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Biomedical subjects

J H Li

Publications and source records attributed to J H Li.

At least 145 records · Page 8Linked to original sources
PubMed1988

Genetic toxicology of lead compounds.

We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a microM basis, than two moderately soluble lead compounds although the exposure time for the soluble salts was five times longer. These findings demonstrate the importance of different cellular mechanism(s) of metal uptake and bioavailability. Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells. Although less mutagenic at the higher concentrations, lead nitrate at a concentration of 500 microM enhanced the mutation frequency greater than 6-fold above background following a 5-day exposure. Although the mechanism(s) by which lead induces mutations is unknown, failure of both compounds to induce SCE and DNA single-strand breaks, detectable by alkaline elution, suggests that lead-induced mutations may not be a result of direct damage to DNA but may occur via indirect mechanisms including disturbances in enzyme functions important in DNA synthesis and/or repair, or in DNA-helical structure. Lead acetate also transformed SHE cells in a dose-response fashion following a 48-h exposure. Our results indicate that lead compounds may be genotoxic by an indirect mechanism, and lend support to the view that lead is a carcinogen.

Animals↗
PubMed1988

Bumetanide stimulation of sodium permeability of the apical membrane of toad urinary bladder.

The effects of bumetanide on Na transport in the isolated toad urinary bladder were investigated. When applied to the serosal side, this loop diuretic inhibited Na transport. By contrast, when applied to the mucosal side, it stimulated Na transport by increasing the apical Na permeability. These dual effects of bumetanide were also observed with the loop diuretic furosemide. The mucosal action of bumetanide was attributable to release of Na self-inhibition, as evidenced by its dependency on mucosal Na concentration and its interaction with another apical Na permeability stimulator, p-chloromercuriphenyl sulfonate. The stimulatory action of bumetanide was not reduced by the natriferic effect of antidiuretic hormone, but it was totally blockable by the epithelial Na channel blocker amiloride. Bumetanide, however, caused a leftward shift of the concentration-response curve of amiloride on Na current as predicted from its effect on Na self-inhibition. This stimulatory activity of bumetanide and furosemide as demonstrated in the in vitro isolated amphibian epithelia suggests that these loop diuretics also have the potential to stimulate Na transport at the distal portion of the mammalian nephron. Thus, this property of these diuretics might be one of the factors contributing to the observation of increased Na reabsorption along the distal tubule after in vivo administration of furosemide and piretanide as reported in some micropuncture studies.

4-Chloromercuribenzenesulfonate↗
PubMed1987

Structure-activity relationship of amiloride analogs as blockers of epithelial Na channels: II. Side-chain modifications.

The overall on- and off-rate constants for blockage of epithelial Na channels by amiloride analogs were estimated by noise analysis of the stationary Na current traversing frog skin epithelium. The (2-position) side chain structure of amiloride was varied in order to obtain structure/rate constant relationships. Hydrophobic chain elongations (benzamil and related compounds of high blocking potency) increase the stability of the blocking complex (lowered off-rate), explained by attachment of the added phenyl moiety to a hydrophobic area near the site of side chain interaction with the channel protein. Some other chain modifications show that the on-rate, which is smaller than a diffusion-limited rate, varies with side chain structure. In several cases this effect is not attributable to steric hindrance on encounter, and implies that the side chain interacts briefly with the channel protein (encounter complex) before the main blocking position of the molecule is attained. The encounter complex must be labile since the overall rate constants of blockage are not concentration-dependent. In two cases, changes at the 2-position side chain and at other ring ligands, with known effects on the blocking rate constants, could be combined in one analog. The rate constants of blocking by the resulting compounds indicate that the structural changes have additive effects in terms of activation energies. Along with other observations (voltage dependence of the rate constants and competition with the transported Na ion), these results suggest a blocking process of at least two steps. It appears that initially the 2-position side chain invades the outward-facing channel entrance, establishing a labile complex. Then the molecule is either released completely (no block) or the 6-ligand of the pyrazine ring gains access to its receptor counterpart, thus establishing the blocking complex, the lifetime of which is strongly determined by the electronegativity of the 6-ligand.

Amiloride↗
PubMed1987

Amphibian cornea as a model for studying intrinsic activities of loop diuretics.

The inhibitory activity of various standard diuretics and compounds on Cl- transport in the toad cornea has been investigated. The relative potency of these diuretics shows a pattern and follows a sequence similar to their inhibitory potency on salt reabsorption in the isolated mammalian cortical thick ascending limb of Henle's loop. The suitability and convenience of using toad cornea as an in vitro model for that segment of the mammalian nephron is well demonstrated.

Animals↗
PubMed1987

ICI 147,798: a novel diuretic agent with beta adrenoceptor blocking activity.

ICI 147,798 is a novel compound which has both diuretic and beta adrenoceptor blocking properties in a single molecule. The natriuretic activity at 30 mg/kg p.o. was about 65% of the hydrochlorothiazide value at 10 mg/kg p.o. in saline-loaded rats; the corresponding kaliuretic activity was 42%. The natriuretic and the kaliuretic activity of ICI 147,798 in dogs were similar to that of hydrochlorothiazide over the doses 1 to 20 mg/kg p.o., although significantly less kaliuresis was obtained with ICI 147,798 at 1 mg/kg p.o. In the toad bladder preparation (analogous to the distal mammalian nephron), ICI 147,798 inhibited Na+ transport with mucosal and serosal IC50 values of 56 and 120 microM, respectively. ICI 147,798 inhibited isoproterenol-induced tachycardia in rats, cats, guinea pigs and dogs; these effects were associated with antagonism of isoproterenol vasodepressor responses. The pKB values of ICI 147,798 were 9.1 and 8.8 in isolated right atria and trachea of guinea pigs, respectively. ICI 147,798 did not exhibit local anesthetic activity in rabbit cornea and intrinsic sympathomimetic activity in catecholamine-depleted dogs and rats. Duration of beta blockade after a p.o. dose of 1 mg/kg in dogs followed the sequence: nadolol greater than ICI 147,798 greater than atenolol greater than timolol greater than propranolol. It is concluded that ICI 147,798 is a novel diuretic agent with nonselective beta blockade, and it appears to have the potential of a direct tubular action.

Adrenergic beta-Agonists↗
PubMed1986

Chronotropic cardiac effects of histamine in the conscious dog with chronic atrioventricular block: interactions with the autonomic nervous system.

Chronotropic effects of histamine and dimaprit were studied in the conscious dog with chronic atrioventricular block. Histamine at 0.2-5 micrograms/kg and dimaprit at equimolar doses (i.e. 0.25-6.25 micrograms/kg) increased atrial rate dose-relatedly. Blockade of muscarinic receptors reduced these effects and simultaneous blockade of muscarinic and beta-adrenergic receptors abolished them. Histamine and dimaprit moderately increased ventricular rate. Blockade of muscarinic receptors did not modify these effects, but blockade of beta-adrenoceptors with or without simultaneous blockade of muscarinic receptors suppressed them. After blockade of beta-adrenoceptors, histamine and more rarely dimaprit sometimes decreased atrial and ventricular rates. These effects were prevented by additional muscarinic blockade. Histamine and dimaprit lowered mean blood pressure to the same degree before and after each antagonist. The positive chronotropic effects of histamine and dimaprit, at these doses, are probably reflex responses to their hypotensive effects. The negative chronotropic effects of histamine after pindolol are due to muscarinic receptor activation. No evidence was found to implicate histamine-specific receptors in any of the chronotropic effects of histamine and dimaprit.

Adrenergic beta-Antagonists↗
PubMed1986

Phorbol myristate acetate inhibits anti-IgM-mediated signaling in resting B cells.

Cross-linking the membrane immunoglobulins of resting B cells leads to activation as judged by increased inositol phospholipid metabolism, intracellular free calcium concentration ([Ca2+]i), and cell volume. Such activated B cells enter S phase in the presence of B-cell stimulatory factor 1. Phorbol myristate acetate (PMA) is a potent inhibitor of anti-IgM- and anti-IgD-stimulated B-cell responses. In B cells concentrations of PMA ranging from 0.1 to 100 ng/ml completely inhibit anti-IgM-stimulated DNA synthesis and block anti-IgM-stimulated increases in inositol phospholipid metabolism and in [Ca2+]i. Preincubation periods as short as 4 min block these effects although longer preincubations are somewhat more effective in inhibiting increases in [Ca2+]i. Preincubation with PMA for 1.5 hr does not diminish expression of membrane IgM. This strongly suggests that PMA inhibits responses of resting B cells to anti-IgM by interrupting signal transmission rather than by diminishing cross-linking of membrane immunoglobulin on B cells. In contrast to resting B cells, B cells activated in vitro for 29 hr show enhanced responses to anti-IgM in the presence of PMA.

Animals↗
PubMed1986

Effects of detergents on sodium transport in toad urinary bladder.

The effects of ionic, nonionic and zwitterionic detergents (zwittergents) on apical sodium permeability of toad urinary bladder were investigated. Applied to the mucosal side at concentrations less than 1/100 of their respective critical micellar concentration (CMC), sodium lauryl sulfate, Triton X-100 and a series of sulfobetaine zwittergents reversibly increased amiloride-sensitive sodium current. These detergents decreased the current at concentrations higher than 1/100 of the CMC and caused large, irreversible increases of tissue electrical conductance at a concentration close to the CMC. Nonionic detergent Tween 80, however, stimulated the current at concentrations from 1/100 to 10,000 of its CMC. The maximum stimulation of current by each zwittergent occurred at 1/100 of its CMC, and the larger the CMC, the greater the stimulation attainable. Analysis of the dependence of current on mucosal sodium concentration in the presence of stimulating doses of a zwittergent and Tween 80 showed that the increase in current was not the result of increased apical maximum sodium permeability, but the consequence of removal of sodium self-inhibition. The amiloride dose-response curve in the presence of stimulating dose of zwittergent was shown to shift to the left and yield a smaller apparent inhibition constant as predicted on the basis of such a removal and an unaltered intrinsic amiloride blocking kinetic.

Amiloride↗
PubMed1985

T cell receptors for responses to Mls determinants and allo-H-2 determinants appear to be encoded on different chromosomes.

Previous studies have shown that T cell clones specific for strong Mlsa,d determinants concomitantly display apparently random reactivity to allo-H-2 determinants. One explanation for this finding is that T cell recognition of Mlsa,d and allo-H-2 determinants is controlled by separate sets of receptors. If these receptors were chromosomally unlinked, karyotypically unstable T cell hybrids with dual reactivity for Mlsa,d and particular allo-H-2 determinants would be expected, occasionally, to lose reactivity for one set of determinants, but not the other. The results presented here provide direct support for this prediction.

Animals↗