Subtype-specific effects of lithium on glutamate receptor function. (1/267)

We report that substitution of sodium with lithium (Li+) in the extracellular solution causes subtype-specific changes in the inward and outward currents of glutamate receptors (GluRs), without a shift in reversal potential. Li+ produces an increase of inward and outward currents of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors and decreases in the currents of kainate (KA) and N-methyl-D-aspartate receptors. The greatest effect of Li+ was observed with GluR3. A concentration-response curve for GluR3 reveals that the potentiation caused by Li+ is greatest at saturating agonist concentrations. GluR1, which shows no potentiation by Li+ at 100 microM KA, shows a small but significant potentiation at saturating KA and glutamate concentrations. The effects of Li+ on outward current, where Li+ is not the primary charge carrier, and the lack of reversal potential shift argue for a mechanism of potentiation not associated with Li+ permeation. This potentiation of current is specific for Li+ because rubidium, although causing an increase of inward current, shifted the reversal potential and did not increase outward current. The effects of Li+ are different for KA, a weak desensitizing agonist, and glutamate, a strong desensitizing agonist, suggesting that Li+ might interact with a mechanism of desensitization. By using cyclothiazide (CTZ) to reduce desensitization of GluR3, we find that for low concentrations of KA and glutamate potentiation of the response by a combination of CTZ and Li+ is no greater than by CTZ or Li+ alone. However, at high concentrations of agonist, the potentiation of the response by a combination of CTZ and Li+ is significantly greater than by CTZ or Li+ alone. This potentiation was additive for glutamate but not for KA. At high agonist concentration in the presence of CTZ, the intrinsically lower desensitization produced with KA-evoked responses may preclude Li+ from potentiating the current to the same degree as it can potentiate glutamate-evoked responses. The additive effects of CTZ and Li+ were unique to the flop variant of GluR3.  (+info)

Trends in antihypertensive drug advertising, 1985-1996. (2/267)

BACKGROUND: Over the past decade, calcium channel blockers (CCBs) and ACE inhibitors have been used increasingly in the treatment of hypertension. In contrast, beta-blocker and diuretic use has decreased. It has been suggested that pharmaceutical marketing has influenced these prescribing patterns. No objective analysis of advertising for antihypertensive therapies exists, however. METHODS AND RESULTS: We reviewed the January, April, July, and October issues of the New England Journal of Medicine from 1985 to 1996 (210 issues). The intensity of drug promotion was measured as the proportion of advertising pages used to promote a given medication. Statistical analyses used the chi2 test for trend. Advertising for CCBs increased from 4.6% of advertising pages in 1985 to 26.9% in 1996, while advertising for beta-blockers (12.4% in 1985 to 0% in 1996) and diuretics (4.2% to 0%) decreased (all P<0.0001). A nonsignificant increase was observed in advertising for ACE inhibitors (3.5% to 4.3%, P=0.17). Although the total number of drug advertising pages per issue decreased from 60 pages in 1985 to 42 pages in 1996 (P<0.001), the number of pages devoted to calcium channel blocker advertisements nearly quadrupled. CONCLUSIONS: Increasing promotion of CCBs has mirrored trends in physician prescribing. An association between advertising and prescribing patterns could explain why CCBs have supplanted better-substantiated therapies for hypertension.  (+info)

A numerical model of the renal distal tubule. (3/267)

A numerical model of the rat distal tubule was developed to simulate water and solute transport in this nephron segment. This model incorporates the following: 1) Na-Cl cotransporter, K-Cl cotransporter, Na channel, K channel, and Cl channel in the luminal membrane; 2) Na-K-ATPase, K channel, and Cl channel in the basolateral membrane; and 3) conductances for Na, K, and Cl in the paracellular pathway. Transport rates were calculated using kinetic equations. Axial heterogeneity was represented by partitioning the model into two subsegments with different sets of model parameters. Model equations derived from the principles of mass conservation and electrical neutrality were solved numerically. Values of the model parameters were adjusted to minimize a penalty function that was devised to quantify the difference between model predictions and experimental results. The developed model could simulate the water and solute transport of the distal tubule in the normal state, as well as in conditions including thiazide or amiloride application and various levels of sodium load and tubular flow rate.  (+info)

A kinetic model of the thiazide-sensitive Na-Cl cotransporter. (4/267)

The aim of this study was to construct a numerical model of the thiazide-sensitive Na-Cl cotransporter (TSC) that can predict kinetics of thiazide binding and substrate transport of TSC. We hypothesized that the mechanisms underlying these kinetic properties can be approximated by a state diagram in which the transporter has two binding sites, one for sodium and another for chloride and thiazide. On the basis of the state diagram, a system of linear equations that should be satisfied in the steady state was postulated. Numerical solution of these equations yielded model prediction of kinetics of thiazide binding and substrate transport. Rate constants, which determine transitional rates between states, were systematically adjusted to minimize a penalty function that was devised to quantitatively estimate the difference between model predictions and experimental results. With the resultant rate constants, the model could simulate the following experimental results: 1) dissociation constant of thiazide in the absence of sodium and chloride; 2) inhibitory effect of chloride on thiazide binding; 3) stimulatory effect of sodium on thiazide binding; 4) combined effects of sodium and chloride on thiazide binding; 5) dependence of sodium influx on extracellular sodium and chloride; and 6) inhibition of sodium influx by extracellular thiazide. We conclude that known kinetic properties of TSC can be predicted by a model which is based on a state diagram.  (+info)

Lack of AMPA receptor desensitization during basal synaptic transmission in the hippocampal slice. (5/267)

Excitatory postsynaptic currents in the CA1 region of rat hippocampal slices are mediated primarily by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in response to synaptically released glutamate. Outside-out patches from pyramidal cells in this region have shown that AMPA receptors are desensitized by short (1 ms) pulses of glutamate. We have taken a number of approaches to ask whether synaptic receptors desensitize in response to synaptically released glutamate in the slice. Recordings with paired pulses and minimal stimulation conditions that are presumably activating only a single release site do not show evidence for desensitization. Furthermore, cyclothiazide, a drug that blocks desensitization, does not alter paired-pulse ratios even under conditions of high probability of release, which should maximize desensitization. These results suggest that synaptic receptors do not desensitize in response to synaptically released glutamate during basal synaptic transmission.  (+info)

The concentration of synaptically released glutamate outside of the climbing fiber-Purkinje cell synaptic cleft. (6/267)

AMPA receptors and glutamate transporters expressed by cerebellar Bergmann glial cells are activated by neurotransmitter released from climbing fibers (). Based on anatomical evidence, this is most likely the result of glutamate diffusing out of the climbing fiber-Purkinje cell synaptic clefts (). We used the change in the EC50 of the Bergmann glia AMPA receptors produced by cyclothiazide (CTZ) to estimate the concentration of glutamate reached at the glial membrane. The decrease of the EC50 gives rise to a concentration-dependent potentiation of the AMPA receptor-mediated responses (). By comparing the increase in amplitude of the AMPA receptor response in the Bergmann glia (840 +/- 240%; n = 8) with the shift in the glutamate dose-response curve measured in excised patches (EC50, 1810 microM in control vs 304 microM in CTZ), we estimate that the extrasynaptic transmitter concentration reaches 160-190 microM. This contrasts with the concentration in the synaptic cleft, thought to rapidly rise above 1 mM, but is still high enough to activate glutamate receptors. These results indicate that the sphere of influence of synaptically released glutamate can extend beyond the synaptic cleft.  (+info)

The management of hypertensive disease in black patients. (7/267)

The ethnic differences in the incidence, pathophysiology and management of hypertensive disease, are particularly pertinent to the Black or Afro-Caribbean populations, who have a high prevalence of hypertension and associated complications, such as strokes and renal impairment. Our understanding of the underlying pathophysiology of hypertensive disease and the optimal treatment of hypertension in Black patients continues to evolve, especially with the introduction of new drugs and the need for prognostic data in this ethnic population. We review the management of hypertensive disease in the black population, emphasizing race-related differences in the pathophysiology of hypertension and the importance of tailored management in this group of patients, including sensible application of non-pharmacological measures with effective antihypertensive agents. For example, diuretics and calcium antagonists are suitable first-line agents in black hypertensives, whilst beta-blockers and the ACE inhibitors tend to be less effective at lowering blood pressure, due to the low renin state in these patients.  (+info)

A novel presynaptic inhibitory mechanism underlies paired pulse depression at a fast central synapse. (8/267)

Several distinct mechanisms may cause synaptic depression, a common form of short-term synaptic plasticity. These include postsynaptic receptor desensitization, presynaptic depletion of releasable vesicles, or other presynaptic mechanisms depressing vesicle release. At the endbulb of Held, a fast central calyceal synapse in the auditory pathway, cyclothiazide (CTZ) abolished marked paired pulse depression (PPD) by acting presynaptically to enhance transmitter release, rather than by blocking postsynaptic receptor desensitization. PPD and its response to CTZ were not altered by prior depletion of the releasable vesicle pool but were blocked by lowering external calcium concentration, while raising external calcium enhanced PPD. We conclude that a major component of PPD at the endbulb is due to a novel, transient depression of release, which is dependent on the level of presynaptic calcium entry and is CTZ sensitive.  (+info)