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Comparative effects of indapamide and hydrochlorothiazide on cardiac hypertrophy and vascular smooth-muscle phenotype in the stroke-prone, spontaneously hypertensive rat.

Contard F, Glukhova M, Sabri A, Marotte F, Sartore S, Narcisse G, Schatz C, Guez D, Rappaport L, Samuel JL.

Unite 127 INSERM, Hopital Lariboisiere, Paris, France.

The effects of two diuretics, indapamide (3 mg/kg/day) and hydrochlorothiazide (20 mg/kg/day), were analyzed over a 44-day period on the cardiovascular hypertrophy of stroke-prone spontaneously hypertensive rats (SHR-SP). Untreated SHR-SP developed severe hypertension and cardiac hypertrophy when compared to normotensive Wistar-Kyoto (WKY) rats after 8 weeks on 1% sodium chloride. In diuretic-treated animals, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP (-13 and -18%, respectively, p < or = 0.05). Morphometric analysis of myocyte cross-sectional areas evidenced that indapamide was the most effective in preventing myocyte hypertrophy (-33%, p < or = 0.0001). Small coronary artery wall thickness was efficiently prevented in the two treated groups, but medial hypertrophy was prevented by hydrochlorothiazide only. Among markers of smooth-muscle cell phenotype (contractile or extracellular matrix proteins) EIIIA-fibronectin (FN), one FN cellular isoform, was shown to be the most sensitive marker by an immunohistochemical technic. Medial expression of EIIIA-FN, which was characteristic of SHR-SP coronary arteries, was prevented by the two treatments. The two diuretic treatments, despite similar effects on blood pressure and smooth-muscle phenotype, prevent SHR-SP cardiovascular hypertrophy with a drug-specific efficiency.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7508058&dopt=Abstract hydrochlorothiazide Microzide



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Indapamide inhibits human platelet aggregation in vitro: comparison with hydrochlorothiazide.

Rendu F, Bachelot C, Molle D, Caen J, Guez D.

CJF 9101 INSERM, Courbevoie, France.

Among antihypertensive drugs with diuretic properties, indapamide was shown to inhibit platelet growth factors production in diabetic hypertensive patients, suggesting an antiplatelet activity. The present study aimed to demonstrate the antiaggregating properties of indapamide. The effect of indapamide on platelet function was compared in vitro to that of hydrochlorothiazide. Indapamide (100 microM) inhibited the second wave of adenosine diphosphate-induced aggregation and inhibited collagen-induced aggregation of platelet rich plasma by 50%. Using isolated platelets, indapamide also inhibited aggregation induced by low doses of thrombin (70% inhibition with 0.035 U/ml). This inhibition was dose-dependent and was still observed in presence of high thrombin concentrations, although the inhibition was moderate. Inhibitory effect of indapamide was more pronounced on the release reaction. Indapamide inhibited the thrombin-induced release of serotonin from dense granules by up to 80%. Hydrochlorothiazide at the same concentrations had no effect on platelet aggregation, and the inhibitory effect on the secretion was inconsistent and never exceeded 30%. By contrast, when the aggregation inducer was arachidonic acid, indapamide had no effect either on aggregation or on thromboxane formation, indicating that it was not acting on arachidonic catabolism. Calcium mobilization evoked by thrombin stimulation and measured with the fluorescent dye Indo 1 was also reduced in presence of indapamide by 30%. Myosin light chain and pleckstrin phosphorylation induced by thrombin were also reduced. These results demonstrate that indapamide inhibits platelet responses by inhibiting calcium mobilization. The anti-aggregating properties of indapamide could contribute to normalize the hyperresponsiveness of platelets from hypertensive patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7508063&dopt=Abstract hydrochlorothiazide Microzide



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Hydrochlorothiazide improves ventricular compliance and thus performance without reducing hypertrophy in renal artery stenosis in rats.

Norton GR, Tsotetsi OJ, Woodiwiss AJ.

Department of Physiology, University of the Witwatersrand Medical School, Johannesburg, South Africa.

The effect of hydrochlorothiazide (1 mg/kg per day) on left ventricular (LV) mass and systolic and diastolic function was investigated in two-kidney, one clip (2K1C) renovascular hypertensive rats. Hydrochlorothiazide was administered from 8 weeks, and LV mass and function were measured at 16 weeks after surgery to induce hypertension. Cardiac performance was determined from cardiac output, stroke volume (per 100 g of body weight), and stroke work (per gram of LV weight) versus LV end-diastolic pressure (LVEDP) and versus LV strain relations in anesthetized open-chest, ventilated rats. LV compliance was determined from the LVEDP versus strain relation. Strain was calculated from LV end-diastolic short-axis diameter values. Hydrochlorothiazide reduced systolic blood pressure in 2K1C rats to levels similar to those in sham-operated controls (sham) at 12 weeks after surgery. A reduced afterload failed to influence LV mass, as left LV hypertrophy developed to the same extent in treated 2K1C rats. 2K1C hypertension produced abnormal cardiac performance with altered cardiac output, stroke volume, and stroke work versus LVEDP relations (stroke work versus LVEDP, intercept of 2K1C versus sham, p < 0.001). This was attributed to a decreased ventricular compliance (strain versus LVEDP, slope of 2K1C versus sham, p < 0.001). In contrast, hydrochlorothiazide improved ventricular compliance (strain versus LVEDP, slope of 2K1C versus 2K1C hydrochlorothiazide, p < 0.01) and thus returned the stroke work versus LVEDP relation to sham values (intercept of 2K1C versus 2K1C hydrochlorothiazide, p < 0.001). We conclude that hydrochlorothiazide reduces blood pressure but not the development of ventricular hypertrophy in 2K1C rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Ion channel involvement in the acute vascular effects of thiazide diuretics and related compounds.

Calder JA, Schachter M, Sever PS.

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

The involvement of calcium and potassium channels in mediating the vascular actions of hydrochlorothiazide, indapamide and cicletanine were investigated in guinea pig small vessels mounted on the Mulvany myograph. Hydrochlorothiazide (10 microM) and cicletanine (10 microM) were weak calcium antagonists shifting the calcium dose-response curve half a log unit to the right. Indapamide was a far more potent inhibitor, a 10 microM concentration shifting the calcium dose-response curve 3 log units to the right and reducing maximal calcium contraction by 72% (P < .001). Relaxations to hydrochlorothiazide and cicletanine were reduced in the presence of charybdotoxin, a blocker of calcium-activated potassium channels (KCa). Maximal relaxation induced by hydrochlorothiazide (30 microM) was reduced by 91% and cicletanine-induced relaxation by 63%. In the presence of iberiotoxin, a more selective KCa inhibitor, maximal hydrochlorothiazide and cicletanine-induced relaxations were reduced by 73 and 60%, respectively. Neither drug's action was affected by incubation with glibenclamide, which inhibits ATP-sensitive K+ channels. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no effect on the indapamide-induced relaxation. These results show differences in the involvement of ion channels in the acute vasorelaxation produced by these drugs. Hydrochlorothiazide and cicletanine-induced relaxations appear to be mediated via KCa, whereas indapamide is a potent calcium antagonist.

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Comparison of indapamide and hydrochlorothiazide on spontaneous contraction of cardiomyocytes in culture: the effect on alterations of extracellular calcium or potassium.

Rabkin SW.

Faculty of Medicine, University of British Columbia, Vancouver, Canada.

1. The purpose of this study was to determine whether indapamide or hydrochlorothiazide had a direct action on the heart, specifically to determine whether either diuretic affected spontaneous contractile function of cardiomyocytes in culture or altered the response to increases in extracellular potassium or calcium. 2. Chick embryonic ventricular cells were cultured from 7-day-old chick embryo and myocardial cell aggregates were prepared. Spontaneous cardiac contractile frequency of ventricular myocyte aggregates was monitored. Indapamide [chloro-4-N-(methyl-2-indolinyl-1)-sulfamoyal-3-benzamide] over a concentration range of 10(-9)-10(-6) M did not alter cardiac contractile frequency. 3. Indapamide, in a dose dependent manner, significantly (P < 0.05) antagonized the effect of increases in extracellular potassium [K+]0 that produced a concentration dependent reduction in cardiac contractile frequency. In contrast, hydrochlorothiazide accentuated the effect of increased [K+]0 while hydrochlorothiazide did not alter spontaneous contractile frequency at the usual [K+]0 of 2.0 mM. 4. Indapamide produced a significant (P < 0.05) reduction in the effect of increases in extracellular calcium [Ca2+]0 on cardiac contractility while hydrochlorothiazide was associated with a slight accentuation of the effect of increased [Ca2+]0. Indapamide also slightly reduced the effect of the calcium agonist Bay K 8644, which increases intracellular calcium through voltage operated calcium channels. 5. These data indicate that diuretics modulate a cardiac response to changes in extracellular potassium and calcium. Indapamide antagonizes the effects of increases in extracellular potassium and calcium while hydrochlorothiazide has the opposite effect on the cardiac response to increases in [K+]0 or [Ca2+]0.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7689999&dopt=Abstract hydrochlorothiazide Microzide