PubMed · 4793102
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A R Remmers, G A Beathard, J D Lindley, H E Sarles. 1973. Diuretics.. https://pubmed.ncbi.nlm.nih.gov/4793102/
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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.
OBJECTIVE: To investigate the effects of the association spironolactone (25 mg)/altizide (15 mg) as monotherapy on left ventricular hypertrophy (LVH) in patients with mild to moderate hypertension. Additionally, to study the correlation between left ventricular mass (LVM) index and electrocardiographic (ECG) criteria for LVH. METHODS AND RESULTS: This was an open, prospective study of 6 months. Patients with mild to moderate essential hypertension were treated with spironolactone/altizide for two months and were included in the study if their blood pressure (BP) at the end of this first treatment period was normalised according to protocol criteria (systolic BP < 160 mm Hg and diastolic BP < 95 mm Hg). Patients then entered a second 4-month treatment period. LVM was determined by echocardiography performed at the beginning of treatment and after 6 months. LVH was defined as LVM > or = 100 g/m2 in women and LVM > or = 131 g/m2 in men. Echocardiograms were interpreted blindly by two echocardiography reading laboratories. Seventy-one patients with a normalised BP after two months of treatment, were enrolled in the study. Changes in LVM index were studied in 31/71 patients with LVH (25 women and 6 men, mean LVM index +/- (SD) 119.9 +/- 16.4 g/m2 in women and 147.8 +/- 10.9 g/m2 in men). Spironolactone/altizide significantly reduced LVM index by 10%, from 125.3 +/- 22.5 to 114.2 +/- 25.1 g/m2 (p < 0.005). Posterior and septal wall thickness decreased by 4% (p = 0.06) and 5% (p = 0.026), respectively. End-diastolic dimension was reduced by 3%, from 50.3 +/- 3.3 to 48.9 +/- 3.4 mm (p = 0.006). The posterior wall thickness to end-diastolic dimension ratio remained unchanged. Complete regression of LVH according to mass criteria occurred in 11 patients out of 31 (34.5%). The observed changes in ECG voltage criteria were in accordance with a decrease of LVM index. CONCLUSION: In this open study, the potassium-sparing diuretic spironolactone/altizide decreases LVM index in hypertensive patients, who were selected for follow-up because they had echocardiographic LVH and because their BP had normalised during an initial 2-month treatment period.
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