PubMed · 716032
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D K Gilding, G F Green, D Annis, J G Wilson. 1978. Soft tissue ingrowth into hydrogels.. https://pubmed.ncbi.nlm.nih.gov/716032/
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Four types of ion-selective channels were found by the patch-clamp technique in the human erythroleukemia K562 cells. I) in cell-attached configuration at potentials less negative than -40 mV an 8 ps channel was detected. The potential dependence of channel activity suggests that this is the TTX-sensitive Na+ channel. II) A cation-selective channel was observed with equal permeability for Na+ and K+ and a potential-independent single-channel conductance of 19 pS. The channel is activated by intracellular Ca2+ and inhibited by TEA, III) A predominantly anion-selective channel was identified with the selectivity sequence NO3- > J- > Cl- = Br- >> SO4(2-). The single-channel conductance shows outward rectification, and is in symmetrical NaCl solution 19 pS at -60 mV and 54pS at +50 mV. The open- and closed-time distributions suggest one open and at least four closed states. At submicromolar concentrations, the open state is blocked by H2DIDS leading to channel flicker between open and blocked channel; higher concentrations (apparent KI = 6.8 uM) lead to a longer-lasting blocked state. Both components of inhibition are reversible. IV) In addition, an 8 pS, Na(+)- and K(+)- selective channel could be induced by application of palytoxin. For channel activity, the presence of extracellular Na+ is essential. It is assumed that the Na+, K(+)-pump molecule is involved in the channel formation. Similarly, it is discussed whether the anion-selective channel represents a pore conformation of an electrically silent anion exchanger.
We examined the nature of the palytoxin (PTX)-induced channel and its relevance to the Ca2+ mobilizing effect of the toxin on smooth muscle cells isolated from rabbit portal vein using whole-cell voltage-clamp and microfluorimetric techniques. PTX (1 nM) induced a sustained, irreversible inward current at a holding potential of -40 mV. The PTX-induced current reversed at 0.5 +/- 0.6 mV, and the PTX-induced channel permitted the passage of Na+, K+, Cs+ and, to a lesser extent, Li+, but not choline+ or Ca2+. During the sustained phase of the current, superfusion of Ni2+ (5 mM), La3+ (0.5 mM) or 2,4-dichlorobenzamil (2,4-DCB, 25 microM) reduced the current amplitude and decreased the slope conductance without changing the reversal potential. In 5 of 7 experiments, ouabain transiently increased the PTX-induced inward current and shifted the reversal potential in a positive direction. Subsequently, ouabain inhibited the current in every cell. PTX (10 nM) induced a sustained rise in cytosolic Ca2+ ([Ca2+]i), which was resistant to verapamil but suppressed by omission of extracellular Ca2+. When external Na+ was replaced by choline+, PTX did not increase [Ca2+]i. Pretreatment with 2,4-DCB prevented the elevation of [Ca2+]i due to PTX. These results suggest that PTX does not directly stimulate Ca2+ entry but induces entry through Na(+)-Ca2+ exchange as a consequence of increased cytosolic Na+. Ni2+, La3+, 2,4-DCB and ouabain were shown to act as blockers of the PTX-induced channel. Ouabain may also inhibit Na+ pump current activated by cytosolic Na+.
The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.