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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have studied the acute effects of frusemide, triamterene and amiloride on potassium exchange, the action potential and mechanical function of isolated rabbit myocardium. 2. Potassium exchange in the myocardium was unaltered by these diuretics. 3. Frusemide and amiloride did not affect the action potential of rabbit papillary muscles. Triamterene caused a transient shortening of the action potential. 4. Frusemide and triamterene did not alter myocardial mechanical function in rabbit papillary muscles or the interventricular septum. Amiloride caused a reduction of about 5% in developed tension in two out of three papillary muscles.
Clin Sci Mol Med Suppl 1978 Dec
PMID:Acute effects of diuretics on potassium exchange, mechanical function and the action potential in rabbit myocardium. 28 46

The rat thyrotropin-releasing hormone (TRH) precursor (prepro-TRH) contains five copies of the TRH progenitor sequence linked together by intervening sequences. Recently, we have shown that the connecting peptides prepro-TRH-(160-169) (Ps4) and prepro-TRH-(178-199) (Ps5) are released from rat hypothalamic neurones in response to elevated potassium concentrations, in a calcium-dependent manner. In the present study, the role of voltage-operated calcium channels in potassium-induced release of Ps4 and Ps5 was investigated, using a perifusion system for rat hypothalamic slices. The release of Ps4 and Ps5 stimulated by potassium (70 mM) was blocked by the inorganic ions Co2+ (2.6 mM) and Ni2+ (5 mM). In contrast, the stimulatory effect of KCl was insensitive to Cd2+ (100 microM). The dihydropyridine antagonist nifedipine (10 microM) had no effect on K(+)-evoked release of Ps4 and Ps5. Furthermore, the response to KCl was not affected by nifedipine (10 microM) in combination with diltiazem (1 microM), a benzothiazepine which increases the affinity of dihydropyridine antagonists for their receptor. The dihydropyridine agonist BAY K 8644, at concentrations as high as 1 mM, did not stimulate the basal secretion of Ps4 and Ps5. In addition, BAY K 8644 had no potentiating effect on K(+)-induced release of Ps4 and Ps5. The marine cone snail toxin omega-conotoxin, a blocker of both L- and N-type calcium channels had no effect on the release of Ps4 and Ps5 stimulated by potassium. Similarly, the omega-conopeptide SNX-111, a selective blocker of N-type calcium channels, did not inhibit the stimulatory effect of potassium. The release of Ps4 and Ps5 evoked by high K+ was insensitive to the non-selective calcium channel blocker verapamil (20 microM). Amiloride (1 microM), a putative blocker of T-type calcium channels, did not affect KCl-induced secretion of the two connecting peptides. Taken together, these results indicate that two connecting peptides derived from the pro-TRH, Ps4 and Ps5, are released by K(+)-induced depolarization through activation of voltage-sensitive calcium channels. The calcium channels appear to have a pharmacological profile different from that of L- and N-type channels. Although, their insensitivity to low Cd2+ concentrations and sensitivity to Ni2+ ions would support the involvement of T-type calcium channels, the lack of effect of amiloride suggests that they belong to a yet undefined class of calcium channels.
Brain Res Mol Brain Res 1992 Jul
PMID:Omega-conotoxin- and nifedipine-insensitive voltage-operated calcium channels mediate K(+)-induced release of pro-thyrotropin-releasing hormone-connecting peptides Ps4 and Ps5 from perifused rat hypothalamic slices. 133 51

Amiloride, a potent blocker of the sodium channel in airway epithelium, has been administered by aerosol as a therapeutic agent for cystic fibrosis. Because amiloride in high concentration has been reported to interfere with cell functions, including adrenergic responses, we tested the ability of amiloride to inhibit beta-adrenergic responses in human tracheal epithelial cells. Amiloride (10(-4) M), applied from the basolateral surface of a cell monolayer, inhibited the changes in transepithelial potential and short circuit current to isoproterenol (10(-6) M). The stimulation of cyclic adenosine monophosphate (cAMP) synthesis by isoproterenol was inhibited in dose-dependent fashion by amiloride (P = 0.007 by multivariate ANOVA with multiple samples correction). Amiloride did not affect baseline transepithelial potential, short circuit current, basal cAMP levels, cAMP response to prostaglandin E2, or basal adenylate cyclase activity measured directly in membrane preparations. Therefore, it is unlikely that amiloride exerts a nonspecific toxic effect on adenylate cyclase, receptor-cyclase coupling, or substrate or cofactor supply. The binding of [125I]iodocyanopindolol (ICYP), a beta-adrenergic receptor antagonist, to membranes from human tracheal epithelial cells could be displaced by amiloride with IC50 = 410 microM; displacement was 70% at 10(-3) M amiloride. These data are most consistent with the hypothesis that amiloride inhibits beta-adrenergic responses in airway epithelial cells by occupying beta-adrenergic receptor sites. Therapeutic administration of amiloride should take into account its affinity for adrenergic receptors.
Am J Respir Cell Mol Biol 1992 Feb
PMID:Amiloride antagonizes beta-adrenergic stimulation of cAMP synthesis and Cl- secretion in human tracheal epithelial cells. 134 24

Various human alveolar macrophage (AM)-derived cytokines in the lungs have been shown to be present under conditions of normal homeostasis as well as during the pathogenesis of inflammation. Although extensive investigation has demonstrated the induction of cytokines from AM, relatively little is known regarding endogenous and exogenous regulation of their production. Several pharmacologic agents, including corticosteroids, cyclooxygenase inhibitors, prostaglandins, and methyl-xanthines have been examined for their role in the modulation of mononuclear phagocyte-derived cytokines. In this study, we examine the role of amiloride for the regulation of AM-derived interleukin (IL)-8, tumor necrosis factor (TNF), IL-6, and IL-1 beta. Amiloride in concentrations of 10(-4) to 10(-6) M, concentrations capable of being achieved in the distal airways via nebulization, were shown to inhibit lipopolysaccharide-stimulated, AM-derived IL-8 and TNF in both a time- and dose-dependent fashion. In addition, 5-(N,N-hexamethylene) amiloride hydrochloride, an amiloride analogue with specific sodium channel antiport inhibition, resulted in a similar dose-dependent suppression of lipopolysaccharide-stimulated, AM-derived IL-8 production. Furthermore, the suppressive effect of amiloride appeared to be at the level of mRNA for IL-8, TNF, IL-1 beta, and IL-6, whereas steady-state levels of beta-actin mRNA remained unaltered. These findings would suggest that amiloride has a potentially important modulating influence for the regulation of AM-derived cytokines.
Am J Respir Cell Mol Biol 1992 Jun
PMID:Suppression of human alveolar macrophage-derived cytokines by amiloride. 159 Oct 7

The influence of amiloride, a known blocker of Na/H exchange, on the positive inotropic action of alpha-adrenoceptor stimulation was investigated in isolated rat left atria. Amiloride (300 microM) rapidly (within 10 min) and reversibly abolished the positive inotropic effect of phenylephrine (10 microM; 3 microM propranolol present). Lower concentrations of amiloride inhibited the increase in contractile force caused by phenylephrine in a concentration dependent manner (IC50 of 50 microM). At a concentration of 50 microM, amiloride caused a rightward and downward shift in the concentration-response curve to phenylephrine. Amiloride (10 to 300 microM) affected to only a small extent the increased contractile force in the presence of inotropic interventions known to increase Ca2+ influx via L-type calcium channels (Bay K 8644) and the Na/Ca exchanger (reduced extracellular Na+). To provide evidence that amiloride inhibits the Na/H antiporter intact atria, a contracture that depends on Na+ influx by the Na/H antiporter was examined. Amiloride fully relaxed the contracture induced by ouabain (1 mM) or potassium-free solutions in the identical concentration range over which amiloride inhibited the positive inotropic effect of phenylephrine. Phenylephrine increased the rate of development and the peak amplitude of the amiloride-sensitive contracture (ouabain-induced). The inhibitory action of amiloride on the positive inotropic response to phenylephrine may, in part, be the result of inhibition of the Na/H antiporter.
J Mol Cell Cardiol 1990 Apr
PMID:Amiloride-sensitive actions of an alpha-adrenoceptor agonist and ouabain in rat atria. 169 95

The role of Na+ and H+ in the regulation of D2 receptor affinity for ligands was studied to determine the molecular mechanisms of this phenomenon. The potency of substituted benzamide derivatives and agonists at D2 receptors depended on the concentration of Na+ and H+, whereas the potency of other antagonists was relatively unaltered by changes in pH or Na+ concentration. The potency of agonists was generally decreased in the presence of NaCl or lowered pH. For example, in the absence of sodium the affinity of D2 receptors for dopamine was decreased 17-fold by lowering of the pH from 8.0 to pH 6.8. Addition of NaCl caused 2-4-fold decreases in affinity for most agonists. The affinity of the receptors for two substituted benzamide derivatives, on the other hand, was reduced 6-44-fold by elevated concentrations of H+ but was enhanced 7-24-fold in the presence of Na+. The regulation by H+ of the potency of dopamine was selective for D2 receptors, because binding of dopamine to neostriatal D1 receptors was unaffected by changes in pH. Decreasing of the pH from 8.0 or 7.3 to 6.8 facilitated the dissociation of the substituted benzamide ligand [125I]epidepride from D2 receptors but inhibited dissociation of [3H]spiperone. Furthermore, the presence of NaCl or lowered pH slowed inactivation of D2 receptors by N-ethylmaleimide. Together, these data suggest that the conformation of D2 receptors is regulated by both Na+ and H+. The affinity of D2 receptors for agonists and substituted benzamide antagonists varies according to the conformational state of the receptors, whereas other antagonists bind to both forms with approximately equal potency. Amiloride is a compound that interacts with many sodium-binding macromolecules. At equilibrium, amiloride inhibited the binding of [3H]spiperone and [125I]epidepride in a manner suggesting a more complex interaction than simple competitive inhibition. The rate of dissociation of both radioligands was enhanced by amiloride, as would be expected for allosteric inhibition of binding. The sensitivity of D2 receptors to pH, sodium, and amiloride may be a reflection of the ability of D2 receptors to modulate Na+/H+ exchange.
Mol Pharmacol 1991 Apr
PMID:Regulation of dopamine D2 receptors by sodium and pH. 201 57

Calcium uptake was measured using 47Ca2+ in the isolated and arterially perfused interventricular septum of the rabbit. Experiments were undertaken to determine whether calcium uptake on reoxygenation is linked to recovery of mechanical function and whether calcium uptake is through the sodium-calcium exchange mechanism. During substrate-free hypoxia for 45 min total tissue calcium remained unchanged but immediately upon reoxygenation there was a substantial net gain of calcium. Recovery of mechanical function upon reoxygenation was inversely related to the increase in tissue calcium. Activation of sodium-calcium exchange by perfusion with a low-sodium, zero-potassium, sucrose solution also increased tissue calcium and the relation to mechanical recovery was similar to that observed on reoxygenation. The sodium-calcium exchange mechanism was not affected by hypoxia and could be demonstrated during perfusion with a substrate-free hypoxic solution. Lithium (100 mM) substitution for sucrose prevented the calcium influx induced by a low-sodium and zero-potassium perfusate under normoxic conditions. Lithium substitution early during hypoxia or on reoxygenation did not affect the increase in myocardial calcium on reoxygenation. Amiloride (10(-4)M), presumed to inhibit sodium-hydrogen exchange during hypoxia, had no effect upon reoxygenation induced calcium uptake. It is concluded that the increase in calcium uptake that occurs on reoxygenation after a period of substrate-free hypoxia is related to mechanical recovery. Sodium-calcium exchange may contribute to calcium uptake on reoxygenation in this experimental model but is not the major mechanism.
J Mol Cell Cardiol 1990 Oct
PMID:Calcium exchange in rabbit myocardium during and after hypoxia: role of sodium-calcium exchange. 209 31

Beta-cell-rich pancreatic islets from ob/ob-mice were used for evaluating the early effects of hypotonic stress. The beta-cells responded to an abrupt lowering of the osmotic pressure by 102 mOsm with both a transient stimulation of insulin release (peak value 25 times above basal) and a loss of potassium without major effects on sodium. The secretory response was obtained also in the presence of 100 microM quinine or 20 mM tetraethylammonium+. The loss of potassium was not affected by 20 mM glucose or 10 microM bumetanide, but became less apparent in the presence of 100 microM quinine and disappeared when the islets were exposed to 20 mM tetraethylammonium+. Amiloride and high concentrations of the hypoglycemic sulfonylureas tolbutamide and glibenclamide had only a slight suppressive action on potassium mobilization. Patch clamp analyses revealed an increased frequency of small channel openings after exposure to the hypotonic medium. It is concluded that the pancreatic beta-cells have the ability for a regulatory volume decrease involving activation of tetraethylammonium-sensitive K+ conductance. The stimulation of insulin release obtained by lowering the osmotic pressure seems to be related to the entry of water rather than to the ion movements responsible for the readjustment of the beta-cell volume.
Mol Cell Biochem 1990 Jul 17
PMID:Regulatory volume decrease of pancreatic beta-cells involving activation of tetraethylammonium-sensitive K+ conductance. 223 3

The direct effects of amiloride on myocardial contractility were examined in electrically stimulated left atrial muscle of guinea-pig heart. Amiloride (0.3 to 1.5 mM) produced a positive inotropic effect which, at higher concentrations, was followed by a decline in developed tension. These effects were not accompanied by contracture or arrhythmia and were not affected by a combination of phentolamine, nadolol, cimetidine, tripelennamine and atropine. The above concentrations of amiloride prolonged the action potential duration during the development of the positive inotropic effect; however, no further change in the action potential duration was observed during the decline in developed tension caused by high concentrations of amiloride. Myocardial membrane Na,K-ATPase, ouabain-sensitive 86Rb+ uptake and Na+-dependent Ca2+ efflux from sarcolemmal membrane vesicles were all inhibited by amiloride. The positive inotropic effect of the agent is reduced and the negative inotropic action is enhanced in low Na+ solutions, i.e., under conditions likely to favor Ca2+ influx via Na+/Ca2+ exchange. These results suggest that amiloride, under the present conditions, has a complex interaction with cardiac muscle fibers. Amiloride may produce its inotropic effects in guinea-pig atrial muscle by several mechanisms including sodium pump inhibition, Na+/Ca2+ exchange inhibition, prolongation of the action potential duration, and/or actions such as Na+/H+ exchange inhibition which were not directly addressed in this study.
J Mol Cell Cardiol 1986 Feb
PMID:Amiloride: effects on myocardial force of contraction, sodium pump and Na+/Ca2+ exchange. 242 Sep 97

Oocytes of the frog Xenopus laevis express various exogenous neurotransmitter receptors and ion channels when injected with RNA from excitable tissues. The oocytes serve as a convenient model system in which modulation of neurotransmitter responses can be studied. We examined the effects of activators and an inhibitor of protein kinase C (PKC) on responses to serotonin (5-HT), acetylcholine (ACh), kainate, and gamma-aminobutyric acid (GABA) in oocytes injected with RNA from rat brain. The PKC activators beta-phorbol esters 4 beta-phorbol-12-myristate-13-acetate (PMA) and 4 beta-phorbol-12,13-dibutyrate (PDBu), as well as the synthetic diacylglycerol, 1-oleyl-2-acetylglycerol (OAG), significantly inhibited the responses to 5-HT and ACh (both known to be mediated by mobilization of intracellular Ca2+); the first (transient) phase of these responses was affected stronger than the second, slow phase. PKC activators also reduced the response to GABA. The effect of PDBu on the response to kainate was dual; either inhibition or potentiation were observed at different concentrations of PDBu. The inactive analogue of PMA, the alpha-PMA, was without effect on the responses to 5-HT and GABA. The PKC inhibitor 1,5-isoquinolinesulfonyl-2-methylpiperazine (H7) suppressed the inhibitory effect of PDBu on 5-HT response. Amiloride, a blocker of the Na+/H+ exchange (which is known to be activated by PKC in some tissues), did not suppress the effects of PDBu. We concluded that activation of PKC down-regulates the responses to 5-HT, ACh and GABA, and has a dual effect on response to kainate. Possible mechanisms of these effects are discussed.
Brain Res Mol Brain Res 1989 May
PMID:Protein kinase C modulates neurotransmitter responses in Xenopus oocytes injected with rat brain RNA. 247 Oct 32


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