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Indapamide accentuates cardiac chronotropic responses to epidermal growth factor in chick cardiomyocytes.

We have previously shown that indapamide [chloro-4-N-(methyl-2-indolinyl-1)-sulfamoyal-3-benzamide] has a direct action on the heart to alter ion fluxes. This study sought to examine the potential interaction between indapamide and epidermal growth factor (EGF). Cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts as aggregates that have a pattern of consistent spontaneous contraction. Indapamide enhanced the positive chronotropic response to EGF observed in chick embryonic ventricular myocyte aggregates while indapamide itself did not alter cardiac contractile frequency. Taken in conjunction with data that calcium channel blockade, inhibition of sodium entry or Na(+)-Ca2+ exchange in the cardiomyocyte opposes the positive chronotropic action of EGF on the cardiomyocyte, this study has identified an agent, indapamide, that accentuates the cardiomyocyte response to EGF.

Animals↗

Comparison of spectrophotometric and an LC method for the determination perindopril and indapamide in pharmaceutical formulations.

A new sensitive, simple, rapid and precise reversed-phase high performance liquid chromatographic (HPLC) and two spectrophotometric methods have been developed for resolving binary mixture of perindopril and indapamide in the pharmaceutical dosage forms. The first method is based on HPLC on a reversed-phase column using a mobile phase of phosphate buffer pH 2.4 and acetonitrile (7:3 v/v) was used. Linearity range for perindopril and indapamide was 5.0-70.0 and 8.0-35.0 microg ml(-1). In the second method, the first derivative spectrophotometry with a zero-crossing technique of measurement is used for the simultaneous quantitative determination of perindopril and indapamide in binary mixtures without previous separation step. Linear calibration graphs of first derivative values at 225.7 and 255.4 nm for perindopril and indapamide, respectively. The third method is based on ratio derivative spectrophotometry, the amplitudes in the first derivative of the ratio spectra at 226.5 and at 255.3 nm were selected to determine perindopril and indapamide in the binary mixture. All the proposed methods showed good linearity, precision and reproducibility. The proposed methods were successfully applied to the pharmaceutical dosage forms containing the above-mentioned drug combination without any interference by the excipients.

Antihypertensive Agents↗

Flow-injection inhibition chemiluminescence determination of indapamide based on luminol-ferricyanide reaction.

A novel and sensitive chemiluminescence (CL) method for the determination of indapamide coupled with flow-injection analysis (FIA) technique is developed in this paper. It is based on the inhibition effect of the studied drug on the chemiluminescence emission of luminol-potassium ferricyanide system. Under the optimum conditions, the decreased CL intensity is proportional with the concentration of indapamide in the range of 1 x 10(-8) to 1.0 x 10(-6) g ml(-1). The detection limit is 3.4 x 10(-9) g ml(-1) (3sigma). A complete analysis could be performed in 45 s including washing and sampling, giving a throughout of about 90 h(-1). The relative standard deviation (R.S.D.) for 11 parallel measurements of 1.0 x 10(-7) g ml(-1) indapamide is 3.0%. The proposed method has been applied for the determination of indapamide in its pharmaceutical formulations. The results obtained compared well with those by an official method. The possible inhibition mechanism of indapamide on luminol-potassium ferricyanide CL system was discussed briefly.

Antihypertensive Agents↗

Efficacy of indapamide 1.5 mg, sustained release, in the lowering of systolic blood pressure.

The relationship between the increase in blood pressure and the incidence of cardiovascular disease is well recognized today. Studies have shown that more attention should be paid to systolic blood pressure (SBP) in relation to cardiovascular risk and that therapeutic interventions should preferably focus on reducing SBP. The antihypertensive efficacy of indapamide 1.5 mg sustained release (indapamide SR), a low-dose thiazide-type diuretic, was assessed on SBP. Three randomized, double-blind, controlled studies were conducted with indapamide SR, over a period of 3 to 12 months. Elderly patients or patients with target-organ damage, hypertension and left ventricular hypertrophy (LVH) (LIVE study) or with type II diabetes with microalbuminuria (NESTOR study) showed a decrease in SBP varying from 22.7 to 31.8 mmHg. The treatment with indapamide SR resulted in a better or equivalent control of SBP than treatment with a standard dose of a true thiazide diuretic (hydrochlorothiazide), a calcium channel blocker (amlodipine), and an angiotensin-converting enzyme inhibitor (enalapril). No therapeutic escape was observed. All treatments showed good acceptability with no unexpected adverse event. In conclusion, indapamide SR is very effective in lowering SBP-a major independent cardiovascular risk factor-notably in hypertensive high-risk patients with LVH, the elderly and diabetics, when compared to major antihypertensive treatments. This SBP-lowering effect is maintained over the long term.

Aged↗

Protective effects of delapril, indapamide and their combination chronically administered to stroke-prone spontaneously hypertensive rats fed a high-sodium diet.

1. Stroke-prone spontaneously hypertensive rats (SHRsp) have been used widely to test agents putatively capable of vascular protection. These animals present an accelerated time course of hypertension and a reduced life-span. When fed a high-sodium diet from the eighth week of life, a further acceleration in blood pressure increase is obtained, and rats start to die after 5 weeks of diet as a consequence of cerebral haemorrhage. In this model, angiotensin-converting enzyme (ACE) inhibitors were repeatedly proved to prevent vascular lesions and death. Notably, this effect was independent of any hypotensive effect. On the contrary, diuretics were shown not to be equally effective. A combination of ACE inhibitors and diuretics, although known to have synergistic effects in the therapy of hypertension, has never previously been tested. 2. Our aim was to study the effects of long-term treatment with the ACE inhibitor delapril (12 mg day-1 kg-1), the thiazide-like diuretic indapamide (1 mg day-1 kg-1), and their combination (12 and 1 mg day-1 kg-1 respectively), on the survival of SHRsp rats fed a high-sodium diet from the eighth week of life onwards. The effects of the treatments on blood pressure, body weight, food and fluid intake, diuresis, proteinuria and the appearance of lesion signs and death were assessed weekly. When control rats reached 50% mortality, they were killed, together with some drug-treated rats, to compare lesions in brain and kidney. The other drug-treated rats continued treatments until 50% mortality was reached in two treatment groups. 3. All drug treatments were able to delay death significantly when compared with control rats, which reached 50% mortality after 6 weeks of salt loading. This event was preceded by a highly significant increase in proteinuria, diuresis and fluid intake that took place 3 weeks after the increase in blood pressure over the initial range. In delapril- or indapamide-treated SHRsp these changes were never seen, even when animals started to die. In the combination-treated group, a significant increase (P < 0.01) in fluid intake and diuresis, but not proteinuria, was observed from the third week of treatment onwards. 4. Treatment with delapril or indapamide did not block the progressive increase in blood pressure as observed in control animals. However, the increase in blood pressure was markedly retarded with respect to control rats. At variance with this, in combination-treated animals blood pressure levels were maintained until the end of the experiment within the 99% confidence interval initially observed in control animals. 5. Infarctual and haemorrhagic cerebral lesions were observed in 38% of control rats; no lesions were noted in brains of age-matched rats receiving a drug treatment. Kidneys from control animals presented major degenerative lesions of glomeruli and arteries, characterized by fibrinoid necrosis. This condition was absent in drug-treated animals, which presented minor signs of ischaemic lesion. Heart hypertrophy, when heart weight was expressed as a percentage of body weight, was similar in saline-, delapril- or indapamide-treated rats. At variance with this, in combination-treated animals the heart weight to body weight ratio was significantly (P < 0.01) lower than in the other groups. 6. In conclusion, the diuretic indapamide showed similar protective effects as the ACE inhibitor delapril on acute vascular lesions and survival of SHRsp. Moreover, their combination synergized in preventing heart hypertrophy consequent to longterm hypertension. This results is probably related to the enhanced diuresis and the better control of blood pressure levels selectively found in combination-treated animals.

Analysis of Variance↗

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension.

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.

Adult↗

Protective effects of delapril combined with indapamide or hydrochlorothiazide in spontaneously hypertensive stroke-prone rats: a comparative dose-response analysis.

In previous articles, we have shown that the combination of the angiotensin-converting enzyme (ACE) inhibitor delapril (12 mg/kg/day) and the diuretic indapamide (1 mg/kg/ day) was able to prolong the life span significantly in salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Because this finding was partly dependent on the antagonism of salt-loading effects by pharmacologic induction of diuresis, which prevented any increase in blood pressure values, we decided to evaluate whether lower doses of the combination could be equally protective without changing the progression of hypertension. Thus, we studied several treatments with progressively lower doses of delapril (6, 3, or 1.5 mg/kg/day) combined with indapamide (0.5, 0.25, or 0.125 mg/kg/day) or hydrochlorothiazide (2.5, 1.25, or 0.625 mg/kg/day) in salt-loaded SHRsp. Salt-loaded untreated animals were considered to be the control group. In agreement with previous experiments, control rats reached 50% mortality approximately 7 weeks after the beginning of salt loading. The combination of delapril and hydrochlorothiazide at the two lowest doses was not able to delay animal death significantly, whereas treatment with delapril and indapamide at the lowest dose was effective (50% survival rate, 15 weeks). The groups treated with the highest dose of delapril and hydrochlorothiazide or with the intermediate or highest dose of delapril and indapamide did not reach 50% mortality by the end of the experiment, at 44 weeks of treatment (i.e., when animals reached age 1 year). Only the highest delapril and indapamide doses were able to increase diuresis, but for a relatively short period. None of the treatments was able to lower or control blood pressure levels adequately. Therefore, blood pressure levels by themselves were not predictive of rat mortality. In contrast, the maximal value of proteinuria in the weeks preceding death was inversely correlated with the survival time. In conclusion, this study shows that low doses of an ACE inhibitor in combination with a diuretic can be effectively protective in a model of severe hypertension, independent of any change in blood pressure levels.

Angiotensin-Converting Enzyme Inhibitors↗

Indapamide: a unique diuretic?

Indapamide (Lozol) is a new diuretic and antihypertensive agent. The drug appears to have a unique mechanism of action, combining diuretic effects with a direct vascular action, presumably secondary to calcium channel blockade. Available studies indicate that indapamide is comparable to hydrochlorothiazide, chlorothiazide, furosemide, and other diuretic agents in the management of hypertension and edema. The drug produces toxicity similar to that of the thiazide and loop diuretics; however, it does not appear to increase cholesterol levels. Although it is claimed that indapamide produces no effect on glucose levels, hyperglycemia has been reported. Indapamide is safe and effective for treatment of hypertension in mild to severe renal impairment, but advantages over furosemide are questionable. Indapamide is a unique diuretic, but does not appear to offer advantages over other available agents.

Antihypertensive Agents↗

Evaluation of long-term efficacy and acceptability of indapamide SR in elderly hypertensive patients.

OBJECTIVE: To assess the long-term antihypertensive efficacy and acceptability of indapamide SR 1.5 mg in elderly hypertensive patients (> or = 65 years). STUDY DESIGN: Open, 12-month, follow-up study of 444 patients, treated with indapamide SR, who were responders and/or achieved target BP levels following a 3-month, randomised, controlled, double-blind short-term comparison of indapamide SR versus hydrochlorothiazide 25 mg and amlodipine 5 mg. RESULTS: The long-term decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) after 12 months follow-up with indapamide SR was -24.0/-13.1 mmHg from baseline (M0). The percentage of patients that achieved target BP levels (DBP < 95 mmHg, SBP < or = 160 mmHg) was 80.1% [84.3% for isolated systolic hypertension (ISH) subgroup], and the response rate (BP < 140/90 mmHg or decrease in supine diastolic BP > or = 10 mmHg or in supine systolic BP > or = 20 mmHg) 81.5%. Blood pressure (BP) remained stable throughout the 12 months follow-up period (M3-M15), whatever the previous treatment received during the 3-month, doubleblind period (M0-M3). Clinical and biological acceptability was good. A low occurrence of withdrawals (7.2%), was reported. CONCLUSION: Over the course of the long-term, 12-month follow-up study, indapamide SR was shown to be an effective and well tolerated antihypertensive therapy, even after a switch from amlodipine or hydrochlorothiazide, in patients aged 65 years-80 years with systolo-diastolic hypertension (SDH) or ISH.

Aged↗

Effect of indapamide on volume-dependent hypertension, renal haemodynamics, solute excretion and proximal nephron fractional reabsorption in the dog.

Indapamide, a newly developed antihypertensive agent with modest diuretic properties, reduced mean arterial pressure toward normal in dogs made hypertensive with salt and DOCA, while low-dose furosemide (0.1 mg per day) and hydrochlorothiazide (1 and 50 mg per day) did not result in similar degrees of blood pressure control. Indapamide, low-dose furosemide and hydrochlorothiazide treatment all resulted in similar decreases in body weight suggesting that the antihypertensive effect of indapamide occurs through a mechanism independent of contraction of extracellular fluid volume. Intravenous indapamide at doses of 0.3, 1.0 and 3.0 mg/kg caused progressive increases in sodium, potassium and chloride excretion when urine losses were replaced by isotonic saline to prevent extracellular fluid volume contraction. Only at 3.0 mg/kg did plasma potassium decrease significantly (2.92 +/- 0.03 to 2.69 +/- 0.05 mmol/l; p less than 0.05). Neither glomerular filtration rate (GFR) nor renal blood flow (flowmeter) decreased in a dose-related manner; however, effective renal plasma flow assessed by para-aminohippurate clearance did decrease about 15% at the highest dose (p less than 0.05). Proximal re-collection micropuncture studies demonstrated decreased proximal reabsorption. Cortical diluting segment reabsorption was decreased, but CNa + CH2O/GFR increased from 7% to 11% (p less than 0.05). These results indicate that, at doses up to 3.0 mg/kg, indapamide causes a natriuresis which is modest and similar to that seen with thiazides. No decrease in GFR or renal blood flow was observed. This drug apparently exerts a natriuretic effect through an inhibition of solute reabsorption in both the proximal nephron and the cortical diluting segment.

Animals↗

The treatment of hypertension with indapamide alone or in combination with other drugs.

Twenty-six patients (average age 50 years) with essential hypertension were treated for 4 months with 2.5 mg indapamide per day, alone or in combination with other drugs. Before treatment, the average blood pressure was 208/128 mmHg, and each patient had undergone at least 6-months' therapy with hydrochlorothiazide alone (6 patients), in combination with reserpine (11 patients), or with methyldopa, hydralazine, propranolol, metoprolol or guanethidine (9 patients). Indapamide was prescribed to replace hydrochlorothiazide, the other antihypertensive drugs being continued in those patients receiving combination therapy. The average supine blood pressure decreased from 148/93 mmHg with hydrochlorothiazide to 143/92 mmHg during an intermediate 4-week placebo period, and to 135/86 mmHg with indapamide. Effects on blood pressure and all other parameters were the same, whether indapamide was used alone or in combination with other drugs. Serum potassium levels at the end of treatment averaged 3.6 mmol/l, a value similar to that obtained with hydrochlorothiazide. Plasma bicarbonate was unchanged (27.5 mmol/l), serum uric acid averaged 7.4 mg/dl, and renal function remained normal. Other parameters showing no change included blood glucose, cholesterol, triglycerides, total bilirubin, transaminases, platelets, etc. All the patients reported a sensation of well-being during treatment with indapamide; this drug shows clinical and biochemical effects similar to those of the thiazide-type diuretics.

Adrenergic beta-Antagonists↗

Metabolic profile of indapamide sustained-release in patients with hypertension: data from three randomised double-blind studies.

OBJECTIVE: To evaluate the influence of indapamide sustained-release (SR) 1.5 mg/day, a thiazide-related sulfonamide diuretic, on serum levels of lipids (total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and triglycerides), glucose and uric acid, and renal function (serum urea and creatinine levels). METHODS: Pooled data from three randomised, double-blind, controlled studies are analysed. Two of these studies were of short duration (2 and 3 months), one of which included a 9-month nonblind extension phase, and the third was a 12-month prospective study. Short- and long-term metabolic effects of the treatment could thus be analysed. All studies were conducted in patients with mild-to-moderate hypertension; the total population randomised in these studies comprised 1195 patients, of whom 505 had left ventricular hypertrophy (LVH). RESULTS: After 2 to 3 months' treatment with indapamide SR 1.5 mg/day, there was no significant change from baseline in serum lipid levels and glucose levels. This neutral effect was maintained after 9 and 12 months of treatment. Renal function was not affected by short- or long-term indapamide SR 1.5 mg/day therapy. Serum uric acid level was slightly increased after short-term therapy, but was restored to baseline values during long-term therapy with indapamide SR 1.5 mg/day. CONCLUSIONS: Indapamide SR 1.5 mg/day has no deleterious effect on glucose metabolism, serum levels of lipids and uric acid, or renal function. This antihypertensive agent can be considered to be an attractive therapeutic choice for all patients with mild-to-moderate hypertension, including the elderly and patients with increased cardiovascular risks, i.e. those with LVH.

Adolescent↗

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension.

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.

Antihypertensive Agents↗

Clinical benefit of very-low-dose perindopril-indapamide combination in hypertension.

OBJECTIVE: To review the efficacy and safety of the very-low-dose combination of 2 mg perindopril and 0.625 mg indapamide in essential hypertension. STUDY SELECTION: The five main studies from the European registration file were performed in hypertensive outpatients and included two phase II double-blind randomised dose-ranging studies, and three phase III double-blind randomised studies (one study comparing placebo with each of the components, one long-term study over 15 months and one study comparing the combination and losartan). MAIN OUTCOME MEASURES: Decreases in systolic (SBP) and diastolic (DBP) blood pressures measured at trough with a mercury sphygmomanometer, an automatic device (Omron), and 24 h ambulatory blood pressure measurements (ABPM). RESULTS: The combination 2 mg perindopril and 0.625 mg indapamide was selected from the dose-finding studies. Twelve weeks after participants in the randomised studies were allocated to groups, the reductions in SBP, measured with an Omron device, were 12.3 +/- 15.0 mmHg with the combination, 8.0 +/- 16.5 mmHg with 2 mg perindopril (P = 0.001), 9.4 +/- 14.3 mmHg with 0.625 mg indapamide (P = 0.023), and 2.1 +/- 16.8 mmHg with placebo (P < 0.001) (mean +/- SD; all P values are for comparisons with the combination). The reductions in DBP were 6.8 +/- 9.2 mmHg, 5.0 +/- 9.5 mmHg (P = 0.02), 4.7 +/- 8.2 mmHg (P = 0.004), and 2.4 +/- 9.6 mmHg (P < 0.001) in the combination, 2 mg perindopril, 0.625 mg indapamide and placebo groups, respectively. During the long-term study, among 235 patients who achieved initial blood pressure normalisation with the fixed combination, 79.8% sustained their normalisation over 1 year, with no significant difference regarding safety criteria: the occurrence of adverse drug reactions per patient per year was 0.37 and 0.28 in the combination and placebo groups, respectively. A significantly (P < 0.05) larger blood pressure decreasing effect on nocturnal mean SBP (by ABPM) was demonstrated for the combination compared with that achieved with losartan, with no difference in safety. CONCLUSIONS: The proven efficacy on DBP and SBP, and the good safety profile, confirm that the new low-dose combination of 2 mg perindopril and 0.625 mg indapamide is a valuable option in the first-line treatment of hypertension.

Antihypertensive Agents↗

Comparison of indapamide and low-dose hydrochlorothiazide monotherapy in black patients with mild to moderate hypertension.

OBJECTIVES: To assess, using ambulatory blood pressure monitoring (ABPM), the antihypertensive efficacy of hydrochlorothiazide 12.5 mg and indapamide 2.5 mg given as a monotherapy over 3 months to black patients with mild to moderate essential hypertension. DESIGN: Single-centre, prospective, randomised open pilot study in three phases: (i) 1-week drug-free washout period; (ii) 2-week placebo run-in phase; and (iii) 3-month prospective open-label active treatment period. RESULTS: Forty-two black patients with mean daytime diastolic BP (DBP) > or = 90 mmHg and < or = 115 mmHg (mean age 57 +/- 11 years, 28 women/14 men) were enrolled into the study. Overall, a profound and sustained BP reduction was achieved with indapamide at 3 months (N = 20). The 24-hour BP decreased from 150 +/- 17/94 +/- 6 mmHg to 130 +/- 19/82 +/- 9 mmHg (P < 0.0001 for systolic BP (SBP) and DBP at 3 months versus baseline); the mean daytime BP decreased from 155 +/- 15/98 +/- 6 mmHg to 134 +/- 18/87 +/- 10 mmHg (P < 0.0001 for SBP and DBP at 3 months versus baseline). The overall control (mean daytime DBP < 90 mmHg) and response (decrease in daytime DBP > or = 10 mmHg) rates achieved with indapamide were 10/20 (50%) and 13/20 (65%), respectively. In contrast, monotherapy with hydrochlorothiazide resulted in more modest BP reduction and control and response rates at 3 months (N = 22). The 24-hour BP decreased from 147 +/- 14/94 +/- 7 mmHg to 139 +/- 19/88 +/- 2 mmHg (P < 0.05 for DBP at 3 months versus baseline, P = NS for SBP); the mean daytime BP decreased from 151 +/- 14/98 +/- 5 mmHg to 144 +/- 16/93 +/- 10 mmHg (P < 0.05 for DBP at 3 months versus baseline, P = NS for SBP). The corresponding control and response rates were 7/22 (32%) and 8/22 (36%). Both hydrocholorothiazide and indapamide caused significant hypokalaemia. CONCLUSIONS: Monotherapy with indapamide is associated with greater BP reduction and control and response rates than monotherapy with low-dose hydrochlorothiazide and may be an appropriate choice of antihypertensive diuretic therapy in black South African patients with mild to moderate hypertension.

Adult↗

Antihypertensive action of indapamide. Comparative studies in several experimental models.

1-(4-Chloro-3-sulfamylbenzamido)-2-methyl-indoline (indapamide), after single oral dose administration, showed antihypertensive activity in genetically hypertensive rats, DOCA/saline hypertensive rats, unilaterally-nephrectomised DOCA/saline hypertensive rats and dogs made hypertensive by renal encapsulation. The activity was observed at doses as low as 1-3 mg/kg and lasted at least 48 h. Increasing the dose level considerably prolonged the duration of action but did not substantially enhance the maximum antihypertensive effect. In genetically hypertensive rats indapamide was 30-300 times more potent than furosemide, spironolactone and chlorthalidone. Indapamide had no effect on blood pressure in normotensive rats. In concentrations of 1 X 10(-5) to 1 X 10(-3) g/ml, indapamide antagonised contractions of arterial and venous strips to angiotensin, epinephrine and norepinephrine revealing a direct vascular action. Indapamide has a prolonged saluretic action which in combination with the direct vascular effects may well account for its antihypertensive activity.

Animals↗

Modification of the antihypertensive effect of indapamide by indomethacin.

Oral treatment with indapamide was found to reduce blood pressure of hypertensive rats but not of normotensive rats. Chronic indomethacin treatment had no effect on blood pressure of untreated normotensive and hypertensive rats. Also indomethacin did not modify the antihypertensive effect of indapamide excluding the direct involvement of PGs in the antihypertensive effect of indapamide. Vascular reactivity to pressor agents NA, ADR and ANG was significantly increased after indomethacin treatment. This may be due to the blockade of the actions of PG in modifying vascular reactivity to vasoconstrictor agents or may be a direct effect of indomethacin on calcium fluxes. Indapamide reduced the reactivity to NA and ANG in the presence of indomethacin suggesting that the antihypertensive effect of indapamide may be through a decrease in reactivity to pressor agents which is independent of increase in the synthesis of vasodilator PGs.

Angiotensin II↗

Analysis of well-being and 24-hour blood pressure recording in a comparative study between indapamide and captopril.

The effects of indapamide and captopril on office and ambulatory blood pressure control and on general well-being were investigated in 30 active, randomly selected patients from 25 to 68 years old, with mild to moderate essential hypertension (diastolic blood pressure, 92 to 114 mm Hg). Twenty-four-hour ambulatory blood pressure monitoring using an ICR model 5200 portable recorder and evaluation of general well-being were performed prior to and at the end of three months of therapy with indapamide 2.5 mg given once daily, or captopril 12.5 to 50 mg given twice daily. Indapamide and captopril were equally effective in controlling blood pressures in clinic and during 24-hour activities. Although general well-being and subjective symptomatology improved with both treatments, the only significant difference between the two drugs was improvement in the sleep dysfunction scale with indapamide (p less than 0.02). The results shown in this study suggest that both indapamide (2.5 mg) once daily and captopril (12.5 to 50 mg) twice daily are suitable drugs for initial therapy of active patients with mild to moderate hypertension. A fixed once-daily dosage of an antihypertensive agent may, however, increase patient compliance and convenience.

Adult↗