Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients. Chlorthalidone has significantly reduced stroke and cardiovascular end points in several landmark trials; however, hydrochlorothiazide remains favored in practice. Most clinicians assume that the drugs are interchangeable, but their antihypertensive effects at lower doses have not been directly compared. We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. The main outcome, 24-hour ambulatory blood pressure (BP) monitoring, was assessed at baseline and week 8, along with standard office BP readings every 2 weeks. Thirty patients completed the first active treatment period, whereas 24 patients completed both. An order-drug-time interaction was observed with chlorthalidone; therefore, data from only the first active treatment period was considered. Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = -12.4+/-1.8 mm Hg versus -7.4+/-1.7 mm Hg; P=0.054; nighttime mean = -13.5+/-1.9 mm Hg versus -6.4+/-1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (-15.7+/-2.2 mm Hg versus -4.5+/-2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (-17.1+/-3.7 versus -10.8+/-3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.

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Comparative Antihypertensive Effects of Hydrochlorothiazide and Chlorthalidone on Ambulatory and Office Blood Pressure

The 24-hour patterns of body temperature and plasma thyrotropin (TSH) were measured in eight bipolar patients in both depressed and recovered (after 3 weeks of treatment) states and in eight normal control subjects. Clear circadian patterns were detected for both temperature and TSH. Nocturnal body temperature was increased and the nocturnal surge of TSH was blunted during depression; these abnormalities were corrected after recovery. The inverse relationship between changes in body temperature and TSH levels at night suggests that changes in thermoregulation may be responsible for the neuroendocrine disturbance and may play a role in the pathophysiology of depression.

Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects.

Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain-Na,K-ATPase (Na(+)- and K(+)-dependent adenosine triphosphatase) complex can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interaction with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain-Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper.

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Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

Renin-angiotensin system reactivity and the constitutive capacity of the renal tubule to reabsorb sodium play a role in the individual response to diuretic therapy; therefore we evaluated the blood pressure (BP) response to hydrochlorothiazide in 87 never-treated individuals with mild essential hypertension, according to ACE gene I/D and α-adducin Gly460Trp polymorphism. These genotypes where chosen because previous data showed their interaction in determining the BP response to salt probably was the result of their involvement in the activation of the renin-angiotensin system (ACE) and in the constitutive capacity of the kidney to reabsorb sodium (α-adducin) (treatment for 2 months). BP was measured after 3 run-in visits and after the first and second months of treatment by means of a standardized procedure. Data were analyzed by ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for gender, age, and body mass index). Although basal mean BP (MBP) was similar in the different ACE and α-adducin genotypes, patients carrying at least one I allele of ACE and one 460Trp allele of α-adducin had the largest MBP decrease with treatment (12.7±1.9 mm Hg), the effect of the combination of genotypes being additive but not epistatic. These patients had an odds ratio of 15.75 of being a responder to hydrochlorothiazide compared with patients with Gly460Gly+DD, with the least MBP decrease (3.4±1.7 mm Hg). α-Adducin and ACE I/D polymorphism may be useful to predict the interindividual degree of response to hydrochlorothiazide; the analysis of the combination of the 2 genotypes increases the accuracy of the prediction of response to the drug.

ACE and α-Adducin Polymorphism as Markers of Individual Response to Diuretic Therapy

Prazosin is an orally active post-synaptic selective alpha 1-adrenoreceptor antagonist that has been widely used in treating hypertension and congestive heart failure (CHF). Its role in the treatment of hypertension has previously been reviewed in this journal. Subsequent reports confirm its efficacy in treating mild to severe hypertension as a single agent or, more frequently, in combination with another antihypertensive agent and/or a diuretic. Recent studies of the metabolic effect of prazosin indicate that the drug may have a favourable effect on plasma lipids in hypertensive patients. Its recent use in treatment of congestive heart failure has shown prazosin to be comparable with nitroprusside in producing balanced arterial and venous dilation with generally sustained haemodynamic and clinical effects during long term therapy. Initial studies in Raynaud's phenomenon and in patients with aortic regurgitation or aortic stenosis or with mitral regurgitation are promising, but require confirmation from wider clinical experience. The drug has generally been well tolerated. The primary side effect of orthostatic hypotension can be largely avoided by beginning treatment with a low dose.

Prazosin update. A review of its pharmacological properties and therapeutic use in hypertension and congestive heart failure.

1. Plasma renin activity, body weight and blood pressure were measured before and after 7 days9 treatment with bendrofluazide in ten hypertensive subjects. They were then treated with bendrofluazide alone (5 mg daily) for a minimum of 3 years. The diuretic was then discontinued and the measurements were repeated before and again after 7 days with bendrofluazide. The results were compared with those obtained before chronic treatment with the diuretic. 2. Chronic diuretic treatment was associated with a persistent and progressive rise in plasma renin activity, that fell promptly to pretreatment levels when diuretics were discontinued. This was associated with significant weight gain but no immediate significant rise in blood pressure. 3. When acutely challenged with bendrofluazide the patients showed a greater increase in plasma renin activity on the second occasion than on the first. Three out of five patients with an initially subnormal response had normal responses after chronic diuretic treatment. 4. Chronic diuretic treatment increased the responsiveness of the juxtaglomerular apparatus in some hypertensive patients. 5. Classification of hypertensive patients into renin subgroups may be influenced by previous therapy, even when that therapy has been discontinued for 4 weeks. In particular ‘low renin hypertension’ may be masked by recent use of diuretics, as shown by three of the five patients in this subgroup in the present study.

Plasma renin in long-term diuretic treatment of hypertension: effect of discontinuation and restarting therapy

1. The diurnal rhythms of body temperature and serum thyrotrophin (TSH) levels in euthyroid individuals behaved inversely to one another. 2. An artificially induced rise in the body temperature of these individuals was accompanied by a fall in serum thyrotrophin levels, the amplitudes of their respective rhythms decreasing simultaneously. 3. There was a marked correlation between the degrees of change in body temperature and circulating thyrotrophin levels respectively during warming. 4. In normal subjects manipulation of the diurnal rhythm of body temperature brings about inverse alterations in the thyrotrophin rhythm.

Circadian rhythms of serum thyrotrophin and body temperature in euthyroid individuals and their responses to warming

Combined prazosin and hydralazine in resistant hypertension

Twenty-four-hour urinary sodium excretion and plasma renin activity were monitored in 36 patients receiving bendrofluazide as sole antihypertensive therapy. There was no increase in urinary sodium output compared with pretreatment values during a 2-year period, and there is therefore no evidence that an increase in salt appetite as a result of salt depletion occurred. However, plasma renin activity progressively increased over a 2-year period. In five of eight patients who initially had a subnormal renin response to the diuretic, plasma renin level rose into the normal stimulated range. When administration of the diuretic was stopped in 10 patients after a mean treatment period of 49 months, plasma renin activity promptly fell and weight increased significantly, although blood pressure did not rise. However, on rechallenging with bendrofluazide 28 days later, a greater response was observed than when treatment was originally instituted. Further, three of five patients with low renin hypertension had a normal response on the second occasion. Thus prolonged diuretic therapy has a persistent effect on the activity of the renin-angiotensin system as well as on blood pressure for at least 4 weeks after the discontinuation of diuretics.

Diuretics, sodium intake, and renin in the management of hypertension.

In the first part of this study, we have demonstrated that, in 7 patients with untreated thyrotoxicosis, a 7 day regime of the long acting dopamine antagonist metoclopramide (10 mg orally 8 hourly) produces more adequate dopaminergic blockade at pituitary level than a single oral 10 mg dose of the compound as assessed by serum prolactin responses. Subsequently, we have employed this protracted oral metoclopramide regime to evaluate the contribution of dopaminergic tone to the abnormal TSH and prolactin responsiveness of thyrotoxicosis. Serum TSH and prolactin responses to iv TRH (200 micrograms) were measured in 10 untreated thyrotoxic patients before and after a 7 day period of metoclopramide 10 mg orally 8 hourly. Ten euthyroid individuals were studied in similar fashion, their serum samples being analysed for prolactin levels alone, thus providing a control group for prolactin responsiveness to TRH, before and after metoclopramide. In the thyrotoxic patients basal TSH levels did not change as a consequence of metoclopramide therapy and the TSH response to TRH remained flat. Basal prolactin levels were similar in thyrotoxic and euthyroid individuals and the increase in prolactin, seen in both groups after metoclopramide, was smaller in the thyrotoxic group than in the euthyroid group. Prolactin responsiveness to TRH was significantly impaired in the thyrotoxic subjects as compared to euthyroid subjects. After metoclopramide there was a significant decline in prolactin responsiveness in the euthyroid group, and a similar, though insignificant, trend in the thyrotoxic patients. We conclude that in thyrotoxicosis dopaminergic tone plays no major part in the suppression of TSH levels, nor in the impaired prolactin responsiveness to TRH.

S. Swart

Papers

Plasma renin in long-term diuretic treatment of hypertension: effect of discontinuation and restarting therapy

Circadian rhythms of serum thyrotrophin and body temperature in euthyroid individuals and their responses to warming

Combined prazosin and hydralazine in resistant hypertension

Diuretics, sodium intake, and renin in the management of hypertension.

The effects of dopaminergic blockade on serum TSH and prolactin levels in thyrotoxicosis.