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At least 19 recordsLinked to original sources
PubMed1991

Indapamide potentiates the endothelium-dependent production of cyclic guanosine monophosphate by bradykinin in the canine femoral artery.

Indapamide is a sulfonamide diuretic agent that has antihypertensive properties. In the canine femoral artery, indomethacin reduces the endothelium-dependent relaxation induced by bradykinin, and indapamide restores the response. The aim of this study was to determine whether indapamide affects the release or the effects of endothelium-derived nitric oxide and prostanoids. The effect of indapamide on the production of endothelium-derived nitric oxide and prostacyclin was assessed indirectly by the measurement of the tissue content of cyclic guanosine monophosphate (GMP) and the accumulation of 6-keto-prostaglandin F1 alpha in the incubation medium, respectively. Indapamide did not affect the basal production of either cyclic GMP, cyclic adenosine monophosphate (AMP), or 6-keto-prostaglandin F1 alpha in the presence or absence of indomethacin. Indomethacin decreased the production of cyclic AMP and the release of 6-keto-prostaglandin F1 alpha induced by bradykinin, and this was unaffected by indapamide. Indapamide enhanced the bradykinin-stimulated production of cyclic GMP in the presence of indomethacin and did not affect that evoked by 3 morpholino-sydnonimine, an exogenous donor of nitric oxide. Indomethacin had no significant effect on the production of cyclic GMP stimulated by either bradykinin or 3 morpholino-sydnonimine. These studies demonstrate that the potentiation by indapamide of the relaxation evoked by bradykinin is associated with an enhanced production of cyclic GMP in the presence of indomethacin, which suggests that the production of endothelium-derived nitric oxide is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Radical scavengers of indapamide in prostacyclin synthesis in rat smooth muscle cell.

Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A2. Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [14C]arachidonate liberation nor prostacyclin synthase of the smooth muscle cells. Indapamide eliminated a stable free radical in a cell-free system, lowered the formation of malondialdehyde from lipid peroxides in rat brain homogenate, and reduced lipid peroxidation by the free radical generating system of xanthine-xanthine oxidase. Indeed, the scavenging action of indapamide significantly attenuated the inhibitory activity of 15-hydroperoxy-arachidonate to prostacyclin synthase activity. These results indicate that indapamide diuretic increases prostacyclin generation in the vascular smooth muscle cells possibly through antioxidant effects and that the enhanced prostacyclin generation is partly responsible for its direct vasodilator action.

Animals↗
PubMed1990

Effects of indapamide on endothelium-dependent relaxations in isolated canine femoral arteries.

Indapamide is an effective antihypertensive agent in humans and in experimental hypertensive animals. The aim of the present study was to investigate whether indapamide affects endothelium-dependent and independent relaxations in canine femoral arteries. Rings (with or without endothelium) were contracted with prostaglandin F2 alpha (2 X 10(-6) mol/liter) before the addition, in a cumulative fashion, of relaxing agents. Indapamide (10(-7) to 10(-4) mol/liter) had no direct effect on unstimulated or prostaglandin-stimulated preparations; it did not alter relaxations of preparations with endothelium induced by acetylcholine, bradykinin, adenosine diphosphate or the calcium ionophore A23187. Similarly, it did not affect relaxations induced by sodium nitroprusside, prostacyclin or forskolin in preparations with or without endothelium. Indomethacin shifted the concentration-response curve to bradykinin to the right and did not alter that to the other relaxing drugs. The reduced relaxation to bradykinin was reversed in a concentration-dependent manner by indapamide (10(-7) to 10(-5) mol/liter). In the presence of indomethacin, indapamide shifted the concentration response curve to prostacyclin (in rings with endothelium) and to forskolin (in rings with and without endothelium) to the left. Thus, indapamide does not directly affect endothelium-dependent and independent relaxations. However, when prostanoid production is impaired, indapamide facilitates the release of endothelium-derived relaxing factor(s), and to a lesser extent, the direct action on vascular smooth muscle of prostanoids (prostacyclin) released from the endothelium.

Acetylcholine↗
PubMed1978

[Influence of indapamide on isolated rabbit arteries (author's transl)].

The effect of indapamide, a high ceiling diuretic, antihypertensive drug, was investigated in helically-cut strips of rabbit cerebral, coronary, renal, mesenteric and femoral arteries and aortae. The addition of indapamide in concentrations higher than 3 X 10(-5)M relaxed those arterial strips contracted with prostaglandin F2alpha; the relaxation being greater in cerebral, coronary and renal arteries. Atropine propranolol and aminophylline did not reduce the relaxing effect. Hydrochlorothiazide produced fewer incidences of relaxation. Treatment for 20 min with indapamide (3 X 10(-5) or higher) significantly attenuated the contractile response of mesentric arteries to nicotine and tyramine. Contractile responses to transmural electrical stimulation were not reduced but rather potentiated. The dose-response curve of norepinephrine was not significantly affected by indapamide. The contractile response of nictitating membranes of anesthetized cats to stimulation of preganglionic sympathetic nerves was not influenced by indapamide but was abolished by hexamethonium. It may be concluded that arterial relaxations induced by indapamide are due to a direct action on smooth muscles. Indapamide appears to attenuate the response to nicotine and tyramine by interfering with the mechanism of neuronal amine uptake. However, such does not involve a ganglionic blockade nor a reduction of the release of norepinephrine from adrenergic nerve terminals.

Animals↗
PubMed1979

The effects of long term oral treatment with indapamide on the development of DOCA-salt hypertension in rats: vascular reactivity studies.

The onset of DOCA-salt hypertension in male Sprague-Dawley rats was prevented during 11 weeks of oral treatment with indapamide (0.5, or 10.0 mg/kg) or propranolol (60 mg/kg) administered in the diet. The body weights of the indapamide treated groups were significantly (P < 0.01) greater, at weeks 4, 5, 6, 7 and 11, while the body weights and food intake of the propranolol treated group were significantly (P < 0.05) lower at week 11, than the control group. A significant reduction in heart wet weight (P < 0.001) was measured in the indapamide treated animals only. No significant diuresis nor natriuresis was measured in any group during week 11 of treatment. When all groups were subjected to an increased salt load, four weeks after cessation of drug treatment only the indapamide (10 mg/kg) treated animals failed to show an increased blood pressure. Vascular reactivity studies carried out six weeks after termination of drug treatment, indicated a significant (P < 0.01) reduction in pressor activity elicited by electrical stimulation of the entire sympathetic outflow in indapamide (10 mg/kg) treated pithed rats. No significant difference in the pressor activity elicited by noradrenaline (5 x 10(-8) - 5 x 10(-6) g/kg, i.v.) or tyramine (10(-5) - 5 x 10(-5) g/kg i.v.) was observed in any treatment group. In conclusion, chronic oral treatment with indapamide or propranolol, prevented the onset of DOCA-salt hypertension in rats. A long lasting antihypertensive action of indapamide involving the sympathetic nervous system is also indicated.

Animals↗
PubMed1990

[Role of prostaglandins in the mechanism of action of indapamide].

The role of prostaglandins (PG) has been evoked in the mechanism of action of indapamide. Indeed, PG can act in the regulation of the blood pressure (BP) at different levels: vasodilatation, diuretic, natriuretic, antagonism of angiotensin II and vasopressin (VP), action on adrenergic system. To confirm this hypothesis, we studied the action of certain eicosanoids inhibitors on the antihypertensive action of indapamide in the SHR rat, anaesthetized with pentobarbital (40 mg/kg i.p.). Indapamide (3 mg/kg i.p.) induces significant decrease on BP over 60 min. Mepacrine (5 mg/kg i.p.), phospholipase A2 inhibitor, indomethacin (5 mg/kg i.p), cyclo-oxygenase inhibitor, and tranylcypromine (0,1 mg/kg i.p.), prostacyclin synthase inhibitor, antagonize the antihypertensive action of indapamide. In order to eliminate the importance of VP, we used Brattleboro rats (genetically depleted in VP): indapamide (3 mg/kg i.p.) maintains its hypotensive activity. To eliminate the role of kidney in PG synthesis, we have used cyclo-oxygenase extrarenal inhibitor (sulindac) and the bilateral nephrectomy. Sulindac (1,25 mg/kg i.p.) and the bilateral nephrectomy do not remove the hypotensive action of indapamide. These results, demonstrating the PG extrarenal role and probably that of PGI2, localized in the vascular wall, could explain part of the antihypertensive mechanism of indapamide.

Animals↗
PubMed1975

Antihypertensive activity of a new agent, indapamide: a double-blind study.

In a double-blind trail in 22 patients with mild to moderate essential hypertension, indapamide was compared with chlorathiazide and placebo. Dosage levels were set at 5 mg. indapamide and 500 mg. chlorothiazide daily, for 5 days out of 7, and patients were treated alternately, in random sequence, with each drug for a month over a 3-month period. Blood pressure readings and blood chemistry investigations were carried out before and after each treatment period and a careful history was kept of subjective symptoms and patients' tolerance of therapy. The results show that both active treatments produced drops in systolic and diastolic pressures, but were only statisically significant and different from placebo in the case of indapamide. Indapamide also produce much greater subjective improvement (74%) in patients with functional symptoms compared with chlorothiazide (15%). In an overall assessment, indapamide produced an excellent to good response to treatment in 57% of patients. Comparable responses for chlorotiazide and placebo were 25% and 20% respectivlely. Using patients as their own controls to compare the relative effectiveness of the three periods of treatment, indapamide was shown to be more effective than placebo in 65% of cases and more effective han chlorothiazide in 60%. Although patient tolerance of indapamide was slightly better, both drugs were well accepted and no significant changes from baseline levels were noted in any of the laboratory parameters investigated.

Adult↗
PubMed1990

Cardiovascular protective properties of indapamide.

Although indapamide has been used for many years as a first-line treatment of hypertension, it is only recently that some of its activities on the changes of the cardiovascular system, brought on by age and high blood pressure, have been studied. Indapamide appears to reduce blood pressure by a combined diuretic and direct vascular activity reducing vascular reactivity and total peripheral resistance. In addition, it has discrete effects on a number of interrelated systems that may protect the cardiovascular system. Indapamide reduces intracellular calcium levels, maintains magnesium ions, but reduces phosphate ions that may be involved in arterial rigidity. Circulating catecholamines remain unchanged but there is a reduction in normetanephrine, suggesting a reduction in sympathetic tone. It stimulates prostacyclin synthesis, increases levels of circulating prostacyclin, reduces platelet aggregation and stimulates the vasodilation elicited by endothelium-derived relaxing factor in the presence of bradykinin. In addition, it inhibits the formation of the vasoconstrictor prostanoid, thromboxane A2. The free radical scavenging activity of indapamide could also protect the vascular smooth muscle from the reperfusion injury of cerebral and myocardial ischemia. Indapamide induces a reduction in cerebral ischemia after carotid ligation. Unlike some other antihypertensives, it does not upset the high-density/low-density lipoprotein-cholesterol balance, reducing the possible risk of atherosclerosis. Moreover, the combination of binding to elastin and reduction in uptake of calcium and phosphate into the smooth muscle could be a mechanism for reducing arterial rigidity seen in the elderly and hypertensive patient. In hypertensive patients, these properties induce an improvement in arterial compliance, and in the long term a reduction in left ventricular hypertrophy. These pharmacologic and clinical results, together with a good antihypertensive efficacy and acceptability, suggest that indapamide may be a preferential agent in the long-term cardiovascular protection of the hypertensive patient.

Blood Vessels↗
PubMed1990

Beneficial effects of indapamide on lipoproteins and apoproteins in ambulatory hypertensive patients.

Among the numerous risk factors for atherosclerosis, 2 are particularly important: hypertension and primary or secondary abnormalities of plasma lipids and lipoproteins. Antihypertensive treatments significantly decrease the risk of cerebrovascular accidents, renal failure or hypertensive cardiomyopathy, but they have little influence on coronary artery disease. It has been suggested that some antihypertensive agents may have deleterious effects by altering serum lipoproteins and this may override the benefit of blood pressure reduction. Diuretics increase the blood concentration of total cholesterol, low-density lipoproteins and triglycerides. Indapamide, a methylindoline agent with vasodilator activity, has no adverse lipid effects. Twenty-six studies have clearly demonstrated that indapamide appears to be unique among diuretics because of an absence of adverse lipid effects. In some studies indapamide significantly increased high-density lipoprotein cholesterol, apoproteins A1, A2 and apoprotein E. When a thiazide diuretic had been given previously, indapamide treatment normalized the lipid and lipoprotein profiles. The reason for the lack of adverse lipid effects of indapamide is discussed. Thus indapamide, 2.5 mg once daily, is effective and safe for the control of mild to moderate hypertension, both in young and older patients. It may be an optimal diuretic for use in normolipidemic or hyperlipidemic patients, as it increases high-density lipoprotein but not low-density lipoprotein cholesterol.

Apoproteins↗
PubMed1992

In vitro and ex vivo inhibition of the modification of low-density lipoprotein by indapamide.

The effect of an antihypertensive drug, indapamide, on copper- and endothelial cell-induced peroxidation of human low-density lipoprotein (LDL) was studied and compared with that of drugs previously shown to protect LDL against peroxidation: probucol and vitamin E and other thiazidic and nonthiazidic diuretics (clopamide, hydrochlorothiazide, and furosemide). Incubation with indapamide inhibited in a dose-dependent manner LDL peroxidation induced either by copper ions or by cultured endothelial cells. Both electrophoretic mobility and thiobarbituric acid-reactive substances (TBARS) content of LDL returned to almost normal values in the presence of 1 microM indapamide. This drug was at least 10 times more potent than probucol and vitamin E in inhibiting LDL peroxidation. No inhibitory effect has been observed with clopamide, hydrochlorothiazide, and furosemide in the same experimental conditions. Homozygote Watanabe rabbits were treated orally with indapamide (10 mg/kg/d for 3 days) to evaluate the potential protective effect of the compound on LDL peroxidation in vivo. Purified LDL from placebo and treated rabbits were submitted to peroxidation induced by copper ions, and indapamide was effectively able to protect LDL in these experimental conditions. This effect was especially obvious 6 and 8 h after the start of the incubation when LDL of the placebo-treated animals were modified. The mechanism of action of these drugs was examined in vitro using the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) test and in kinetic studies of arachidonic acid photoperoxidation. Indapamide as well as vitamin E and probucol were effective free radical scavengers, but the other diuretic molecules were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

A comparative study of the activity of a new agent, indapamide, in essential arterial hypertension.

A single-blind crossover trial was carried out in 38 elderly, hospitalised patients with essential hypertension to compare the hypotensive activity of 5 mg. indapamide daily with 100 mg. chlorthalidone daily. After initial treatment for 10 days with placebo, patients received treatment for 45 days with either indapamide or chlorthalidone and were then crossed over to the alternative drug for a similar period. Potassium supplementation was necessary in 25 of the patients receiving chlorthalidone, but was precribed as a precautionary measure in only 1 patients whilst on indapamide. Results showed that there were significant drops in blood pressure following both active medications, but that the percentage reduction in diastolic pressure was greater after indapamide. Indapamide also proved more effective than chlorthalidone in controlling the patients' subjective and functional symptoms of their hypertension. In an overall assessment of the effectiveness of both drugs, indapamide was judged to be better tolerated as well as more effective than chlorthalidone in 18 of the 38 patients, whilst chlorthalidone was preferred in only 7 instances.

Aged↗
PubMed1978

Fluorometric assay for urinary indapamide.

A sensitive fluorescence method for the determination of indapamide was developed. Reaction of indapamide with sodium hydroxide at 100 degrees yielded a fluorescent product, and addition of formaldehyde to the fluorescent product increased its fluorescence intensity by a factor of three. The assay is sensitive to levels of indapamide of 0.025 microgram/ml in an aqueous solution, and a linear response between 0.025 and 2.0 microgram/ml was observed. The procedure was adapted to the analysis of intact indapamide in urine. Concentrations of indapamide of 0.05 microgram/ml can be detected in dogs given 20 mg of the drug.

Animals↗
PubMed1990

Clinical efficacy and quality of life with indapamide alone or in combination with beta blockers or angiotensin-converting enzyme inhibitors.

A multicenter study was performed to assess the efficacy and the acceptability of indapamide in hypertensive patients previously untreated, or treated and unsatisfactorily controlled with either angiotensin-converting enzyme (ACE) inhibitor or beta-blocking therapy. Four centers participated in the study, which included patients whose supine diastolic blood pressure was between 95 and 115 mmHg with no treatment (group I, n = 40), those taking captopril (group II, n = 40) or those taking propranolol (group III, n = 40). After a 2-week single-blind placebo run-in period, patients received indapamide either alone (group I) or in combination with the previous therapy (groups II and III) for 4 months. Blood pressure, heart rate, weight, and clinical and biochemical acceptability were measured before and after 2 and 4 months of treatment. At the same time points, quality of life was determined using standardized questionnaires completed by the patient (20 items) and the physician (10 items) and a visual analog scale completed by the patient. In all groups, administration of indapamide induced a clinically and statistically significant reduction in both systolic and diastolic blood pressures in the supine position after 2 months. Indapamide alone controlled blood pressure in 82% of the patients previously untreated, and indapamide in combined therapy controlled blood pressure, respectively, in 67 and 85% of patients previously uncontrolled with ACE inhibitors or beta blockers. In all groups, questionnaires on quality of life showed a progressive and significant improvement in general well-being. After 4 months of treatment, the percentage of improvement in the physician questionnaire was 77.1% in group I, 60.6% in group II and 71.4% in group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Identification and pharmacological properties of binding sites for the atypical thiazide diuretic, indapamide.

[3H]Indapamide bound to a single class of binding sites in pig renal cortex membranes with a dissociation constant Kd = 35 +/- 13 nM and a binding site density Bmax = 40 +/- 9 pmol/mg of protein. [3H]Indapamide binding was inhibited by the carbonic anhydrase inhibitor, acetazolamide, and by thiazide diuretics with the following rank order of potency: chlorothiazide greater than hydrochlorothiazide approximately metolazone greater than hydroflumethiazide. The effect of the latter drugs to inhibit [3H]indapamide binding was not related to their activity as thiazide diuretics, but was significantly correlated with their inhibitory effect on carbonic anhydrase II. These results suggest that the major renal binding site of [3H]indapamide is a membrane form of carbonic anhydrase. Inhibition of carbonic anhydrase may play a role in the antihypertensive effect of indapamide.

Animals↗
PubMed1992

Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels.

The mechanism by which thiazides lower peripheral resistance is unresolved. The aim of this study was to investigate the mechanisms of the acute vasodilator action of hydrochlorothiazide and the 'thiazide-like' diuretic indapamide on human, guinea pig and rat small arteries. Vessels were mounted on a myograph and the relaxation profile of both drugs and interactions with K+ channels and the vascular eicosanoid system were studied. Neither drug had any relaxant effect in rat mesenteric vessels and indapamide did not relax human arteries. Hydrochlorothiazide in both human and guinea pig vessels produced significantly more relaxation of noradrenaline than K(+)-constricted vessels (P less than 0.001). Relaxation to hydrochlorothiazide was reduced in the presence of charybdotoxin. Maximal-induced hydrochlorothiazide relaxation was reduced by 64% in human arteries (P less than 0.001) and by 91% in guinea pig vessels (P less than 0.001). Incubation with glibenclamide and indomethacin had no effect on the relaxant activity of hydrochlorothiazide and indapamide. Indapamide-induced relaxation was unaffected in the presence of charybdotoxin. These results show marked differences in the acute vasodilator action of hydrochlorothiazide and indapamide. There appears to be involvement of Ca(2+)-activated K+ channels in the acute vasorelaxant activity of hydrochlorothiazide.

Animals↗
PubMedDate not supplied

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↗
PubMed1975

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↗
PubMedDate not supplied

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↗