Effect of diuretics on fetal growth: A drug effect or confounding by indication? Pooled Danish and Scottish cohort data. (33/267)

AIMS: The diabetogenic effect of diuretics, as well as the indication for prescribing them, may impact on fetal growth. We analysed whether the purchase of prescription drugs for diuretics during pregnancy was associated with measures of fetal growth. METHODS: During 1991-98 all women who purchased prescription drugs for diuretics during pregnancy were identified in the Northern Jutland Prescription Database (NJDP), Denmark, and in the Medicines Monitoring Unit's Database (MEMO), Scotland. Information on birth weight and gestational age was obtained from the Danish Birth Registry, the Danish Hospital Discharge Registry and the Scottish Tayside Neonatal Database. Information on diabetes, hypertension and prepregnancy weight were obtained by hospital record review in a sample of women in the Danish cohort. Women who did not purchase prescription diuretics during pregnancy were used as a reference group in both cohorts. RESULTS: Danish women who purchased prescription loop diuretics during pregnancy gave birth to infants with higher birth weights than women who did not use diuretics; mean difference 104.7 g (95% CI; 2.6, 206.9). However, the high prevalence of diabetes (10.3%) among Danish women who purchased prescription loop diuretics during pregnancy might explain this result. Both the Danish and the Scottish women who purchased prescription diuretics during their pregnancy were at increased risk of preterm delivery (< 37 completed weeks); ORs: 1.8 (CI; 1.2, 2.7)NJDP, 1.9 (CI; 0.9, 4.3)MEMO. The proportion of hypertension among women who purchased prescription thiazides was 15.8%, and the risk of having an infant with a birth weight (BW) < 2500 g was increased; ORs: 2.6 (CI; 1.4, 5.0)NJDP, 2.4 (CI; 0.8, 7.8)MEMO. CONCLUSIONS: Prescribing diuretics during pregnancy was associated with differences in birth weight and incidence of preterm delivery. Confounding by indication may explain the findings.  (+info)

Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. (34/267)

The activation of silent synapses is a proposed mechanism to account for rapid increases in synaptic efficacy such as long-term potentiation (LTP). Using simultaneous recordings from individual pre- and postsynaptic neurons in organotypic hippocampal slices, we show that two CA3 neurons can be connected entirely by silent synapses. Increasing release probability or application of cyclothiazide does not produce responses from these silent synapses. Direct measurement of NMDAR-mediated postsynaptic responses in all-silent synaptic connections before and after LTP induction show no change in failure rate, amplitude, or area. These data do not support hypotheses that synapse silent results from presynaptic factors or that LTP results from increases in presynaptic glutamate release. LTP is also associated with an increase in postsynaptic responsiveness to exogenous AMPA. We conclude that synapse silence, activation, and expression of LTP are postsynaptic.  (+info)

Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons. (35/267)

Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC(50) of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.  (+info)

Trends in antihypertensive drugs in the elderly: the decline of thiazides. (36/267)

The last decade has seen the publication of different editions of guidelines for the pharmacological treatment of hypertension that were based on the results of large, randomised trials. Since these guidelines were meant to inform practitioners, we analysed the pattern of prescription of antihypertensive agents between 1988 and 1997 among older hospitalised adults. Because of the wealth of data supporting the use of thiazides diuretics, we focused on diuretic prescription, to identify independent predictors of their utilisation. To this end, we used the GIFA database that includes patients admitted to academic medical centres throughout Italy between 1988 and 1997. We studied 5061 patients over 65 years of age selected among a population of 28 411, based on the diagnosis of arterial hypertension at discharge. The use of ACE-inhibitors has been raising steadily through the years, and they are the agents most commonly used since 1996. Calcium channel blockers showed a similar trend and were the top prescribing drug until 1995; afterwards, the documentation of potentially severe side effects has resulted in a nearly 20% reduction of their use. Beta-blockers have remained unpopular throughout the decade. Instead, the prescription of diuretics as a class showed a biphasic trend; an initial decrease with a prolonged steady state and a more recent raise. However, at a separate analysis, it was a evident that a progressive increase of the use of loop diuretics since 1988 has been paralleled by a nearly 50% reduction of thiazides prescriptions. Loop diuretics were more likely to be prescribed to older individuals, those with cardiac heart failure, coronary heart disease and high creatinine level. In contrast, independent predictors of thiazides use were female gender, good functional status, preserved renal function, and absence of cardiovascular comorbidity. In conclusion, despite continued recommendations to use thiazides diuretics for the treatment of hypertension among older individuals, their use has been declining steadily between 1988 and 1997. A possible explanation is that the choice to prescribe a thiazides diuretic is influenced by age, functional status and comorbidity.  (+info)

Properties of synchronous and asynchronous release during pulse train depression in cultured hippocampal neurons. (37/267)

Neurotransmitter release displays at least two kinetically distinct components in response to a single action potential. The majority of release occurs synchronously with action-potential-triggered Ca(2+) influx; however, delayed release--also called asynchronous release--persists for tens of milliseconds following the peak Ca(2+) transient. In response to trains of action potentials, synchronous release eventually declines, whereas asynchronous release often progressively increases, an effect that is primarily attributed to the buildup of intracellular Ca(2+) during repetitive stimulation. The precise relationship between synchronous and asynchronous release remains unclear at central synapses. To gain better insight into the mechanisms that regulate neurotransmitter release, we systematically characterized the two components of release during repetitive stimulation at excitatory autaptic hippocampal synapses formed in culture. Manipulations that increase the Ca(2+) influx triggered by an action potential--elevation of extracellular Ca(2+) or bath application of tetraethylammonium (TEA)--accelerated the progressive decrease in synchronous release (peak excitatory postsynaptic current amplitude) and concomitantly increased asynchronous release. When intracellular Ca(2+) was buffered by extracellular application of EGTA-AM, initial depression of synchronous release was equal to or greater than control; however, it quickly reached a plateau without further depression. In contrast, asynchronous release was largely abolished in EGTA-AM. The total charge transfer following each pulse--accounting for both synchronous and asynchronous release--reached a steady-state level that was similar between control and EGTA-AM. A portion of the decreased synchronous release in control conditions therefore was matched by a higher level of asynchronous release. We also examined the relative changes in synchronous and asynchronous release during repetitive stimulation under conditions that highly favor asynchronous release by substituting extracellular Ca(2+) with Sr(2+). Initially, asynchronous release was twofold greater in Sr(2+). By the end of the train, the difference was approximately 50%; consequently, the total release per pulse during the plateau phase was slightly larger in Sr(2+) compared with Ca(2+). We thus conclude that while asynchronous release--like synchronous release--is limited by vesicle availability, it may be able to access a slightly larger subset of the readily releasable pool. Our results are consistent with the view that during repetitive stimulation, the elevation of asynchronous release depletes the vesicles immediately available for release, resulting in depression of synchronous release. This implies that both forms of release share a small pool of immediately releasable vesicles, which is being constantly depleted and refilled during repetitive stimulation.  (+info)

Mechanisms underlying presynaptic facilitatory effect of cyclothiazide at the calyx of Held of juvenile rats. (38/267)

1. Excitatory postsynaptic currents (EPSCs) were recorded using the whole-cell patch-clamp technique at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) in auditory brainstem slices from juvenile rats. 2. Bath application of cyclothiazide (CTZ, 100 microM) significantly increased the amplitude of EPSCs mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Cyclothiazide increased the magnitude of paired-pulse depression of both AMPA-EPSCs (intervals, 50 and 500 ms) and NMDA-EPSCs (interval, 20 ms). In low Ca(2+), high Mg(2+) solution, CTZ decreased the number of failures and increased the mean amplitude of AMPA-EPSCs more than three-fold. 3. Presynaptic Ca(2+) currents and K(+) currents were directly recorded from the calyceal nerve terminals. These currents were attenuated by CTZ in a reversible manner. The magnitude of inhibition of presynaptic K(+) currents by CTZ (100 microM) was comparable to that by 5 microM 4-aminopyridine (4-AP). Both CTZ and 4-AP slowed the repolarizing phase of presynaptic action potentials. 4. The inhibitory effects of CTZ on presynaptic ion channels were mimicked by a solution having reduced Ca(2+) concentration and 5 microM 4-AP. This solution facilitated EPSCs, but the magnitude of facilitation was significantly less than that caused by CTZ. 5. In the presence of tetrodotoxin (TTX), CTZ increased the mean frequency of miniature EPSCs three-fold. CTZ prolonged their decay time but had no effect on their amplitude. The facilitatory effect of CTZ on the miniature frequency was neither blocked by a protein kinase C inhibitor nor occluded by phorbol ester, suggesting that a distinct mechanism underlies the effect of CTZ. 6. We conclude that CTZ facilitates transmitter release through suppression of presynaptic potassium conductance and stimulation of exocytotic machinery downstream of Ca(2+) influx.  (+info)

Diet and medication in the treatment of hyperuricemia in hypertensive patients. (39/267)

OBJECTIVE: To evaluate the effects of diet and medication, either isolated or associated, on serum levels of uric acid in patients with hyperuricemia. METHODS: We studied patients from the Hypertension Unit of the University of Goias who had hyperuricemia (men > or =8.5 mg/dL and women > or =7.5 mg/dL). We divided the patients into three groups: G1 (low purine diet), G2 (low purine diet + medication), and G3 (medication only). Patients received allopurinol, 150 mg/day titrated up to 300 mg/dL when necessary. Patients were evaluated with regards to their lifestyles (diet, smoking, physical, activity, alcohol consumption), uric acid, blood pressure, use of medication, body mass index, cholesterol, and triglyceride. Follow-up took place in weeks 0 (M1), 6 (M2), 12 (M3) during the intervention and in week 36 (M4) after the study was completed. RESULTS: Fifty-five patients participated in the study, 31 women, mean age 54.4+/-10.6 years, body mass index 28.6+/-3.9 kg/m2. A similar reduction (p<0.001) in uric acid levels occurred in the three intervention groups. In week 36 (M4), after 24 weeks without intervention, a tendency toward elevation of uricemia was noted in G2 and G3, and a continuous drop in uricemia was noted in G1. No significant modifications were observed in the other variables analyzed. CONCLUSION: Considering the cost x benefit relationship, a diet low in purine should be the 1st therapeutic option for controlling hyperuricemia in patients with similar characteristic to the ones presented in this study.  (+info)

Correlation of AMPA receptor subunit composition with synaptic input in the mammalian cochlear nuclei. (40/267)

The composition of AMPA receptors in patches excised from somata and dendrites of six cell types in the mammalian cochlear nuclei was probed and compared electrophysiologically and pharmacologically with the rapid application of glutamate. Cells excited predominantly by auditory nerve fibers had AMPA receptors with exceptionally rapid gating (submillisecond deactivation and desensitization time constants). The nonlinear current-voltage relationship in the presence of spermine showed that few of these receptors had GluR2 subunits, and the insensitivity of desensitization to cyclothiazide indicated that they contained mostly flop splice variants. At synapses made by parallel fibers, AMPA receptors were slowly gating (time constants of deactivation and desensitization >1 msec) and contained higher levels of GluR2 and flip isoforms. However, receptors at auditory nerve synapses on cells that also receive parallel fiber input, the fusiform cells, had intermediate properties with respect to kinetics and contained GluR2 and flip isoforms. Given the diverse biophysical properties, patterns of innervation, patterns of electrical activity, and targets of each cell type in vivo, these data indicate that the kinetics and permeation properties of AMPA receptors are linked to factors associated with synaptic connectivity.  (+info)