Sympatho-adrenal mechanisms and the antihypertensive response to thiazide diuretics

Abstract: Thazide diuretics lower the blood pressure during long-term treatment by reducing the peripheral vascular resistance. This seems to be related to the natriuresis rather than to a direct vasodilating effect of the thiazides. There is evidence that the volume depletion caused by thiazide treatment initially triggers an increase in sympathetic nerve activity, which may account for initial increases in vascular resistance. Although both responses subside during long-term treatment, there is no evidence showing a causal relationship between these changes. The long-term hemodynamic adaptation to thiazide treatment may be related to altered cardiovascular reflexes. Changes in sympathetic nerve activity and reduced vascular sensitivity to noradrenaline may contribute to the adaptation. An analysis of the relative importance of these mechanisms requires further studies comparing the time courses for various effects in respondcrs and non-responders to the treament.     

Is It Possible to Characterize Recurrent Urinary Stone Formers Who Benefit from Thiazide Prophylaxis?

ABSTRACT. Laerum E, Larsen S (Institute of General Practice, University of Oslo, Oslo, and MEDSTAT, Center for Administration Design and Statistical Analysis in Medical Research, Strømmen, Norway). Is it possible to characterize recurrent urinary stone formers who benefit from thiazide prophylaxis? Application of discrimination analysis. Acta Med Scand 1987; 221: 103–8. Twenty-three patients with recurrent urinary stones have been treated for 12–54 months with hydrochlorthiazide and 25 with placebo. Discrimination analysis was performed in order to distinguish patients with new stone formation (non-responders) from those without stone recurrence (responders) during the treatment. The discriminant function classified 16 out of 18 responders as such and 5 non-responders as such by using a combination of the three intital varibles urinary pH, 24-h urine volume and serum phosphate. Eighteen other analysed variables and patient factors did not contribute to this discrimination. By using “leaving-one-out-technique”, the probability for erroneously classifying a patient increased from 9 to 17%. Applying the discriminant function on the group receiving placebo, 92% of these patients were classified as responders to thiazide. It is concluded that discrimination analysis may give valuable information in charcterizing patients who will benefit from a special therapy.     

Comparison of Effects of Low Dose of Spironolactone and a Thiazide Diuretic in Patients with Hypertension Treated with an Angiotensin-Converting Enzyme Inhibitor or an Angiotensin Type 1 Receptor Blocker

This study was performed to investigate the additional anti-hypertensive effects and safety of low-dose thiazide diuretic, trichlormethiazide (TCTZ), and a mineralocorticoid receptor blocker, spironolactone (SPI), as add-on therapy in 64 patients whose blood pressure (BP) at office were over 140/90 mmHg, while receiving anti-hypertensive medication including an angiotensin-converting enzyme inhibitor or angiotensin II type I receptor antagonist. After 6 months, we observed a decrease of office and home BP. Moreover, urinary albumin excretion (UAE) was reduced in SPI-treated group, but not in the TCTZ-treated group. No significant change in serum potassium, lipids, glucose, or uric acid was observed. In conclusion, low-dose thiazide diuretic or SPI provided a significant additional anti-hypertensive effect in patients in whom hypertension was not controlled by medication, and SPI-reduced UAE.     

Chlorthalidone inhibits the KvLQT1 potassium current in guinea-pig ventricular myocytes and oocytes from Xenopus laevis

BACKGROUND AND PURPOSE: Chlorthalidone is used for the treatment of hypertension as it produces a lengthening of the cardiac action potential. However, there is no experimental evidence that chlorthalidone has electrophysiological effects on the potassium currents involved in cardiac repolarization. EXPERIMENTAL APPROACH: Ventricular myocytes and oocytes, transfected with human ionic channels that produce IK current, were exposed to different concentrations of chlorthalidone. Action potentials and potassium currents were recorded using a patch clamp technique. To determine which component of the current was affected by chlorthalidone, human channel proteins (hERG, minK and KvLQT1) were used. KEY RESULTS: Chlorthalidone prolonged the ventricular action potential at 50 and 90% by 13 and 14%, respectively. The cardiac potassium currents I(to) and IK(1) were not affected by chlorthalidone at any concentration, whereas the delayed rectifier potassium current, IK, was blocked in a dose-response, voltage-independent fashion. In our preparation, 100 microM chlorthalidone blocked the two components of the delayed rectifier potassium current with the same potency (50.1+/-5% for IK(r) and 54.6+/-6% for IK(s)) (n=7, P<0.05). The chlorthalidone-sensitive current was slow and saturated at potentials greater than +30 mV. In our conditions only the KvLQT1 potassium current was affected by the drug, by 14%. CONCLUSIONS AND IMPLICATIONS: Chlorthalidone was demonstrated to have a direct effect on cardiac ventricular myocytes; it blocked the delayed rectifier potassium current (IK), specifically the KvLQT1 component of the potassium current. These results indicate that it has potential for use as an antiarrhythmic but further studies are needed.     

美托洛尔及厄贝沙坦氢氯噻嗪在老年重症心力衰竭急诊内科治疗中的应用

目的:探讨急诊内科治疗老年重症心力衰竭患者的临床疗效。方法:选取老年重症心力衰竭患者150例,将其随机分为观察组和对照组各75例,对照组采用常规治疗,观察组在常规治疗基础上加用美托洛尔及厄贝沙坦氢氯噻嗪联合治疗,两组均治疗3个月,治疗后比较两组的临床治疗效果。结果:治疗后观察组总有效率为97.33%,明显高于对照组的88.00%,两组差异有统计学意义(P<0.05)。结论:美托洛尔联合厄贝沙坦氢氯噻嗪治疗老年重症心力衰竭,疗效显著,患者心功能明显改善,值得临床推广应用。     

Metabolic complications associated with use of diuretics

Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium-sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses.     

A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM

Summary In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA_{1 c} concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8 ± 2.9 vs 27.3 ± 3.5 μmol · kg^{− 1}· min^{− 1}, p < 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8 ± 3.6 vs 27.3 ± 3.5 μmol · kg^{− 1}· min^{− 1}, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 ± 0.5 vs 10.2 ± 0.3 μmol · kg^{− 1}· min^{− 1}, p < 0.05) and suppressed to a lesser extent following insulin (4.0 ± 0.7 vs 2.0 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline (11.7 ± 0.5 vs 10.6 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p < 0.05) whereas bendrofluazide 1.25 mg did not (10.2 ± 0.3 vs 10.6 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p = NS). At a dose of 1.25 mg bendrofluazide is as effective as conventional doses but has less adverse metabolic effects. In contrast to conventional doses which worsen both hepatic and peripheral insulin resistance, low-dose bendrofluazide has no effect on insulin action in non-insulin-dependent diabetic subjects. [Diabetologia (1995) 38: 853–859] Received: 6 September 1994 and in revised form: 29 December 1994