Disease relevance of C13752

• Mutations conferring resistance to phenamil and amiloride, inhibitors of sodium-driven motility of Vibrio parahaemolyticus [1].
• Sodium-calcium exchange, as assessed by twin rapid cooling contractures, was not inhibited by phenamil [2].
• Like E. coli, but unlike wild-type V. cholerae, motility of some V. cholerae strains containing the hybrid motor was inhibited by the protonophore carbonyl cyanide m-chlorophenylhydrazone under neutral as well as alkaline conditions but not by the sodium motor-specific inhibitor phenamil [3].
• Cystic fibrosis and non-cystic-fibrosis human nasal epithelium show analogous Na+ absorption and reversible block by phenamil [4].

High impact information on C13752

• Thus, cecum exhibits a distinct type of electrogenic Na electrogenic Na absorption which is partially dependent on the presence of Cl and HCO3, not blocked by amiloride but by phenamil [5].
• Phenamil inhibits electrogenic sodium absorption in rabbit ileum [6].
• The sodium-channel-blocking drugs phenamil and amiloride inhibit rotation of the polar flagellum and therefore can be used to probe the architecture of the motor [1].
• Benzamil, phenamil, and 2',4'-dichlorobenzamil, analogues of amiloride which selectively block Na+/Ca2+ exchange in neutrophils, likewise suppressed the release of O(-2) with apparent Ki values of approximately 30 microM [7].
• Co-expression of the PomA D148Y and PomB P16S proteins resulted in an Mpar phenotype which seemed to be less sensitive to phenamil than either of the single mutants, although motility was more severely impaired in the absence of inhibitors [8].

Biological context of C13752

• The steadier rotation of the Mpa(r) motors can be explained by an increase in the phenamil dissociation rate from a sodium channel of the motor, which suggests that a phenamil-specific binding site of the motor is mutated in the Mpa(r) strain [9].
• A concentration of 50 microM phenamil completely inhibited the motility of strain RA-1 but showed no effect on the membrane potential, the intracellular pH, or Na(+)-coupled amino acid transport, which was consistent with the fact that there was no effect on cell growth [10].
• We have demonstrated recently that prolongation of cardiac action potential duration with phenamil is due to inhibition of the inwardly rectifying potassium current without any direct effect on cardiac calcium channels [2].
• On the other hand, phenamil, an amiloride analog, inhibited motor rotation without affecting cell growth [10].
• Kinetics experiments, equilibrium binding studies and competition experiments between [3H]phenamil and unlabelled phenamil indicate that phenamil recognizes a single family of binding sites with a Kd value of 20 nM and a maximum binding capacity of 11.5 pmol/mg of protein [11].

Anatomical context of C13752

• The biochemical basis for these differences was analyzed by using phenamil, the most potent inhibitor known so far for the epithelium Na+ channel [12].
• Effects of phenamil on potassium and calcium channels of guinea pig ventricular myocytes [13].
• In vitro potency, maximal efficacy, rate of recovery from maximal block of ENaC, and rate of drug absorption were compared for amiloride, benzamil, and phenamil in cultured human and ovine bronchial epithelial cells [14].
• Phenamil did not alkalinize or acidify the cytosol (measured with 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, BCECF) during the induction of positive inotropy, therefore the sodium-hydrogen exchange is not affected [2].
• Sarcoplasmic reticulum does not appear to be essential for phenamil-induced inotropy, because cyclopiazonic acid and ryanodine do not abolish this effect [2].

Associations of C13752 with other chemical compounds

• Micropuncture studies showed that follicles had a lumen-negative, basal-positive transepithelial potential difference which was progressively reduced in magnitude by the serial addition of bumetanide (10 microM) and phenamil (1 microM) [15].
• Dichlorobenzamil, phenamil and other amiloride analogs (1-100 microM) elicit transient tension in rabbit skinned muscle fibers [16].
• Application of phenamil (100 microM) to the anterior tongue blocked integrated responses to NaCl from the chorda tympani nerve by 98.04%, but had no significant effect on sucrose or NH4Cl [17].

Gene context of C13752

• The [3H]phenamil binding of alpha ENACa resembles that of alpha ENAC, being inhibited more potently by phenamil (Kd = 65 nM) than amiloride [18].
• Na(+) influx was inhibited by amiloride (10(-4) mol l(-1)) and by two of its analogs, phenamil (4 x 10(-5) mol l(-1)) and HMA (4 x 10(-5) mol l(-1)), with the latter being slightly more potent, while Cl(-) fluxes were unaffected [19].
• Astonishingly, phenamil, a blocker which irreversibly blocks all epithelial Na+ channels hitherto described, inhibited the Na+ conductances of human nasal epithelium in a completely reversible way, but nevertheless with high affinity (non-CF: K1/2 = 12.5 +/- 1.2 nM; CF: K1/2 = 17.1 +/- 1.1 nM) [4].
• Under voltage clamped conditions, H+ gradient-dependent 22Na uptake, however, was unaffected by phenamil (20 microM), but was almost completely inhibited by DMA, HMA and EIPA (20 microM each) [20].

References