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Thiazide-induced vasodilation in humans is mediated by potassium channel activation.

Pickkers P, Hughes AD, Russel FG, Thien T, Smits P.

Division of General Internal Medicine, Department of Medicine, and Department of Pharmacology, University Hospital Nijmegen, Nijmegen, Netherlands.

-Hydrochlorothiazide and indapamide are thought to exert their hypotensive efficacy through a combined vasodilator and diuretic effect, but in vivo evidence for a direct vascular effect is lacking. The presence and mechanism of a direct vascular action of hydrochlorothiazide in vivo in humans were examined and compared with those of the thiazide-like drug indapamide. Forearm vasodilator responses to infusion of placebo and increasing doses of hydrochlorothiazide (8, 25, and 75 microg. min-1. dL-1) into the brachial artery were recorded by venous occlusion plethysmography. Dose-response curves were repeated after local tetraethylammonium (TEA) administration to determine the role of potassium channel activation and, in patients with the Gitelman syndrome, to determine the role of the thiazide-sensitive Na-Cl cotransporter in the vasodilator effect of hydrochlorothiazide. Vascular effects of hydrochlorothiazide were compared with those of indapamide in both normotensive (mean arterial pressure, 85+/-7 mm Hg) and hypertensive (mean arterial pressure, 124+/-16 mm Hg) subjects. At the highest infusion rate, local plasma concentrations of hydrochlorothiazide averaged 11.0+/-1.6 microg/mL, and those of indapamide averaged 7. 2+/-1.5 microg/mL. In contrast to indapamide, hydrochlorothiazide showed a direct vascular effect (maximal vasodilation, 55+/-14%; P=0. 013), which was inhibited by TEA (maximal vasodilation after TEA, 13+/-10%; P=0.02). The response was not dependent on blood pressure and was similar in patients with Gitelman syndrome, indicating that absence of the Na-Cl cotransporter does not alter the vasodilatory effect of hydrochlorothiazide. The vasodilator effect of hydrochlorothiazide in the human forearm is small and only occurs at high concentrations. The mechanism of action is not mediated by inhibition of vascular Na-Cl cotransport but involves vascular potassium channel activation. In contrast, indapamide does not exert any direct vasoactivity in the forearm vascular bed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9856976&dopt=Abstract hydrochlorothiazide Microzide



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Telemetry for cardiovascular monitoring in a pharmacological study: new approaches to data analysis.

Anderson NH, Devlin AM, Graham D, Morton JJ, Hamilton CA, Reid JL, Schork NJ, Dominiczak AF.

Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK. niall stats.gla.ac.uk

Radio-telemetry systems offer the ability to measure blood pressure and heart rate in experimental models of hypertension without the stress artifacts induced by some other methods. We therefore aimed to develop improved, nonparametric regression methods for radio-telemetry data and to use these to assess the effects of pharmacological interventions on cardiac and vascular hypertrophy in the stroke-prone spontaneously hypertensive rat. One control group and 5 groups treated either with losartan (alone or in combination with NG-nitro-L-arginine methyl ester [ L-NAME]), perindopril (also alone or in combination with L-NAME), or hydralazine plus hydrochlorothiazide were monitored for 4 weeks. Cardiac hypertrophy was assessed by the left ventricle plus septum weight to body weight ratio and vascular hypertrophy by flow-cytometry analysis of vascular smooth muscle cell polyploidy. Hemodynamic series were split into trend and cyclic components by the seasonal and trend decomposition procedure based on Loess and compared between groups by Loess regression modeling. Systolic and diastolic blood pressures were reduced systematically by losartan and perindopril (P<10(-10)) but to a lesser extent by hydralazine plus hydrochlorothiazide (P<10(-8)), and diurnal variation was reduced in the latter group (P<10(-6)). L-NAME significantly reduced the hypotensive effect only of losartan. Vascular and cardiac hypertrophy were significantly attenuated with losartan or perindopril, but were unchanged with other treatments. The new analysis proposed here identifies differential effects on trends and cyclic variation and associations with regression of end-organ damage for losartan and perindopril compared with hydralazine plus hydrochlorothiazide. The method offers a powerful tool for detailed investigation of radio-telemetry data.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9931112&dopt=Abstract hydrochlorothiazide Microzide



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[Efficacy and safety of combination therapy with losartan and hydrochlorothiazide in elderly hypertension]

[Article in Japanese]

Eto K, Tsuchihashi T, Abe I, Iida M.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University.

We examined the effect and safety of combination therapy with low-dose diuretics (hydrochlorothiazide: HCTZ) and angiotensin II receptor antagonist (losartan) in elderly cases of hypertension, using ambulatory blood pressure monitoring (ABPM). Elderly hypertensive patients (mean age 75 +/- 2 years) were treated with either losartan (25-50 mg/day) or HCTZ (12.5 mg/day) for at least 4 weeks, and then 24-hour blood pressure (BP) was measured by ABPM. Combination therapy with addition of other drug was initiated in 14 patients whose 24-hour systolic BP or daytime systolic BP was over 140 mmHg (160 mmHg for the patients of 80 years or older). After 4 weeks of the combination therapy, ABPM was repeated. Blood cell count and blood chemistry were also done before and after initiation of combination therapy. In the losartan-preceding group (n = 9), the combination therapy with HCTZ reduced 24-hour BP by 19.3 +/- 2.3/6.6 +/- 2.3 mmHg. Similarly, daytime and nighttime BP decreased by 21.4 +/- 4/8.4 +/- 2.8 mmHg and 15.2 +/- 4/4.2 +/- 2.4 mmHg, respectively. In the HCTZ-preceding group, the combination with losartan also decreased 24-hour BP by 12.2 +/- 4.8/3.4 +/- 1.4 mmHg. The decreases of daytime and nighttime BP were 13.8 +/- 6.6/4 +/- 1.1 mmHg and 10 +/- 4.7/3 +/- 2.4 mmHg, respectively. Heart rate did not change with combination therapy in the losartan-preceding group, while heart rate during daytime tended to decrease by addition of losartan in the HCTZ-preceding group (3.8 +/- 1.7/min). Serum electrolytes, uric acid, lipids, renal function and body weight did not change during the study period. Thus, combination therapy of losartan/hydrochlorothiazide seems useful in the treatment of elderly hypertension, showing additive BP lowering effect without metabolic adverse effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11974942&dopt=Abstract hydrochlorothiazide Microzide



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Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries.

Calder JA, Schachter M, Sever PS.

Department of Clinical Pharmacology, St. Mary's Hospital, London, England.

We examined the role of K+ channels in mediating the acute vascular actions of hydrochlorothiazide, indapamide, cicletanine, and cromakalim, studying the effect of K+ channel blockers on drug-induced relaxation and drug-induced 86Rb efflux in guinea pig mesenteric arteries. Cromakalim-induced relaxation was unaffected by charybdotoxin, apamin, or phencyclidine (PCP) but was reduced by 75% (with 30 microM cromakalim) by glibenclamide (p < 0.001). Cromakalim increased 86Rb efflux from guinea pig vessels, an effect that was abolished by glibenclamide. Hydrochlorothiazide and cicletanine-induced relaxations have been shown to be inhibited by charybdotoxin by unaffected by glibenclamide, apamin, or PCP. Hydrochlorothiazide and cicletanine increased 86Rb efflux from guinea pig mesenteric arteries. These increases were abolished by charybdotoxin. Indapamide-induced relaxation was not affected by incubation with any of the K+ channel blockers. Indapamide did not alter basal 86Rb efflux. The results suggest that in guinea pig mesenteric arteries indapamide-induced relaxation is not mediated by an action on K+ channels. Cromakalim-induced effects are mediated by KATP. Large conductance KCa mediates the hydrochlorothiazide and cicletanine-induced vascular effects in part.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7521481&dopt=Abstract hydrochlorothiazide Microzide



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Relaxation and decrease in [Ca2+]i by hydrochlorothiazide in guinea-pig isolated mesenteric arteries.

Pickkers P, Hughes AD.

Department of Clinical Pharmacology, St. Mary's Hospital Medical School, Imperial College of Science Technology and Medicine, London.

1. We examined the effect of the thiazide diuretic, hydrochlorothiazide, on on intracellular calcium concentration ([Ca2+]i) and tone in guinea-pig mesentery arteries. Vessels were mounted on a microvascular myograph and loaded with the Ca(2+)-sensitive fluorescent dye, Fura-2. 2. Hydrochlorothiazide caused relaxation of noradrenaline-precontracted arteries associated with a fall in [Ca2+]i. Preincubation of arteries with hydrochlorothiazide inhibited both contraction and rise in [Ca2+]i in response to noradrenaline. Hydrochlorothiazide did not affect tone and [Ca2+]i when this was elevated by a combination of depolarizing potassium solution and noradrenaline. 3. Hydrochlorothiazide-induced vasorelaxation and decrease of [Ca2+]i was abolished by charybdotoxin, a blocker of large conductance Ca(2+)-activated K channels. 4. The rise in [Ca2+]i elicited by caffeine in Ca(2+)-free physiological salt solution, and presumably reflecting Ca2+ release from intracellular stores, was not altered by preincubation with hydrochlorothiazide. 5. Under depolarizing conditions hydrochlorothiazide did not alter the relationship between the extracellular concentration of Ca2+ and [Ca2+]i; however, hydrochlorothiazide caused a small reduction in the contraction produced for a given rise in [Ca2+]i suggesting hydrochlorothiazide may cause a slight desensitization of the contractile machinery. 6. These findings suggest that hydrochlorothiazide opens Ca(2+)-activated K channels leading to hyperpolarization and consequent closing of voltage-operated calcium channels. The result of this is an impaired influx of extracellular Ca2+, a decrease in [Ca2+]i and vasorelaxation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7537594&dopt=Abstract hydrochlorothiazide Microzide