To evaluate the current status of the management of hypertensive patients in Japan, we investigated 907 treated hypertensive patients (486 females and 421 males; mean age, 66.7 years) followed by cardiologists.

Divalent mercury (Hg(2+)) blocked human skeletal Na(+) channels (hSkM1) in a stable dose-dependent manner (K(d) = 0.96 microM) in the absence of reducing agent. Dithiothreitol (DTT) significantly prevented Hg(2+) block of hSkM1, and Hg(2+) block was also readily reversed by DTT. Both thimerosal and 2,2'-dithiodipyridine had little effect on hSkM1; however, pretreatment with thimerosal attenuated Hg(2+) block of hSkM1. Y401C+E758C rat skeletal muscle Na(+) channels (mu1) that form a disulfide bond spontaneously between two cysteines at the 401 and 758 positions showed a significantly lower sensitivity to Hg(2+) (K(d) = 18 microM). However, Y401C+E758C mu1 after reduction with DTT had a significantly higher sensitivity to Hg(2+) (K(d) = 0.36 microM) than wild-type hSkM1. Mutants C753Amu1 (K(d) = 8.47 microM) or C1521A mu1 (K(d) = 8.63 microM) exhibited significantly lower sensitivity to Hg(2+) than did wild-type hSkM1, suggesting that these two conserved cysteinyl residues of the P-loop region may play an important role in the Hg(2+) block of the hSkM1 isoform. The heart Na(+) channel (hH1) was significantly more sensitive to low-dose Hg(2+) (K(d) = 0.43 microM) than was hSkM1. The C373Y hH1 mutant exhibited higher resistance (K(d) = 1.12 microM) to Hg(2+) than did wild-type hH1. In summary, Hg(2+) probably inhibits the muscle Na(+) channels at more than one cysteinyl residue in the Na(+) channel P-loop region. Hg(2+) exhibits a lower K(d) value (<1. 23 microM) for inhibition by forming a sulfur-Hg-sulfur bridge, as compared to reaction at a single cysteinyl residue with a higher K(d) value (>8.47 microM) by forming sulfur-Hg(+) covalently. The heart Na(+) channel isoform with more than two cysteinyl residues in the P-loop region exhibits an extremely high sensitivity (K(d) < 0. 43 microM) to Hg(+), accounting for heart-specific high sensitivity to the divalent mercury.

The present study investigated the protective effects of L-cysteine on the oxidation-induced blockade of Na + channel -subunits, hH1 (cardiac) and hSkM1 (skeletal), expressed in COS7 cells. Na + currents were recorded by the whole-cell patch clamp technique (n = 3-7). L-cysteine alone blocked hH1 and hSkM1 in a dose-dependent manner, with saturating L-cysteine block at 3,000 mol/L. Hg 2+ , a potent sulfhydryl oxidizing agent, blocked hH1 with a time to 50% inhibition (Time50%) of 20 s. Preperfusion of COS7 cells with 100 mol/L Lcysteine significantly slowed the Hg 2+ block of hH1 (Time50% = 179 s). L-cysteine did not prevent Hg 2+ block of hSkM1 (Time50% = 37 s) or the C373Y hH1 mutant (Time50% = 43 s). As for other sulfo-amino acids, homocysteine prevented the Hg 2+ block of hH1, with the Time50% (70 s) being significantly smaller than that of L-cysteine, whereas methionine did not prevent the Hg 2+ block of hH1. L-cysteine did not prevent the Cd 2+ block of hH1. These results indicate that L-cysteine selectively acts on heart-specific Cys 373 in the P-loop region of hH1 to prevent Cys 373 from the oxidation-induced sulfur-Hg-sulfur bridge formation. (Circ J 2002; 66: 846 -850)

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