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Chemical Compound Review

Benzamil     3,5-diamino-N-(N'- benzylcarbamimidoyl)-6...

Synonyms: GNF-Pf-192, Lopac-B-2417, CHEMBL212579, BSPBio_000693, BSPBio_001580, ...
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Disease relevance of Benzamil

  • The ischemia-induced Ca influx during the second 2.5 min of ischemia was attenuated 25% by nifedipine (50 microM) and an additional 35% by the Na/Ca exchange inhibitor benzamil (100 microM) [1].
  • Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis [2].
  • CONCLUSIONS: These findings suggest that benzamil-sensitive brain sodium channels mediate the increase in brain OLC and the subsequent hypertension induced by increased CSF Na+ [3].
  • The observation suggests that in acutely injured lung treated with HFOV an ENaC blocker, benzamil, can be applied as a therapeutic drug for acute lung injury combing with HFOV [4].
  • Using patch clamp technique, however, it turned out that neither amiloride nor benzamil influenced mechanically induced currents in ganglion nodosum cells in vitro, stimulated by hypoosmotic stress [5].

High impact information on Benzamil

  • The open/closed transitions showed slow kinetics, had a slope conductance of 6-11 pS, and were sensitive to amiloride and benzamil [6].
  • Electrophysiological measurements on lung epithelial cells demonstrated the presence of a Na+ channel that is inhibited by amiloride (K0.5 = 90 nM) and some of its derivatives such as phenamil (K0.5 = 19 nM) and benzamil (K0.5 = 14 nM) but not by ethylisopropylamiloride [7].
  • Na(+)-Ca2+ exchanger blockers (bepridil, benzamil, dichlorobenzamil) significantly protected the optic nerve from anoxic injury [8].
  • Benzamil did not rescue the lack of secretion to forskolin (50 glands, 6 CF subjects) nor did it increase the rate of cholinergically mediated mucus secretion from CF glands [9].
  • LSS induced a dose-dependent and reversible increase in benzamil-sensitive whole cell Na+ currents in oocytes expressing alphabetagamma ENaC [10].

Chemical compound and disease context of Benzamil


Biological context of Benzamil

  • Bromobenzamil is a photoactive amiloride analog with potency similar to benzamil in inhibiting sodium transport (IC50 = 5 nM) and binding to the sodium channel (Kd = 6 nM) [14].
  • We also demonstrated a low benzamil affinity binding site (apparent Kd = 370 nM) in rabbit ATII cell membranes and both high and low benzamil affinity binding sites (apparent Kd = 6 nM and 230 nM) in bovine kidney membranes using [3H]Br-benzamil as a ligand [15].
  • Benzamil, which blocks Na+/Ca2+ exchange, did not alter chemotaxis by itself but prevented the suppressive effects of each of the polyvalent cations on motility [16].
  • This transneural tube potential can be collapsed by iontophoresis of Na+ channel blockers amiloride or benzamil into the lumen, leading to severe cranial defects and incomplete morphogenesis [17].
  • RESULTS: In Wistar rats infused i.c.v. with aCSF, benzamil did not affect blood pressure or brain and peripheral OLC concentrations [3].

Anatomical context of Benzamil

  • Sodium enters tight epithelia across the apical plasma membrane through a sodium channel, a process inhibited by submicromolar concentrations of amiloride and benzamil [14].
  • The pharmacological profile of the channel (phenamil greater than benzamil greater than amiloride) is very similar to that of the epithelium Na+ channel of mammalian kidney and of frog epithelia [18].
  • The rank order potency for inhibition of microvillus membrane [3H]MIA binding by amiloride analogs was: MIA (I50 approximately 10 nM) greater than amiloride (I50 approximately 200 nM) greater than benzamil (I50 approximately 1200 nM) [19].
  • Using membrane vesicles from bovine kidney cortex, we found that sodium transport through the sodium channel was inhibited by benzamil with an IC50 of 4 nM [14].
  • Mutants of the PY motif in beta- and gamma-ENaC subunits (beta-Y618A, beta-P616L, beta-R564stop, and gamma-K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current (Isc) [20].

Associations of Benzamil with other chemical compounds

  • Both the divalent cations and benzamil also inhibited the rise in cytoplasmic Ca2+ as monitored by fura-2 fluorescence: these agents reduced peak cytosolic Ca2+ levels after N-formyl-methionyl-leucyl-phenylalanine stimulation to values seen in the absence of extracellular Ca2+ [21].
  • NH4Cl-induced 22Na uptake by zona glomerulosa cells was dose dependently inhibited by ethylisopropylamiloride (EIPA), amiloride, and benzamil with ED50 values of 0.02, 4.30, and 199 microM, respectively [22].
  • The inward antiport of K+ is inhibited noncompetitively by NH4+ and is also sensitive to benzamil and to 5-N-substituted amiloride analogues with I50 values near 20 microM [23].
  • Selective DEG/ENaC inhibition, with low doses of amiloride and benzamil, abolishes pressure-induced constriction and increases in cytosolic Ca(2+) and Na(+) without diminishing agonist-induced responses in isolated mouse interlobar arteries [24].
  • Isc was decreased by amiloride (IC50 of amiloride-sensitive Isc = 0.3 x 10(-6) M) and benzamil (IC50 of benzamil-sensitive Isc = 0.3 x 10(-7) M) but was unaffected by dimethyl amiloride (10(-4) M) [25].

Gene context of Benzamil

  • The activity of NHE7 was also found to be relatively insensitive to inhibition by amiloride but could be antagonized by the analogue benzamil and the unrelated compound quinine [26].
  • Addition of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 100 microM) or benzamil (100 microM) to the apical solution markedly reduced the secretin-induced I(sc) increase in the transient phase [27].
  • Since the SERCA pump did not appear to be involved in shaping the decay phase of the agonist-evoked Ca(2+) transient, we inhibited the PMCA pump with carboxyeosin, and NCX with benzamil and by removing extracellular Na(+) [28].
  • The effects of TGF-beta were not secondary to the decrease in Na(+) transport per se, inasmuch as benzamil inhibited the increase in Na(+) transport but did not block the increase in pump capacity or Na(+)-K(+)-ATPase mRNA [29].
  • Benzamil may inhibit contraction by the inhibition of both MLC kinase and CaM [30].

Analytical, diagnostic and therapeutic context of Benzamil

  • Amiloride [10(-)3 M (n = 16), 3 x 10(-)3 M (n = 9), 6 x 10(-)3 M (n = 7), 10(-)2 M (n = 3)] or benzamil [1.7 x 10(-)3 M (n = 7), and 7 x 10(-)3 M (n = 5)] were administered to the nasal surface via an aerosol generated by a jet nebulizer and a nasal mask [2].
  • In vivo, the endocochlear potential was recorded in guinea pigs under normoxic and hypoxic conditions after endolymphatic perfusion of ENaC inhibitors (amiloride, benzamil) dissolved either in K-rich or Na-rich solutions [31].
  • 2. At -84 mV transducer currents were reversibly blocked by the extracellular application of the pyrazinecarboxamides amiloride, benzamil, dimethylamiloride, hexamethyleneiminoamiloride, phenamil and methoxynitroiodobenzamil with half-blocking concentrations of 53, 5.5, 40, 4.3, 12 and 1.8 microM, respectively [32].
  • The TNTP can be markedly reduced for several hours by injection of the Na+ channel blockers amiloride or benzamil into the lumen by iontophoresis through microelectrodes [33].
  • At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 or its vehicle, or with benzamil (4 or its vehicle, using osmotic minipumps [34].


  1. Intracellular calcium levels and calcium fluxes in the CA1 region of the rat hippocampal slice during in vitro ischemia: relationship to electrophysiological cell damage. Lobner, D., Lipton, P. J. Neurosci. (1993) [Pubmed]
  2. Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis. Hofmann, T., Stutts, M.J., Ziersch, A., Rückes, C., Weber, W.M., Knowles, M.R., Lindemann, H., Boucher, R.C. Am. J. Respir. Crit. Care Med. (1998) [Pubmed]
  3. Brain sodium channels and central sodium-induced increases in brain ouabain-like compound and blood pressure. Wang, H., Leenen, F.H. J. Hypertens. (2003) [Pubmed]
  4. Benzamil, a blocker of epithelial Na(+) channel-induced upregulation of artery oxygen pressure level in acute lung injury rabbit ventilated with high frequency oscillation. Taguchi, N., Niisato, N., Sawabe, Y., Miyazaki, H., Hirai, Y., Marunaka, Y. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  5. Putative role of epithelial sodium channels (ENaC) in the afferent limb of cardio renal reflexes in rats. Ditting, T., Linz, P., Hilgers, K.F., Jung, O., Geiger, H., Veelken, R. Basic Res. Cardiol. (2003) [Pubmed]
  6. rENaC is the predominant Na+ channel in the apical membrane of the rat renal inner medullary collecting duct. Volk, K.A., Sigmund, R.D., Snyder, P.M., McDonald, F.J., Welsh, M.J., Stokes, J.B. J. Clin. Invest. (1995) [Pubmed]
  7. The lung amiloride-sensitive Na+ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning. Voilley, N., Lingueglia, E., Champigny, G., Mattéi, M.G., Waldmann, R., Lazdunski, M., Barbry, P. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  8. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na(+)-Ca2+ exchanger. Stys, P.K., Waxman, S.G., Ransom, B.R. J. Neurosci. (1992) [Pubmed]
  9. Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands. Joo, N.S., Irokawa, T., Robbins, R.C., Wine, J.J. J. Biol. Chem. (2006) [Pubmed]
  10. Epithelial Na+ channels are activated by laminar shear stress. Carattino, M.D., Sheng, S., Kleyman, T.R. J. Biol. Chem. (2004) [Pubmed]
  11. Intracellular Ca2+ mediates the cytotoxicity induced by bepridil and benzamil in human brain tumor cells. Lee, Y.S., Sayeed, M.M., Wurster, R.D. Cancer Lett. (1995) [Pubmed]
  12. The effects of benzamil on in vitro contracture responses of human skeletal muscle to halothane. Hopkins, P.M., Ellis, F.R., Halsall, P.J. Gen. Pharmacol. (1994) [Pubmed]
  13. Benzamil blockade of brain Na+ channels averts Na(+)-induced hypertension in rats. Nishimura, M., Ohtsuka, K., Nanbu, A., Takahashi, H., Yoshimura, M. Am. J. Physiol. (1998) [Pubmed]
  14. Photoaffinity labeling of the epithelial sodium channel. Kleyman, T.R., Yulo, T., Ashbaugh, C., Landry, D., Cragoe, E., Karlin, A., Al-Awqati, Q. J. Biol. Chem. (1986) [Pubmed]
  15. Biochemical evidence for the presence of an amiloride binding protein in adult alveolar type II pneumocytes. Oh, Y., Matalon, S., Kleyman, T.R., Benos, D.J. J. Biol. Chem. (1992) [Pubmed]
  16. Polyvalent cations inhibit human neutrophil chemotaxis by interfering with the polymerization of actin. Simchowitz, L., Cragoe, E.J. J. Biol. Chem. (1990) [Pubmed]
  17. Embryonic neuroepithelial sodium transport, the resulting physiological potential, and cranial development. Shi, R., Borgens, R.B. Dev. Biol. (1994) [Pubmed]
  18. A new type of amiloride-sensitive cationic channel in endothelial cells of brain microvessels. Vigne, P., Champigny, G., Marsault, R., Barbry, P., Frelin, C., Lazdunski, M. J. Biol. Chem. (1989) [Pubmed]
  19. High affinity binding of amiloride analogs at an internal site in renal microvillus membrane vesicles. Desir, G.V., Cragoe, E.J., Aronson, P.S. J. Biol. Chem. (1991) [Pubmed]
  20. Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin. Auberson, M., Hoffmann-Pochon, N., Vandewalle, A., Kellenberger, S., Schild, L. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  21. A role for Na+/Ca2+ exchange in the generation of superoxide radicals by human neutrophils. Simchowitz, L., Foy, M.A., Cragoe, E.J. J. Biol. Chem. (1990) [Pubmed]
  22. Regulation of aldosterone biosynthesis by Na+/H+ antiport: relationships between intracellular pH and angiotensin II. Horiuchi, T., Nguyen, T.T., Cragoe, E.J., De Léan, A. Endocrinology (1989) [Pubmed]
  23. Kinetic properties of the K+/H+ antiport of heart mitochondria. Brierley, G.P., Jung, D.W. Biochemistry (1990) [Pubmed]
  24. Vascular ENaC proteins are required for renal myogenic constriction. Jernigan, N.L., Drummond, H.A. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  25. Sodium channel but neither Na(+)-H+ nor Na-glucose symport inhibitors slow neonatal lung water clearance. O'Brodovich, H., Hannam, V., Rafii, B. Am. J. Respir. Cell Mol. Biol. (1991) [Pubmed]
  26. Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. Numata, M., Orlowski, J. J. Biol. Chem. (2001) [Pubmed]
  27. Activation of transepithelial ion transport by secretin in human intestinal Caco-2 cells. Fukuda, M., Ohara, A., Bamba, T., Saek, Y. Jpn. J. Physiol. (2000) [Pubmed]
  28. Ca2+ uptake by the endoplasmic reticulum Ca2+-ATPase in rat microvascular endothelial cells. Moccia, F., Berra-Romani, R., Baruffi, S., Spaggiari, S., Signorelli, S., Castelli, L., Magistretti, J., Taglietti, V., Tanzi, F. Biochem. J. (2002) [Pubmed]
  29. Mechanisms of inactivation of the action of aldosterone on collecting duct by TGF-beta. Husted, R.F., Sigmund, R.D., Stokes, J.B. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  30. Direct inhibition of contractile apparatus by analogues of amiloride in the smooth muscle of guinea-pig taenia caecum and chicken gizzard. Ozaki, H., Moriyama, T., Karaki, H., Kohama, K., Cragoe, E.J. Biochem. Pharmacol. (1989) [Pubmed]
  31. Location and function of the epithelial Na channel in the cochlea. Couloigner, V., Fay, M., Djelidi, S., Farman, N., Escoubet, B., Runembert, I., Sterkers, O., Friedlander, G., Ferrary, E. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
  32. Block by amiloride and its derivatives of mechano-electrical transduction in outer hair cells of mouse cochlear cultures. Rüsch, A., Kros, C.J., Richardson, G.P. J. Physiol. (Lond.) (1994) [Pubmed]
  33. Uncoupling histogenesis from morphogenesis in the vertebrate embryo by collapse of the transneural tube potential. Borgens, R.B., Shi, R. Dev. Dyn. (1995) [Pubmed]
  34. Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI. Huang, B.S., Leenen, F.H. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
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