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At least 199 records · Page 11Linked to original sources
PubMed1981

Chromatography of human leukocyte interferon on controlled pore glass.

Human leukocyte interferon (HuIFN-alpha ) was adsorbed on controlled pore glass (CPG) beads in 0.01 M potassium phosphate, pH 7.2. Partial recovery fo HuIFN-alpha from CPG, ranging from 50% to 75%, was obtained with ethylene glycol (6.8 M), ammonium chloride (1.0 M) and Tris.HCl (1.0 M). A near complete recovery (90%) was obtained with potassium phosphate (1 M), but there was no selectivity in the elution vis á vis other proteins. An efficient elution of HuIFN-alpha was accomplished with tetramethyl-, and tetraethylammonium chlorides: the recovery of HuIFN-alpha was complete at low concentrations (0.25 M to 0.50 M) of these salts at pH 8.0 and the elution of interferon was more selective than with other eluants.

Ammonium Chloride↗
PubMed1984

Protective effect of organic cation transport inhibitors on cis-diamminedichloroplatinum-induced nephrotoxicity.

Cis-diamminedichloroplatinum (II) (cisplatin) is a frequently used cancer chemotherapeutic agent. Nephrotoxicity is a serious dose-limiting side effect. Many approaches have been studied for protective action against cisplatin-induced nephrotoxicity, but with the exception of diuretics and hydration none are in widespread use. We have used a modified Sperber technique in unanesthetized hens to examine the effect of cisplatin on renal organic cation and anion transport and on renal morphology. The effects of the organic cation transport inhibitors quinine and cyanine on cisplatin-induced toxicity also were evaluated. Administration of cisplatin (3.0 mg/kg i.v.) produced nephrotoxic and lethal effects. Four days after cisplatin administration there was a significant inhibition of renal tubular excretory transport of the organic cation tetraethylammonium and the organic anion p-aminohippuric acid. Acute multifocal tubular necrosis of the proximal tubules was present. Administration of quinine (1.5 mumol/min) and cyanine (0.122 mumol/min) protected against the lethal effects, the inhibition of renal organic cation and anion transport and the renal lesions induced by cisplatin.

Animals↗
PubMed1994

Role of ATP-sensitive K+ channels in antinociception induced by R-PIA, an adenosine A1 receptor agonist.

The influence of several K+ channel-acting drugs on antinociception induced by the adenosine A1 receptor agonist (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA) was evaluated with a tail flick test in mice. The subcutaneous administration of R-PIA (0.5-8 mg/kg) induced a dose-dependent antinociceptive effect. The ATP-sensitive K+ (KATP) channel blocker gliquidone (2-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the R-PIA dose-response line, whereas the KATP channel opener cromakalim (32 micrograms/mouse, i.c.v.) shifted it to the left. Several KATP channel blockers dose-dependently antagonized the antinociceptive effect of R-PIA, the order of potency being gliquidone > glipizide > glibenclamide (i.e., the same order of potency shown by these drugs in blocking KATP channels in neurons). In contrast, the K+ channel blockers 4-aminopyridine and tetraethylammonium did not antagonize the effect of R-PIA. These data suggest that antinociception produced by adenosine A1 receptor agonists is mediated by the opening of ATP-sensitive K+ channels. The present results, together with those of previous studies, further support a role for K+ channel opening in the antinociceptive effect of agonists of receptors coupled to Gi/Go proteins.

4-Aminopyridine↗
PubMed1992

Tetraalkylammonium ion block of potassium currents in mouse neuroblastoma cells.

Experiments were performed to compare the mechanism of block of the delayed rectifier K+ channels in cultured mouse neuroblastoma cells by various derivatives of tetraethylammonium (TEA) which have symmetric alkyl chains of one to six carbons. Current from the whole cell was studied using the patch clamp technique. TEA blocked the whole cell K+ current with a Ki of 0.6 mM when applied to the external solution. The Ki for block by other derivatives were (mM): tetrapropylammonium, 9.2; tetrabutylammonium (TBA), 1.9; tetrapentylammonium (TPeA), 0.088; and tetrahexylammonium, (THA), 0.006. Block of the whole cell current by TEA or tetrapropylammonium did not increase with time after a step depolarization. However, block by TBA, TPeA or THA was time dependent. TEA did not compete with TPeA for the same receptor. Block by externally applied TEA was not appreciably voltage dependent, and the receptor for TPeA had an apparent electrical distance of 0.3. These observations suggest that TEA and TPeA block at separate receptors. THA could block the open channel in cell-attached patches when the compound was applied to the bath. This observation and the observation that externally applied TPeA and TEA do not occupy the same receptor suggest that derivatives having long alkyl chain lengths can reach the internal receptor from the external solution.

Animals↗
PubMed1992

Changes in phospholipid metabolism induced by quinine, 4-aminopyridine and tetraethylammonium in the monocytic cell line THP1.

Quinine, 4-aminopyridine and tetraethylammonium, three compounds generally used as effectors of K+ channels, strongly modify phospholipid metabolism. In the human monocytic cell line THP1, the three drugs enhanced the incorporation of [3H]serine into phosphatidylserine and that of [3H]inositol into phosphatidylinositol in the absence of significant changes in the uptake of the 3H labels. On the contrary, the biosynthesis of both phosphatidylcholine and phosphatidylethanolamine was strongly inhibited. This inhibition appeared to be mainly due to the inhibition of both [3H]choline and [3H]ethanolamine uptake by the cells, by impairment of choline transport in a competitive mode.

4-Aminopyridine↗
PubMed1995

Subgroups among mu-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs.

1. We evaluated the effects of the i.c.v. administration of different K+ channel blockers (gliquidone, 4-aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several mu-opioid receptor agonists in a tail flick test in mice. 2. The s.c. administration of all agonists of mu-opioid receptors tested (morphine, 1-16 mg kg-1; metadone, 1-6 mg kg-1; buprenorphine, 0.04-0.64 mg kg-1; fentanyl, 0.02-0.32 mg kg-1 and levorphanol, 0.2-3.2 mg kg-1) elicited a dose-dependent antinociceptive effect. 3. The ATP-sensitive K+ channel blocker, gliquidone (0.06-16 micrograms per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and metadone. In contrast, gliquidone (0.25-160 micrograms per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4. Cromakalim (4-64 micrograms per mouse, i.c.v.), an opener of ATP-sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5. The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 micrograms per mouse) or 4-aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any mu-opioid receptor agonist tested. 6. These results suggest that the opening of ATP-sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among mu-opioid receptor agonists, each inducing antinociception through different effector mechanisms.

4-Aminopyridine↗
PubMed1994

A possibility that the ATP-sensitive potassium channel in coronary artery has a high-affinity internal binding site for tetraalkylammonium.

The functionally responsible sites for the blocking action of tetraalkylammonium ions (TAAs) in ATP-sensitive K+ (KATP) channels opened by levcromakalim were estimated in canine coronary artery. Tetraethylammonium (TEA) and tetrabutylammonium (TBA) inhibited the levcromakalim-induced relaxation in a noncompetitive manner. Analyses of the noncompetitive antagonism revealed that the binding constant of TBA was about 900 times lower than that of TEA, although the reported affinity of TBA for the internal binding site in various K+ channels was only 10 times higher than that of TEA. TBA is much more lipid-soluble and permeable through membranes than TEA. Thus, TBA blocks KATP channels by binding to a possible high-affinity internal site for TAAs, whereas TEA seems to bind to the external site.

Adenosine Triphosphate↗
PubMed1973

Alteration of the relative stability of dA-dT and dG-dC base pairs in DNA.

Several small alkylammonium ions can eliminate, or even reverse, the usual dependence of the DNA transition temperature on base composition. For example, in 3 M tetramethylammonium chloride, or 2.4 M tetraethylammonium chloride, DNAs of different base compositions all melt at a common temperature, and with a greatly decreased breadth of transition reflecting only the sequence-independent components of melting cooperativity. At still higher concentrations of such additives, dG.dC-rich DNAs melt at lower temperatures than dA.dT-rich molecules. Circular dichroism spectra show that these additives alter the structure of the DNA double helix very little at room temperature. This differential (base-specific) effect on helix stability is investigated with several small additives related to the tetraalkylammonium ions. Additives larger than tetraethylammonium ion have little differential effect on helix stability. Preferential binding of ions to dA.dT base pairs, requiring fit into a "groove" of DNA, is consistent with these data and with equilibrium binding studies. These differential effects can be distinguished from general destabilizing effects, which are independent of specific features of macromolecular conformation or chemistry. Possible experimental uses of this ability to alter the base-composition-dependent components of the stability of the DNA helix are discussed, as well as the insight this phenomenon provides into the molecular basis for the differential stability of dA.dT and dG.dC base pairs.

Animals↗
PubMed1994

Properties of the LP-805-induced potassium currents in cultured bovine pulmonary artery endothelial cells.

The actions of 8-tert-butyl-6,7-dihydropyrolo[3,2-e]-5- methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (LP-805) on membrane K+ currents in cultured bovine pulmonary artery endothelial cells were investigated using the patch-clamp technique. In the whole-cell voltage clamp experiments, with 11 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) in the pipette, membrane currents revealed only an inwardly rectifying K+ current, and no outward current could be observed at depolarized potentials. Using a pipette solution containing 0.3 mM EGTA, outward K+ current was present in response to depolarizing voltage steps from a holding potential of -60 mV. LP-805 (1-10 microM) significantly increased outward K+ currents in a concentration-dependent manner. The increase of this K+ current was inhibited by 5 mM tetraethylammonium and 5 mM tetrabutylammonium to a level less than the control. Partial recovery occurred on washout. However, the increase of outward K+ current by 10 microM LP-805 was unaffected by 5 mM 4-aminopyridine and 1 microM glibenclamide. LP-805 (1-10 microM) significantly decreased the inwardly rectifying K+ current in a concentration-dependent manner. In cell-attached patches, inward single K+ currents were recorded at negative membrane potentials, and single channel conductance was 23 +/- 2 pS (n = 5). No outward current could be observed at positive potentials. LP-805 (10 microM) inhibited the inwardly rectifying K+ currents. Thus LP-805 inhibits inwardly rectifying K+ currents but activates outward Ca(++)-dependent K+ currents in bovine pulmonary artery endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1989

Interaction of potassium channel openers and blockers in canine atrial muscle.

1. The possibility that the interaction between potassium channel openers, e.g. cromakalim, pinacidil and nicorandil, and some potassium channel blockers involves a common site was investigated in canine atrial muscle. 2. Cromakalim, pinacidil and nicorandil produced a negative inotropic effect, their pD2 (-log EC50) values being 6.11 +/- 0.07, 5.37 +/- 0.09 and 4.55 +/- 0.07, respectively. 3. The potassium channel blockers, tetraethylammonium (TEA), tetrabutylammonium (TBA), 3,4-diaminopyridine (DAP), CsCl and BaCl2 all produced a positive inotropic effect. 4. The concentration-effect curves for the negative inotropic actions of pinacidil were shifted in a parallel way to the right by low concentrations of TEA, TBA or BaCl2. Maximum responses to pinacidil were depressed by higher concentrations of the blockers. An analysis of the non-competitive antagonism by TEA yielded pKA (-log KA) values of 4.00-4.05 for pinacidil. 5. The concentration-effect curves for cromakalim and nicorandil were shifted by TEA similarly to those for pinacidil, and a similar analysis yielded pKA values of 4.47-4.68 for cromakalim and 3.47-3.74 for nicorandil. 6. The KA values of cromakalim, pinacidil and nicorandil were about 10-30 times greater than their EC50 values, indicating that there are non-linear stimulus-effect relationships between the binding of the three potassium channel openers to their binding sites at potassium channels and their negative inotropic effects. 7. The dissociation constants for TEA could also be estimated from pA2 and pKB values for antagonizing competitively and non-competitively the negative inotropic effects of the three potassium channel openers; they were 3.47-3.89, and did not differ between the potassium channel openers. 8. The concentration-effect curves for the three potassium channel openers were not affected by DAP or CsCl. 9. These results suggest the following: (i) quaternary ammonium compounds like TEA and TBA antagonize the negative inotropic effect of cromakalim, pinacidil and nicorandil by binding to potassium channels, thus preventing binding of the channel openers to the same sites or closely related sites in canine right atrial muscles.

Animals↗
PubMed1992

Mechanical and ionic response of rat aorta to diazoxide.

Diazoxide provoked concentration-dependent and endothelium-independent relaxations of the mechanical responses evoked by low concentrations of KCl. Glibenclamide, tolbutamide and tetraethylammonium shifted the concentration-response curve for diazoxide to the right. The drug also caused a dose-dependent stimulation of 86Rb outflow which was inhibited by glibenclamide and tolbutamide. Diazoxide (10(-4) and 10(-3) M) inhibited the contractions elicited by 10(-1) M K+ and provoked a concentration-dependent reduction in the contractile responses to Ca2+. Diazoxide also reduced the KCl (8 x 10(-2) M)-induced increase in 45Ca outflow. These data indicate that the vasorelaxant properties of diazoxide are probably related to an inhibition of Ca2+ entry into smooth muscle cells. The reduction in Ca2+ entry appears to result from K+ channel activation. At high concentrations, diazoxide also exhibited antagonistic actions on voltage-sensitive Ca2+ channels.

Animals↗
PubMed1993

Inhibition of slow-wave repolarization and Ca(2+)-activated K+ channels by quaternary ammonium ions.

We studied the effects of the K+ channel blocker tetrapentylammonium (TPeA) on the electrical activity of intact circular smooth muscle from canine colon. TPeA (10 and 20 microM) increased slow-wave duration and "locked" the membrane potential around -30 mV plateau potential after several minutes of application, suggesting that K+ channels are essential for termination of colonic slow waves. Repolarization and normal slow-wave activity resumed after 20-30 min of washout. The patch-clamp technique was used to study the block of large-conductance Ca(2+)-activated K+ channels (BK channels) by TPeA and tetraethylammonium (TEA) in excised and cell-attached patches from isolated colonic smooth muscle cells. Channel block was characterized by a voltage-dependent dissociation constant [Kd(V)] for the binding of TEA and TPeA to a blocking site located a fraction of the distance across the membrane field (delta). The extracellular TEA binding site had a Kd(0) of 0.33 mM and a delta of 0.23. The extracellular TPeA binding site had a Kd(0) of 2.2 mM but showed significantly less voltage dependence (delta = 0.02). The intracellular binding site for TEA was of low affinity [Kd(0) = 76 mM]. Intracellular TPeA was the most potent blocker of BK channel current [Kd(0) = 11.7 microM]. The voltage dependence of block by intracellular TPeA (delta = -0.21) was not significantly different from that of intracellular TEA (delta = -0.3). Internal TPeA (10 microM) also blocked a 70-pS K+ channel and a 23-pS K+ channel.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗
PubMed1995

Pharmacology of ATP-sensitive K+ currents in smooth muscle cells from rabbit mesenteric artery.

The inference that ATP-sensitive K+ (KATP) channels are involved in arterial responses to the synthetic K+ channel openers, hypoxia, adenosine, and calcitonin gene-related peptide, has relied on the sensitivity of these responses to the sulfonylureas glibenclamide and tolbutamide and to tetraethylammonium (TEA+). The inhibition of KATP currents by glibenclamide, tolbutamide, and TEA+ was investigated in single smooth muscle cells from rabbit mesenteric artery by use of the whole cell patch-clamp technique. The synthetic K+ channel openers pinacidil (half-activation 0.6 microM), cromakalim (half-activation 1.9 microM), and diazoxide (half-activation 37.1 microM) activated K(+)-selective currents that were blocked by glibenclamide. Elevation of pipette (intracellular) ATP concentration decreased K+ currents induced by pinacidil. Half-inhibition of KATP currents by glibenclamide and tolbutamide occurred at 101 nM and 351 microM, respectively. KATP currents were also inhibited by external TEA+, with half-inhibition at 6.2 mM. The results indicate that glibenclamide is an effective inhibitor of KATP channels in arterial smooth muscle and that tolbutamide and TEA+ are much less effective. Furthermore, these results support numerous functional studies that have demonstrated that the vasorelaxations to K+ channel openers are inhibited by < 10 microM glibenclamide but not by < 1 mM TEA+.

Adenosine Triphosphate↗
PubMed1993

Sulphonylureas reduce the slowly inactivating D-type outward current in rat hippocampal neurons.

1. Using intracellular recording in hippocampal slices, we have examined, in CA3 pyramidal neurons, the effects of sulphonylureas (blockers of ATP-sensitive K+ channels) on the slowly inactivating D-type K+ current (ID). 2. In the presence of TTX (1 microM) to block Na+ currents, ID had the following characteristics: activation by large depolarizing pulses from membrane potentials negative to -75 mV, slow inactivation kinetics, high sensitivity to 4-aminopyridine (4-AP, 3-40 microM), insensitivity to tetraethylammonium (TEA, 10 mM), Cs+ (3 mM) and carbachol (50 microM). 3. Applications of glibenclamide (10 microM) did not modify the input conductance of the cell, but reduced the amplitude of ID by 31.2 +/- 5.6% (n = 16), without altering its voltage dependence and inactivation kinetics. The effects were usually reversible. 4. Glibenclamide also reduced ID in the presence of TEA (10 mM), Cs+ (3 mM) and carbachol (50 microM), to block several K+ currents (IK, IC, IQ, IM), as well as kynurenate (1 mM) and bicuculline (10 microM) to block on-going synaptic currents mediated by activation of non-NMDA (N-methyl-D-aspartate) and GABA (gamma-aminobutyrate)-A receptors, respectively. 5. Comparable depressions of ID were produced by two other sulphonylureas: gliquidone (10 microM), 42.6 +/- 7.9% (n = 13) and tolbutamide (500 microM), 39.1 +/- 12.8 (n = 8). 6. It is concluded that, in the central nervous system, sulphonylureas can modulate K+ currents which are not generated by ATP-sensitive K+ channels.

Adenosine Triphosphate↗