Clinical observations on an antihypertensive chlorothiazide analogue devoid of diuretic activity. (73/267)

The antihypertensive effect of the diuretic benzothiadiazines has been attributed to salt depletion and the resultant reduction in plasma volume. The study described in this report was concerned with the effects of diazoxide, a non-diuretic analogue which had been found in animal experiments to have a hypotensive effect.Intravenous diazoxide (3 mg./kg.) reduced blood pressure an average of 26/16 mm. Hg in seven hypertensive subjects. An associated rise in cardiac output (0.7 to 5.7 1./min.) and decrease in peripheral vascular resistance occurred. There was no postural hypotension, or change in external salt balance or in the concentration of serum sodium or potassium.Oral administration of the drug (0.2 to 0.5 g./day for eight to 50 weeks) lowered blood pressure more than 15/10 mm. Hg in 26 of 30 hypertensive subjects. Associated effects were: (1) weight gain in 26 of 30 subjects, (2) anorexia in 15 of 30, (3) lacrimation in six of 30, (4) aggravation of diabetes in two, and (5) transient cardiac arrhythmias in four. This study suggests that this benzothiadiazine acts directly on arterioles to reduce peripheral vascular resistance.  (+info)

TREATMENT OF HYPERTENSION. AN EVALUATION OF ALPHA-METHYLDOPA. (74/267)

In a study utilizing an alternating double blind technique 15 patients were given alphamethyldopa in divided doses of 1 gram daily alone and in combination with a benzothiadiazine diuretic. The average blood pressure of patients receiving the drug alone was 157/90 mm of mercury, against the placebo control of 195/109 mm. The average blood pressure of patients receiving the drug in combination with a benzothiadiazine diuretic was 164/98 mm; in the control with placebo plus benzothiadiazine diuretic, it was 169/104 mm. Alpha-methyldopa appeared to be effective in reducing blood pressure in patients with benign essential hypertension.  (+info)

SULFONAMYL DIURETICS--MECHANISM OF ACTION AND THERAPEUTIC USE. (75/267)

The mechanism whereby sulfonamyl diuretics are effective is through the blockage of the renal tubular reabsorption of chloride. The excretion of sodium, potassium and water is a passive one to maintain ionic equilibrium. Chlorothiazide has been shown to be almost ineffective as a diuretic agent per se. Although it does block a moiety of the renal tubular reabsorption of bicarbonate, the effect is merely a transient one.  (+info)

Functional expression of the human thiazide-sensitive NaCl cotransporter in Madin-Darby canine kidney cells. (76/267)

The thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is expressed on the apical membrane of epithelial cells lining the distal convoluted tubule, is responsible for the reabsorption of 5% to 10% of filtered Na(+) and Cl(-). To date, functional studies on the structural and regulatory requirements for localized trafficking and ion-transporting activity of NCC have been hampered by lack of a suitable cell system expressing this cotransporter. Reported here is the functional expression of human NCC (hNCC) in a polarized mammalian cell of renal origin-that is, the high-resistance Madin-Darby canine kidney (MDCK) cell. Western blot testing revealed that the cells predominantly expressed the complex glycosylated (approximately 140 kD) form of hNCC. hNCC was present primarily in the apical part of the cell. The functionality of hNCC was demonstrated by the gain of thiazide-sensitive Na(+) uptake and transepithelial transport activity. Na(+) uptake was significantly increased after short-term (15 min) treatment with forskolin, whereas cyclic guanosine monophosphate, wortmannin, phorbol 12-myriatate 13-acetate, and staurosporine were without effect. This indicates that hNCC activity is regulated through cyclic adenosine monophosphate, rather than via cyclic guanosine monophosphate, phospho-inositide 3-kinases or protein kinase C. Aldosterone did not alter Na(+) uptake in the short term (15 min) but significantly increased the transport activity in the long term (16 h). The latter effect of aldosterone was due to an effect on the cytomegalovirus promoter/enhancer driving the expression of hNCC. hNCC-MDCK cells are a good model for the study of the regulation of apical trafficking and ion-transporting activity of hNCC.  (+info)

Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses. (77/267)

Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.  (+info)

Desensitization of postsynaptic glutamate receptors contributes to high-frequency homosynaptic depression of aplysia sensorimotor connections. (78/267)

Withdrawal reflexes of Aplysia are mediated in part by a monosynaptic circuit of sensory (SN) and motor (MN) neurons. A brief high-frequency burst of spikes in the SN produces excitatory postsynaptic potentials (EPSPs) that rapidly decrease in amplitude during the burst of activity. It is generally believed that this and other (i.e., low-frequency) forms of homosynaptic depression are entirely caused by presynaptic mechanisms (e.g., depletion of releasable transmitter). The present study examines the contribution that desensitization of postsynaptic glutamate receptors makes to homosynaptic depression. Bath application of cyclothiazide, an agent that reduces desensitization of non-NMDA glutamate receptors, reduced high-, but not low-frequency synaptic depression. Thus, a postsynaptic mechanism, desensitization of glutamate receptors, can also contribute to homosynaptic depression of sensorimotor synapses.  (+info)

Resistance profile of a hepatitis C virus RNA-dependent RNA polymerase benzothiadiazine inhibitor. (79/267)

Recently, a benzo-1,2,4-thiadiazine antiviral agent (C(21)H(21)N(3)O(4)S; compound 4) was shown to be a potent, highly specific inhibitor of the primary catalytic enzyme of the hepatitis C virus (HCV) replicase complex. In this study, we selected for resistance to confirm the mechanism of action for compound 4 in HCV replicon cells. As expected, spontaneous mutations or fluidity in the HCV polymerase (NS5B) coding sequence occurred upon routine passage of the HCV replicon cells in the absence of compound 4. After 1 month of culture in the presence of 10 microM compound 4, or 20 times the 50% inhibitory concentration of the replicon, replicon cells were almost 20-fold less susceptible to compound 4. Twenty-one NS5B cDNA clones were generated from the resistant replicon cells. Five mutations in the 21 NS5B clones were present at frequencies higher than that of control replicon cells, and no clone contained more than a single mutation within the polymerase gene. RNA-dependent RNA polymerase studies using purified recombinant NS5B containing these single point mutations allowed the identification of residue 414 as sufficient for biochemical resistance to compound 4. Further, the contribution of this residue to confer cell-based resistance to compound 4 was validated using a stable recombinant mutant replicon cell line which harbors a methionine-to-threonine change at residue 414. The potential for additional mutations in other nonstructural genes of HCV to contribute to the resistance profile of compound 4 is discussed.  (+info)

Risk factors for thiazide-induced hyponatraemia. (80/267)

BACKGROUND: Thiazide-induced hyponatraemia is common and potentially life threatening. In the absence of well-defined risk factors for this complication, guidelines for prescribing cannot be established. AIM: To examine whether a subgroup of patients is particularly susceptible to this complication. DESIGN: Retrospective case-control study. METHODS: We defined and recruited cases of symptomatic hyponatraemia that necessitated hospitalization from January 1996 to April 2002. Controls were selected from 8420 patients being prescribed thiazides and seen at the same institution during that period of time. RESULTS: There were 223 cases and 216 controls, with a median 115 days thiazide use. Cases were older than controls (76 +/- 9 vs. 66 +/- 13 years, p < 0.001) and lighter (52.3 +/- 10.3 vs. 63.4 +/- 3 kg, p < 0.001). By univariate analysis, serum potassium level, use of indapamide, elderly home institutionalization and physical immobility were risk factors for thiazide-induced hyponatraemia, but gender, duration of thiazide use, concomitant therapy with loop diuretics, angiotensin-converting enzyme inhibitors or non-steroidal anti-inflammatory drugs, and renal function were not. By stepwise logistic regression analysis, patient age, body weight and serum potassium were the only independent predictive factors. Each 10-year increment of age was associated with a two-fold increase in risk (hazards ratio 2.14, 95%CI 1.59-2.88). For a 5 kg increment in mass, there was a 27% decrease in odds ratio (odds ratio 0.77, 95%CI 0.68-0.87). One SD increase in serum potassium (0.84 mmol/l) was associated with a 63% decrease in risk (odds ratio 0.37, 95%CI 0.27-0.50; p < 0.0001). DISCUSSION: Hyponatraemia is a common problem after thiazide therapy. Extra caution and close monitoring are warranted when prescribing thiazides for elderly patients with low body mass.  (+info)