Chlorothiazide in Hypertensive and Normotensive Patients

Freis, Edward D.; Wanko, Annemarie; Wilson, Ilse M.; Parrish, Alvin E.

doi:10.1111/j.1749-6632.1958.tb46773.x

Cited by 88 publications

(15 citation statements)

References 2 publications

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“…At 12 weeks, the mean decline in the serum potassium level was significantly (P<.05) greater in the 25-mg group than in the 15-mg group, amounting to 0.55 mmol/L (0.55 mEq/L) vs 0.31 mmol/L (0.31 mEq/L). At the fourth-week visit, 15% of the patients exhibited hypokalemia (serum potas¬ sium level <3.5 mmol/L [3.5 mEq/L]) in the 15-mg group, compared with 23% in the 25-mg group.…”

Section: Potassiummentioning

confidence: 86%

Efficacy and Reduced Metabolic Side Effects of a 15-mg Chlorthalidone Formulation in the Treatment of Mild Hypertension

Vardan

Mehrotra²,

Mookherjee

et al. 1987

JAMA

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We compared a new low-dose chlorthalidone formulation consisting of 15 mg of this compound and a biocompatible polymer in a double-blind placebo-controlled trial with the standard 25-mg dose of chlorthalidone in the management of mild essential hypertension. Two hundred twenty-two patients, ranging in age from 21 to 69 years, with an average standing diastolic blood pressure between 91 and 104 mm Hg participated in this trial. At the end of 12 weeks, the percentage of patients who had a decrease in their standing diastolic blood pressure of 5 mm Hg or more was statistically similar in both of the active-treatment groups and significantly different from the placebo group. With the lower-dose compound, the metabolic side effect of hypokalemia was less of a problem and there was no evidence of glucose intolerance. Thus, this new 15-mg formulation of chlorthalidone appears to be an effective antihypertensive agent with fewer metabolic side effects compared with the standard 25-mg dose in the management of mild essential hypertension.

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Section: Potassiummentioning

confidence: 86%

Efficacy and Reduced Metabolic Side Effects of a 15-mg Chlorthalidone Formulation in the Treatment of Mild Hypertension

Vardan

Mehrotra²,

Mookherjee

et al. 1987

JAMA

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“…There seems to be a tendency for patients whose blood pressure is controlled with chlorothiazide in addition to bethanidine, guanethidine, or methyldopa to have a lower pulse pressure than those not having chlorothiazide in addition (Table X). It is well known that the treatment of hypertension with chlorothiazide (Freis, Wanko, Wilson, and Parrish, 1958) and other diuretics (Cranston, Juel-Jensen, Semmence, Handfield Jones, Forbes, and Mutch, 1963) often produces a greater reduction in systolic than in diastolic pressure, though this might be largely ascribed to an effect of general lowering of the blood pressure.…”

Section: Chlorothiazidementioning

confidence: 99%

Bethanidine, Guanethidine, and Methyldopa in Treatment of Hypertension: a Within-patient Comparison

Prichard¹,

Johnston²,

Hill³

et al. 1968

BMJ

103

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When a new agent is introduced into therapeutics it is important to obtain reliable comparison with existing drugs. Examination of the published reports on guanethidine, methyldopa, and bethanidine provides only an approximate estimate of their comparative merits. Most reports indicate that about 70% of patients achieve reasonable control of their blood pressure with each drug. However, the conditions of the trials varied in many respects, such as levels of blood pressure accepted as good and fair control, the severity of the hypertension in the patients treated, and the clinic routine. In addition, it is difficult to obtain a clear idea of the acceptability of these drugs by patients and of the incidence of side-effects. It was with these factors in mind that, following our initial studies with bethanidine (Johnston, Prichard, andRosenheim, 1962, 1964), we designed a formal trial to compare bethanidine with the established drugs guanethidine and methyldopa.Patients.-Details of the 30 patient-volunteers completing the trial are summarized in Table I; four of the original 34 patients were withdrawn (see below). The patients were selected solely by the criteria that it was thought necessary to treat them with potent hypotensive drugs and that they were able to attend regularly. All except one patient were on potent drugs before the trial-14 on bethanidine, 11 on guanethidine, and 4 on methyldopa. Method Summary of TrialA within-patient comparison was designed in which each patient received bethanidine, guanethidine, and methyldopa. These drugs were prepared in identical capsules and were given in random order, the randomization being stratified according to the treatment the patient was receiving before the trial.Patients were seen at two-weekly intervals during the trial (except for the intrusion of their holidays) under After careful consideration it was not thought desirable for physician A to be " blind." Safe and reasonably rapid adjustment of the dose was essential in order to avoid exposing the patients to unnecessary risk, and as the duration of action of the drugs varies different dose schedules have to be followed. The final decision on instructions to adjust the dose had to be tempered with the knowledge of any side-effects being experienced, most notably symptoms of postural hypotension. In addition, the drugs have several characteristic side-effects which would have permitted physician A in many instances to know which drug was being used.Previous to the " period of assessment " (see below) on each of the three drugs there was a " run-in period." The run-in period was to enable the dose of each drug to be adjusted to obtain the optimal therapeutic effect. The run-in before the first drugs also served to familiarize the patients with clinic procedure, to ensure that they understood the " weekly symptom record sheet" (see below) which they kept, and, lastly, it went some way to ensure that the greater part of the hypotensive effect of increased interest by the physician became stabilized before the tr...

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“…In fact, it is often forgotten that these drugs appear to be effective only when hypertension is present; they have little or no effect on the arterial pressure in normotensive individuals, but reduce it substantially in hypertensive ones. 19–21 Therefore, it would be appealing to find a link between sympathetic overactivity and activated NCC. Here, we confirmed that NCC is activated in salt-sensitive hypertension resulting from adrenergic stimulation.…”

Section: Introductionmentioning

confidence: 99%

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

et al. 2014

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Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. While both hemodynamic and tubular effects likely participate, most evidence supports a major role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive transporter, NCC, by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule (DCT) to show that DCT cells are especially enriched for β1-adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. As two protein kinases, Ste20p-related Proline Alanine-rich kinase (SPAK) and Oxidative stress responsive 1 (OxSR1), phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect SPAK abundance or its localization in the DCT; instead, we observed a striking activation of OxSR1. We confirmed that SPAK is not required for NCC activation, using SPAK knockout mice. Together, the data provide strong support for a signaling system involving β1- receptors in the DCT that activates NCC, at least in part via OxSR1. The results have implications regarding device- and drug-based treatment of hypertension.

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Chlorothiazide in Hypertensive and Normotensive Patients

Cited by 88 publications

References 2 publications

Efficacy and Reduced Metabolic Side Effects of a 15-mg Chlorthalidone Formulation in the Treatment of Mild Hypertension

Efficacy and Reduced Metabolic Side Effects of a 15-mg Chlorthalidone Formulation in the Treatment of Mild Hypertension

Bethanidine, Guanethidine, and Methyldopa in Treatment of Hypertension: a Within-patient Comparison

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

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