Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amiloride analogues with nonaromatic substituents on the 5-amino group or different substituents on carbon-6 of the pyrazine ring were tested as inhibitors of monoamine oxidase A and B in rat brain homogenate. The inhibition was competitive and reversible. 5-(N,N-Tetramethylene)amiloride protected the A type in the homogenate against irreversible inhibition by clorgyline. A reciprocal relation was found to exist between inhibitory constants of 5-N-substituted amiloride analogues for monoamine oxidase A and the ratio of overflows of endogenous noradrenaline and 3,4-dihydroxyphenylethylene glycol from the isolated rat tail artery incubated in the presence of a 50 microM concentration of the analogue, when the tissue was exposed to 10 microM tyramine. The 5-amino group appeared to be essential for inhibition of the A but not of the B type. Bell-shaped relations between inhibitory constants of 5-(N-alkyl)- and 5-(N,N-dialkyl)-substituted analogues and lengths of alkyl chains were different for each type. The presence of a methyl group in the alpha-position of the chain increased substantially the inhibitory constant for the A type. Halogen atoms as substituents on carbon-6 increased inhibitory constants for both types of the enzyme in the sequence: I less than Br less than Cl less than F. These findings are consistent with the existence of hydrophobic binding sites of restricted dimensions in both types of the enzyme.
Mol Pharmacol 1989 Aug
PMID:Inhibition of monoamine oxidase by analogues of amiloride. 277 Jul 5

The ability of a number of analogues of the diuretic, amiloride, to inhibit chemotactic factor-stimulated Na+/H+ exchange in human neutrophils was investigated. Intracellular pH (pHi) changes were measured from the equilibrium distribution of 14C-labeled 5,5-dimethyloxazolidine-2,4-dione (DMO). Exposure of cells to 10 nm N-formyl-methionyl-leucyl-phenylalanine (FMLP) caused activation of Na+/H+ exchange: in 140 mM Na+ medium (extracellular pH 7.40), the pHi rose from a resting value of approximately 7.25 to reach a new steady state of approximately 7.75 by 10-15 min. This intracellular alkalinization was sensitive to amiloride (apparent Ki approximately 75 microM), a known inhibitor of Na+/H+ countertransport. The structure-activity relationships in the amiloride series were characterized by testing the effect of these compounds on the DMO-derived pHi changes and on the FMLP-stimulated rate of 22Na+ efflux from the cells. Substitutions of the guanidino group of amiloride resulted in relatively inactive products (Ki greater than or equal to 1 mM). Replacement of the 6-Cl group of amiloride by other halogen atoms had only modest effects on drug efficacy. However, replacement of one or both H atoms of the 5-amino group by short alkyl groups led to a 10-500-fold increase in potency for inhibition of Na+/H+ exchange. Amiloride and three of its more potent derivatives (compounds I, O, and MM, the 5-N,N-dimethyl, 5-N,N-diethyl, and 5-N,N-hexamethylene analogues, respectively) caused parallel inhibition of FMLP-activated 22Na+ efflux and the rate of intracellular alkalinization, with apparent Ki values of approximately 75, 8, 1, and 0.2 microM, respectively. In each instance, the inhibitory effects of the drugs were readily reversible on washing the cells. None of the compounds altered the binding of 3H-labeled FMLP to its cell surface receptors. The development of potent derivatives of amiloride should provide powerful tools for assessing the role of FMLP-activated Na+/H+ exchange and the resultant pHi transients on stimulated neutrophil functions.
Mol Pharmacol 1986 Aug
PMID:Inhibition of chemotactic factor-activated Na+/H+ exchange in human neutrophils by analogues of amiloride: structure-activity relationships in the amiloride series. 301 97

Interaction of amiloride with adrenergic receptors was studied using radioligand binding techniques. Amiloride competed for [3H]prazosin binding to alpha 1-adrenergic receptors on rat renal cortical membranes and BC3H-1 muscle cell membranes. Non-linear regression analysis of radioligand binding isotherms showed that amiloride increased Kd without a change in Bmax, suggesting the drug binds competitively in a mutually exclusive manner with the radioligand at the receptor-binding site. Similarly, amiloride competitively blocked [125I]iodocyanopindolol binding to beta-adrenergic receptors on both tissues. The addition of guanylyl 5'-imidodiphosphate or sodium chloride did not alter the interaction of amiloride with alpha 1- or beta-adrenergic receptors. The interaction of amiloride with alpha 2-adrenergic receptors was more complex and revealed an allosteric site. In both rat renal cortical membranes and intact human platelets, amiloride increased the Kd for [3H]rauwolscine binding, as well as decreasing the apparent Bmax. In binding experiments where amiloride competed for [3H]rauwolscine-binding sites, pseudo-Hill slopes of less than 1.0 were obtained for both platelet and renal alpha 2 receptors. In addition, amiloride increased the rate of [3H]rauwolscine dissociation from renal alpha 2 receptors. In the presence of 100-120 mM sodium chloride, the Ki for amiloride competition was decreased an average of 54% in renal membranes; in contrast, sodium increased the Kd of the agonist epinephrine. Taken together, these data support the hypothesis that alpha 2-adrenergic receptors, but not alpha 1- or beta-adrenergic receptors, have an allosteric site to which amiloride binds and which we propose to be a cation-binding site.
Mol Pharmacol 1987 Jul
PMID:Interactions of amiloride with alpha- and beta-adrenergic receptors: amiloride reveals an allosteric site on alpha 2-adrenergic receptors. 303 3

Quiescent mouse NIH 3T3 cells responded to microinjection of activated ras p21 with a rapid and sustained rise in intracellular pH (approximately 0.17 pH units). The p21-induced pH change was inhibited by amiloride treatment or growth of cells in medium low in sodium, suggesting a role for the Na+/H+ antiporter. Amiloride was found to suppress p21-induced mitosis, also.
Mol Cell Biol 1987 May
PMID:Microinjection of ras p21 induces a rapid rise in intracellular pH. 303 40

Intracellular pH (pHi) was monitored in dispersed pancreatic islet cells from rats using the fluorescent dye 2'7'bis-carboxyethyl-5'(6')-carboxyfluorescein. The addition of a weak acid (acetate, propionate or formate) provoked a rapid fall in pHi, corresponding to approximately 0.2 units, following by a slower return to the basal value. Amiloride also caused a rapid fall in pHi, but no recovery occurred in this case. Addition of NH4Cl induced a rise in pHi. Of the nutrients tested, only glyceraldehyde produced a fall in pHi, both glucose and alpha-ketoisocaproate causing a gradual and sustained rise in pHi. Insulin secretion and inositol lipid metabolism in response to nutrient stimuli were markedly inhibited by NH4Cl. The responses to non-nutrient stimuli were unaffected. Glucose-induced insulin secretion and inositol lipid metabolism were potentiated in the presence of amiloride. No such potentiation, however, was observed in the presence of weak acids. Amiloride and weak acids shared the ability to reduce the fractional outflow rate of 45Ca2+. It is concluded that pharmacological manipulations of pHi can influence certain aspects of islet cell function, such as calcium handling, though it seems unlikely that the stimulation of islets by nutrient secretagogues occurs as a result of changes in pHi.
J Mol Endocrinol 1988 Jul
PMID:Is intracellular pH a coupling factor in nutrient-stimulated pancreatic islets? 307 78

Amiloride has been reported to reduce the positive inotropic and toxic actions of cardiac glycosides in patients as well as in experimental animals. To investigate the mechanism by which amiloride interacts with glycosides at the cellular level, we examined the effect of amiloride and ouabain on cellular Na content and uptake, Ca flux via Na-Ca exchange, and contractile state. Amiloride (1 mM) reduced cellular Na content by 16% (p less than 0.05) under normal conditions and by 45% in the presence of 1 mM ouabain compared to respective control values observed in the absence of amiloride. Amiloride (1 mM) reduced the initial rate of 45Ca uptake by 40% in ouabain (1 mM)-treated cells. This reduction of 45Ca uptake could be mimicked by lowering cellular Na content by 42%. Amiloride (1 mM) did not alter significantly the initial rate of 24Na uptake under normal conditions but reduced it by 32% in the presence of 3 microM ouabain. Amiloride (1 mM) produced a transient increase followed by a gradual decrease in the amplitude of cell motion over 60 min to 10% of control level. At other concentrations between 0.1 and 3 mM, amiloride produced negative inotropic effects only. Amiloride increased the concentration of ouabain needed to produce rhythm disturbances and contracture, and reduced Na-free contracture amplitude by 18%. These results are consistent with the view that amiloride antagonizes the arrhythmogenic effects of ouabain by inhibiting the glycoside-induced elevation in cellular Na content and, consequently, the increases in [Ca]i that occur via Na-dependent pathways. The reduced cellular Na content appears to be due to decreased Na influx via Na-H exchange.
Mol Pharmacol 1986 Apr
PMID:Effects of amiloride and ouabain on contractile state, Ca and Na fluxes, and Na content in cultured chick heart cells. 370 55

Amiloride and 38 amiloride analogues were tested for their inhibitory action on the Na+/H+ exchanger of chick skeletal muscle cells. The unsubstituted guanidino group of amiloride is essential for the activity of the molecule, since substitution of its results in almost inactive molecules. Selected modification of position 3 and 5 substituents of amiloride have a less dramatic effect on its potency. Substitution of the 5-amino group of amiloride with alkyl or alkenyl groups produced compounds that were up to 140 times more potent than amiloride in inhibiting the Na+/H+ exchanger. Such molecules would appear to be preferable to use in place of amiloride in biochemical and physiological studies of the Na+/H+ exchanger.
Mol Pharmacol 1984 Jan
PMID:Structure-activity relationships of amiloride and certain of its analogues in relation to the blockade of the Na+/H+ exchange system. 632 47

Amiloride (N-amidino-3,5-diamino-6-chloropyrazine carboxamide) reversibly inhibits Na+-dependent 45Ca2+ uptake (Na+-Ca2+ exchange) by plasmalemma-enriched vesicles prepared from microsomes of rat cerebral cortex and by vesicles from osmotically shocked synaptosomes. The drug inhibits Na+-dependent Ca2+ uptake in a competitive manner with a KI of 0.25-0.34 mM. Na+-dependent 45Ca2+ efflux from vesicles is also inhibited by extravesicular amiloride. The drug does not appear to affect nonmitochondrial ATP-dependent Ca2+ transport in these vesicle preparations. Membranes containing Na+-Ca2+ carrier can be solubilized in Na+-cholate and reconstituted into phospholipid vesicles. Na+-dependent Ca2+ uptake by the vesicles is inhibited by amiloride.
Mol Pharmacol 1983 Sep
PMID:Inhibition of Na+-Ca2+ exchange in rat brain by amiloride. 688 68

We have tested two hypotheses: 1) the cystic fibrosis transmembrane conductance regulator (CFTR) represents the predominant Cl conductance in the apical membrane of human tracheal epithelium, and 2) CFTR in this tissue is close to maximally activated under baseline conditions. In support of the first hypothesis, we found 1) when the level of differentiation of cultures was varied by varying the culture conditions, there was a significant positive correlation between the levels of CFTR and the magnitude of mediator-induced Cl secretion. 2) Amiloride-insensitive baseline short-circuit current (Isc) and mediator-induced increases in Isc were inhibited by diphenylamine-2-carboxylic acid (DPAC) but not by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a pharmacology consistent with passage of apical membrane Cl current through CFTR; Ca-activated Cl channels are inhibited by DIDS but not by DPAC. 3) Raising temperature from 22 degrees to 37 degrees C increased 125I efflux, and this increase was inhibited by DPAC and blockers of protein kinase A, but not by DIDS or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester. In support of the second hypothesis, we have earlier shown [M. Yamaya, W.E. Finkbeiner, S.Y. Chun, and J.H. Widdicombe. Am. J. Physiol. 262 (Lung Cell. Mol. Physiol. 6): L713-L724, 1992] that adenosine 3',5'-cyclic monophosphate (cAMP)-elevating agents are essentially without effect on Isc across primary cultures of human tracheal epithelium. Here, we further show that these agents are also usually without effect on 125I efflux; the mean increase in efflux in response to elevating cAMP was approximately 20% that of raising temperature from 22 degrees to 37 degrees C.
 ...
PMID:Role of CFTR in chloride secretion across human tracheal epithelium. 749 73

Previous studies on beta-adrenergic agonist regulation of ion transport in distal airways yielded discordant results. The present study was performed to further investigate this process in isolated bronchiolar epithelial cells and resolve the discrepancies. Epithelial enriched in rabbit nonciliated bronchiolar epithelial (Clara) cells responded to isoproterenol with a biphasic increase in transepithelial short circuit current (Isc) and decrease in transepithelial resistance (Rt). The first phase of the Isc response consisted of a transient, 11 microA/cm2 increase in current that was inhibited by HCO3(-)-free bathing solutions, but was not inhibited by amiloride, bumetanide, or Cl(-)-free bathing solutions. The ED50 for isoproterenol stimulation of the initial peak was 81 pM. The second phase was a prolonged, 27 microA/cm2 elevation in Isc. Amiloride in the apical bath inhibited basal Isc and the prolonged change in Isc induced by isoproterenol. Bumetanide in the basolateral bath and bilateral Cl(-)-free bathing solutions likewise inhibited the plateau phase of the isoproterenol response, and the inhibition was accentuated in the presence of amiloride. HCO3(-)-free bathing solutions did not inhibit the plateau phase. The ED50 for isoproterenol stimulation of the plateau phase was 6.3 nM. The bioelectric response to isoproterenol was mimicked by isobutylmethylxanthine (IBMX) and, to a lesser degree, by dibutyryl-cAMP. Culturing the cells in medium containing cholera toxin completely inhibited the bioelectric response, yet the preparations continued to respond to isoproterenol with an increase in cAMP production. These results indicated that beta-adrenergic stimulation of Clara cells induced electrogenic transepithelial secretion of Cl- and HCO3- and resolved discrepancies between previous studies.
Am J Respir Cell Mol Biol 1995 Sep
PMID:Beta-adrenergic regulation of Cl- and HCO3- secretion by Clara cells. 765 89


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