Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00514 (Amiloride)
 1,513 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natriuretic agent amiloride induces a shift of the dose-response curve of particulate guanylate cyclase to atrial natriuretic factor (ANF) to the left. The ANF concentration for half-maximal activation of guanylate cyclase is shifted from 20 to 3 nM in the presence of 100 microM amiloride. This effect is observed with GTP*Mn2+, but not with GTP*Mg2+ as substrate. Amiloride derivatives, which inhibit a specific Na+-channel, also shift the dose-response curve to the left. These data suggest that some of the effects of amiloride may be mediated by an increased sensitivity of particulate guanylate cyclase to ANF.
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PMID:Amiloride increases the sensitivity of particulate guanylate cyclase to atrial natriuretic factor. 245 2

The effect of amiloride on the hormonal regulation of adenylate cyclase was studied in the rat anterior pituitary. The diuretic did not alter basal adenylate cyclase but augmented the enzyme activity in an irreversible manner in the presence of guanosine 5'-O-(thiotriphosphate) (GTP gamma S) stimulated adenylate cyclase at lower concentrations and inhibited at higher concentrations. Amiloride treatment enhanced the stimulatory and abolished the inhibitory phase of GTP gamma S action. In addition, amiloride also attenuated the inhibitory effects of atrial natriuretic factor (ANF 99-126) and angiotensin II on cAMP levels and adenylate cyclase activity. On the other hand, amiloride showed an additive effect on the stimulation exerted by corticotropin-releasing factor and vasoactive intestinal peptide on adenylate cyclase in anterior pituitary and on isoproterenol-stimulated cAMP levels in cultured vascular smooth muscle cells. Pertussis toxin, in the presence of [alpha-32 P]NAD, catalyzed the ADP-ribosylation of two protein bands of Mr 41,000 and 39,000, referred to as Gi and Go, respectively, in the anterior pituitary, and 40,000-Da protein in the aorta, referred to as Gi. Amiloride treatment inhibited the labeling of all these bands in a concentration- and time-dependent manner. Similarly, the pertussis toxin-catalyzed ADP-ribosylation of purified Gi from bovine brain was also inhibited by amiloride treatment. However, amiloride had no significant effect on the cholera toxin-catalyzed ADP-ribosylation of Gs. These data suggest that amiloride interacts with the guanine nucleotide regulatory proteins Gi and Go. Modification of Gi results in the attenuation of hormone-induced adenylate cyclase and cAMP inhibition. However, the interaction between amiloride and Go and the consequent Ca2+ mobilization and phosphatidylinositol turnover have to be investigated.
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PMID:Amiloride interacts with guanine nucleotide regulatory proteins and attenuates the hormonal inhibition of adenylate cyclase. 254 11

Amiloride has previously been shown to facilitate receptor binding of atrial natriuretic factor (ANF) to membranes of adrenal cortex and to enhance ANF induced inhibition of steroid secretion in vitro. This interaction of amiloride and ANF also holds true for the cardiovascular system. In precontracted rabbit aortic strips the relaxing effect induced by the combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was overadditional. The production of cyclic guanosine monophosphate (cGMP), which parallels ANF induced relaxations of vascular strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of ANF (10(-8) mol/l). In spontaneously hypertensive rats ANF-induced decreases in blood pressure were potentiated by amiloride. Post ischemia reperfusion arrhythmias in isolated rat hearts were reduced by ANF. Amiloride increased this effect. The binding experiments revealed an interaction of amiloride and ANF on the receptor level. Binding of labeled ANF to aortic tissue was concentration-dependently increased by amiloride. Addition of ATP had the opposite effect. Therefore it can be suggested that amiloride and ATP interfere with a mechanism regulating the sensitivity of the vascular ANF-receptor for its ligand regarding binding and signal transforming presumably by a kinase mediated phosphorylation/dephosphorylation process.
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PMID:Potentiation of the effects of atrial natriuretic factor on the cardiovascular system by amiloride. 255 51

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
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PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

The interaction of atrial natriuretic factor (ANF) with the diuretic amiloride was studied in bovine adrenal zona glomerulosa. Amiloride enhances 2 to 3-fold high affinity binding of [125I] ANF to zona glomerulosa membrane receptor with an ED50 of 10 microM. This effect is due to a recruitement of high affinity receptor sites and to an increase of their affinity from a Kd of 23 to 8 pM. This enhancing effect is almost equipotently elicited by guanabenz, while clonidine is 20-fold less potent and arginine is inactive. ATP reduces by 30 to 50% [125I] ANF binding with an IC50 of 50 microM. Amiloride and ATP opposite effects on [125I] ANF binding are mutually competitive. Low concentrations of amiloride (less than 100 microM) potentiate the inhibitory effect of ANF in hormone-stimulated steroid secretion with a 3-fold decrease in ANF IC50 at 10 microM amiloride. Higher concentrations of amiloride (greater than 100 microM) directly inhibit aldosterone secretion with an IC50 of 500 microM and a maximum of 80 to 100% reversal of stimulation by various secretagogues. These results indicate that amiloride synergistically potentiates ANF inhibitory action by altering ANF receptor binding properties. They also suggest a role for sodium transport and for phosphorylation-dephosphorylation mechanisms in the mode of action of ANF.
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PMID:Amiloride potentiates atrial natriuretic factor inhibitory action by increasing receptor binding in bovine adrenal zona glomerulosa. 301 11

Previous studies reported that atrial natriuretic factor (ANF) decreased lung edema in guinea pigs. To determine whether ANF protects against lung edema by increasing active Na+ transport and lung edema clearance, ANF (10(-7) M) was instilled into the air spaces (n = 5) or perfused through the pulmonary circulation (n = 5) of isolated perfused liquid-filled rat lungs. These animals were compared with five control rats and four rats having amiloride (10(-5) M) instilled into the air space. Amiloride reduced lung edema clearance by 65%, perfused ANF reduced lung edema clearance by 32%, and instilled ANF did not change edema clearance compared with responses in control rats after 70 min of experimental protocol. Passive Na+ movement increased by 91% with perfused ANF and by 52% with instilled ANF compared with that in control rats. Albumin flux from the perfusate into the air space increased in ANF-perfused lungs compared with control lungs (P < 0.05) but not when ANF or amiloride was instilled into the air spaces. These results suggest that ANF instilled into rat air spaces or perfused through the pulmonary circulation increases lung epithelial permeability and that ANF perfused through the pulmonary circulation decreases lung edema clearance due to impaired active Na+ transport. Conceivably, the previously observed protective effect of ANF was due to reduced pressures across the pulmonary circulation, which resulted in less edema formation.
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PMID:ANF decreases active sodium transport and increases alveolar epithelial permeability in rats. 750 5