriminator makes specific conformative and constitutional demands on the nonapeptide. The binding results from an angular conformation which exists in the solution. The complete sequence is responsible for this specific conformation. Consequently, the biological activity of partial sequences is low. The conformational analysis of analogues used in studies on the mechanism of action showed but slight differences from bradykinin. The interaction of these analogues with the discriminator protein is disturbed to a varying extent by modifications at positions 1, 5, 8 and 9 in the side chains. The affinity for the discriminator is affected, dependently on the respective configuration, by substitution on the beta-C atom in the two phenylalanine residues.--Bradykinin is not only bound to, but also degraded at, the plasma membranes of the rat uterus and duodenum. The bradykinin-degrading enzyme has been characterized as a kininase II with the aid of various inhibitors. The conformative and configurative prerequisites decisive for enzymatic degradation are others than those decisive for binding to the discriminator.--The changes in the activities of the membrane-bound adenylate and guanylate cyclases (produced by the bradykinin-discriminator complex) that take place at the rat duodenum and uterus in the presence of extracellular calcium ions contrast with each other: At the duodenum, the ratio between these two cyclic nucleotides is changed in favour of adenylate cyclase; and at the uterus, in favour of guanylate cyclase; Substances which increase or decrease the cAMP level may also potentiate or inhibit the relaxation of the duodenum. These bradykinin-induced changes in enzyme activity must be considered in connection with other effectors, e.g. prostaglandins and calcium ions.--The calcium-ion-dependence of the effect of bradykinin on the guinea-pig ileum and the rat uterus indicates the importance of these ions as additional second messengers. Bradykinin stimulates the influx of calcium ions into the ileum; it is ineffective if no extracellular calcium ions into the ileum; it is ineffective if no extracellular calcium ions are available. It seems that intracellular and membranal calcium is mobilized in the uterus, which is evidenced by results from experiments with EGTA on the isolated organ and by the release of calcium from plasma membranes after application of bradykinin. It is assumed that the observed changes in membrane functions are induced by the peptide-discriminator complex simultaneously and not in the form of a causal chain.
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PMID:[On the mode of action of bradykinin on smooth muscle (author's transl)]. 39 90

1. The effect of administration of the angiotensin converting enzyme inhibitor (ACEI), lisinopril (Carace; 10-40 mg twice daily) and the calcium channel blocker, nifedipine (Adalat Retard; 20-40 mg twice daily) on ex vivo [45Ca2+] uptake by platelets from hypertensive diabetic (type 1 and 2) patients was investigated. 2. At the end of at least 3 months treatment, blood was collected prior to the patient taking the morning dose of medication and washed platelets prepared. [45Ca2+] uptake was monitored following the addition of adrenaline, isoprenaline and dibutyryl cAMP (dbcAMP), as well as in unstimulated (zero) platelets. 3. Both nifedipine and lisinopril significantly inhibited the ex vivo uptake of [45Ca2+] by platelets when this process was stimulated by adrenaline, isoprenaline and dibutyryl cAMP. Basal uptake was also inhibited in both groups. 4. These data consolidate the hypothesis that ACE inhibitors may possess calcium channel/calcium mobilisation blocking properties. Apart from its hypertensive action, lisinopril may also reduce platelet activity via modulation of calcium dynamics, thereby reducing the incidence of vascular complications associated with diabetes mellitus.
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PMID:Lisinopril and nifedipine administration inhibits the ex vivo uptake of [45Ca2+] by platelets from hypertensive diabetic patients. 131 54

We have demonstrated previously that a variety of agents including corticosteroids, thyroid hormone, cationophores, methylxanthines, and analogues of cAMP--all of which have diversified functions in various tissues--elevate cellular angiotensin converting enzyme (ACE) activity of bovine endothelial cells in culture. In addition to these agents, we have now found that direct and receptor-mediated stimulators of adenylate cyclase, i.e., forskolin and cholera toxin, increase cellular ACE activity after 48 h incubation in culture. In an attempt to search out a more unifying concept of these stimulatory effects, we have further investigated the roles of second messengers in the stimulatory actions. Ca2+ ionophore A23187 produced significant increases in both intracellular Ca2+ and ACE of endothelial cells. In contrast to Ca2+ ionophore, agents that transiently mobilize Ca2+ from intracellular reserves such as bradykinin, acetylcholine, and ATP have no effect on the level of cellular ACE. Representative agents that elevate cellular cAMP (e.g., isobutyl methylxanthine [IBMX] and dibutyryl cAMP) elevated cellular ACE, but the slightly increased [Ca2+]i produced by these agents did not reach statistical significance. While IBMX, cholera toxin, and forskolin elevated cellular cAMP, other ACE stimulatory agents (hormones and cationophores) had no effect on cAMP. Ca2+ ionophore and the agents that elevated intracellular cAMP potentiated the effect of dexamethasone, thyroid hormone, and aldosterone in elevating cellular ACE activity. Increases in ACE activity produced by all stimulants were inhibited by the presence of 10-50 nM ouabain in the culture medium. Inhibition of ACE elevation by oubain was reversed by increasing the extracellular [K+], thereby implicating Na+, K(+)-ATPase in the ACE regulatory mechanism. These results support the presence of multiple independent mechanisms for the regulation of cellular ACE. In addition to possible involvement of intracellular Ca(2+)- and cAMP-dependent pathways, ACE is also increased by corticosteroids and thyroid hormone through mechanisms unrelated to Ca2+ and cAMP.
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PMID:Involvement of second messenger systems in stimulation of angiotensin converting enzyme of bovine endothelial cells. 165 91

Levels of angiotensin converting enzyme (ACE) in cultured bovine pulmonary artery endothelial cells treated with dexamethasone, aldosterone, 3,3',5'-triiodo-L-thyronine, Ca2+ ionophore, 3-isobutyl-1-methylxanthine, dibutyryl cAMP and forskolin were quantitated by an enzyme linked immunosorbent assay (ELISA). The configuration for the ELISA consisted of purified bovine lung ACE adsorbed to a solid phase competing with endothelial cellular ACE for a limited amount of anti-ACE immunoglobulin. ACE-IgG complex on the solid phase was detected by goat anti-rabbit IgG-alkaline phosphatase conjugate with enzymatic activity measured by p-nitrophenylphosphate as substrate. This ELISA detected ACE with a sensitivity of 32 ng/ml cellular ACE. Elevation in cellular ACE catalytic activity as measured by fluorescent assay of detergent extracts from bovine endothelial cells corresponded well with an increase in ACE protein as determined by the ELISA. These results provide direct evidence that increases in catalytic activity of ACE produced in endothelial cells by a variety of agents result from enhancement of the synthesis of ACE protein.
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PMID:Elevation of angiotensin converting enzyme in bovine endothelial cells quantitated by an ELISA. 169 4

In severe chronic heart failure, myocardial beta-adrenoceptors are downregulated and G-proteins inhibiting adenylate cyclase activity are augmented. Because of these biochemical changes, all positive inotropic drugs that need cAMP for their contractile effects lose their efficacy. Among the positive inotropic drugs used today for treatment of heart failure, only cardiac glycosides remain effective without development of tolerance as long as enough contractile myocardium is left. Controlled studies with phosphodiesterase III inhibitors (milrinone and enoximone) have revealed an unfavorable prognosis in these patients in comparison to placebo. Thus, these drugs are not indicated in chronic heart failure. In higher classes of chronic heart failure, therapy should always be a combination of diuretics, digitalis, and ACE-inhibitors.
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PMID:[Positive inotropic substances--therapeutic perspectives]. 179 36

Prostaglandins (PG) play an important role in the regulation of the renal blood flow and glomerular filtration rate. This study was designed to examine PG synthesis in the presence and absence of the ACE inhibitor captopril, PG binding to specific receptors and the ability of PG to stimulate cAMP accumulation in isolated glomeruli. Glomeruli were isolated from rat kidneys by a passive mechanical sieving technique. PG synthesis was determined by RTLC and RIA. The main eicosanoids synthesized by glomeruli were PGF2 alpha, thromboxane (TX) A2 (measured as TXB2), PGI2 (measured as 6-keto-PGF1 alpha) and PGE2. Binding experiments were performed with PGE1, PGE2 and the PGI2 analogue iloprost. Scatchard analysis revealed that the specific binding was highest for PGE1, followed by iloprost and PGE2. Adenylate cyclase was preferentially stimulated by PGE1 and PGE2, and to a lesser extent by PGI2, whereas PGF2 alpha had almost no effect. Captopril reduced mainly TXB2 concentrations. Glomerular TXB2 reduction, therefore, seems to be an additional hypotensive effect of captopril medication.
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PMID:[Glomerular prostaglandins: synthesis, mechanism of action and interaction with ACE inhibitors]. 185 Sep 40

The role of cyclic AMP in regulating the production of angiotensin converting enzyme (ACE) was investigated using cultured bovine aortic endothelial cells. Addition of dibutyryl cAMP [Bu)2cAMP) at 100 microM increased the ACE activity to 126% of control (P less than 0.005). This effect was blocked by either actinomycin D (0.1 microgram/ml) or cycloheximide (1.7 microM) indicating that RNA as well as protein synthesis was required for induction of the enzyme. After addition of (Bu)2cAMP, a lag period of 8 h was observed before increased ACE activity was detected. The stable analogues, 8-bromo cAMP (100 microM) and N6-monobutyryl cAMP (100 microM) also increased ACE activity but cAMP (100 microM) and O2-monobutyryl cAMP (100 microM) had no effect, in keeping with their susceptibility to phosphodiesterase in this system. Sodium butyrate (100 microM) was also inactive. The effect of (Bu)2cAMP on ACE was still observed in the presence of a maximal dose of dexamethasone, indicating that (Bu)2cAMP stimulates by mechanism(s) independent of the previously observed action of glucocorticoids on these cells. The phosphodiesterase inhibitor IBMX caused a dose-related increase in ACE activity with a threshold at 30 microM (P less than 0.05) and produced a 4-fold increase above control at 1 mM IBMX.
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PMID:Angiotensin converting enzyme induction by cyclic AMP and analogues in cultured endothelial cells. 244 4

The production of angiotensin converting enzyme (ACE) is known to be increased by glucocorticoids, thyroid hormones and converting enzyme inhibitors. We have recently reported that active cAMP analogues also stimulate production of the enzyme. The effect of stimulation of adenylate cyclase in cultured endothelial cells or of phosphodiesterase inhibition on ACE production was therefore evaluated. The phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) (10(-4) M), produced 10.5 +/- 1.3 and 1.3 +/- 0.1 (P less than 0.01 and P greater than 0.1) fold increases in extracellular and cellular cAMP levels and a 1.55 +/- 0.10 (P less than 0.0001) fold increase in ACE accumulation. The adenylate cyclase stimulator, forskolin (0.01-10 microM), acutely stimulated cellular cAMP accumulation in a dose-dependent manner, reaching a 2.8 +/- 0.1-fold increase at 10 microM. After 48 h exposure to 10 microM forskolin, significant increases in cellular (1.90 +/- 0.38-fold increase, P less than 0.0001) and extracellular cAMP (2.35 +/- 0.26-fold increase, P less than 0.0001) were also observed but ACE accumulation was unchanged (108 +/- 10% of control, P greater than 0.5). The beta-adrenoceptor agonist, isoproterenol (1-1000 nM), acutely stimulated cellular cAMP accumulation, with a threshold effect at 10 nM, an ED50 of approximately 30 nM, and a plateau effect of 2.0 +/- 0.13-fold increase by 100 nM. After 48 h exposure to isoproterenol (1 microM), extracellular cAMP levels were increased significantly (1.68 +/- 0.33-fold increase, P less than 0.01) but ACE production was slightly inhibited (83 +/- 7% of control, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of forskolin, isoproterenol and IBMX on angiotensin converting enzyme and cyclic AMP production by cultured bovine endothelial cells. 244 75

Incubation of cultured bovine pulmonary artery endothelial cells with 200 microM of 3-isobutyl-1-methylxanthine (IBMX) for 24 hr produced a five- to tenfold increase in cellular angiotensin converting enzyme activity (ACE) above that of untreated control cells. A lesser increase was observed in medium ACE. Other methylxanthines produced a similar, but less marked, effect. The elevation of ACE seemed to require de novo protein synthesis since it was reduced by 0.1 microgram/ml cycloheximide. Elevation of cellular cAMP was detected at 30 min after introduction of IBMX, then rapidly returned to control levels at 1 hour, while elevation in cellular ACE at 24 hr required contact with IBMX for at least 2 hr. Hence, the transient elevation in cAMP is unlikely to be the cause of the elevation of ACE. Phorbol ester and synthetic diacyl glycerol OAG, activators of protein kinase C, did not elevate ACE. Indomethacin, at a concentration known to inhibit cyclooxygenase activity, had no effect on the elevation of ACE. The elevation of ACE by IBMX was not affected by the calcium channel blocker verapamil or the calcium chelator EGTA. In contrast, the effect of IBMX was totally abolished by the calmodulin inhibitors trifluoperazine and calmidazolium. The data show that IBMX elevates endothelial cell ACE and suggest that the elevation is mediated by a calcium-calmodulin complex. The studies demonstrate a novel effect of methylxanthines on endothelial cells in culture.
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PMID:Elevation of angiotensin converting enzyme by 3-isobutyl-1-methylxanthine in cultured endothelial cells: a possible role for calmodulin. 245 40


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