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PubMedDate not supplied

Bioavailability in man of atenolol and chlorthalidone from a combination formulation.

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drugs as a fixed combination ('Tenoret 50'), as a free combination, and individually, at doses of 50 mg atenolol and 12.5 mg chlorthalidone. There were no statistically or clinically significant differences between the three treatments of atenolol in terms of individual blood levels, areas under the curve, and urinary excretion. The mean half-lives were between 5 and 7 h, in agreement with other published data. The variation in peak systemic levels is less than that observed for a number of other beta-blocking drugs and is of the same order as seen in other investigations involving atenolol. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet. The mean peak blood concentrations of chlorthalidone were 0.94, 1.00, and 0.99 micrograms ml-1 for the fixed and free combinations and the chlorthalidone tablet, respectively. The mean areas under the curve were also similar as were the mean half-lives and urinary recovery. There were no statistically or clinically significant differences between the three treatments. Thus the bioavailability of chlorthalidone from the fixed combination is equivalent to that from the free combination and from the chlorthalidone tablet. It is concluded that combining chlorthalidone and atenolol in a single tablet does not affect the systemic bioavailability of either component.

Adult↗

PubMed1985

Chlorthalidone pharmacodynamics in beagle dogs.

A pharmacodynamic approach was employed to examine the diuretic effect of chlorthalidone in beagle dogs and to identify parameters necessary for optimization of an oral dosage formulation of this drug. The extensive partitioning of chlorthalidone into erythrocytes was shown to be noninstantaneous, with an in vitro partitioning half-life of 18 min. In vivo studies using oral and intravenous solutions confirmed this finding. Additionally, the diuretic effect was demonstrated to be related to the drug concentration in the plasma fraction. These studies led to the development of a relevant pharmacokinetic model which highlighted the importance of the oral absorption rate on the diuretic efficacy of chlorthalidone. A novel, rapidly dissolving, stabilized, amorphous chlorthalidone tablet formulation was compared to various oral solution and tablet formulations. Pharmacokinetic analysis by classical compartmental models and by moment techniques demonstrated that the rapidly dissolving tablet formulation was bioequivalent to an oral solution of chlorthalidone. Preparations containing crystalline chlorthalidone are shown to be incompletely absorbed, and the rates of absorption favor partitioning into the erythrocyte fraction. It is projected from the pharmacodynamic model that the novel chlorthalidone preparation optimizes plasma levels necessary to invoke a diuretic response.

Chemistry, Pharmaceutical↗

PubMed2002

Amlodipine versus chlorthalidone versus placebo in the treatment of stage I isolated systolic hypertension.

The study was to compare the effects of amlodipine (calcium channel antagonist), chlorthalidone (diuretic), and placebo in adults more than 50 years of age with stage 1 isolated systolic hypertension (ISH). After a 4-week placebo run-in phase, 150 patients were randomly assigned in a double-blind fashion to treatment with 5 mg of amlodipine (n = 48), 15 mg of chlorthalidone (n = 50), or placebo (n = 52). Patients who failed to meet the systolic blood pressure (BP) reduction goal by week 4 had their dose increased to 10 mg of amlodipine or 30 mg of chlorthalidone, and maintained at this increased dose for 12 weeks. Results showed a mean reduction (mean +/- SD) in sitting systolic BP from baseline to the last treatment visit of -14.6+/-12.2 mm Hg (95% confidence interval [CI] -18.2, -11.0), -14.0+/-13.46 mm Hg (95% CI -17.8, -10.2), and -3.4+/-11.83 mm Hg (95% CI -6.7, -0.1) for the amlodipine, chlorthalidone, and the placebo treatment groups, respectively. Both active treatments showed significantly greater reductions than the placebo group (P < or = .001), but were not significantly different from each other. Sixty-seven percent of the amlodipine, 69% of the chlorthalidone, and 25% of the placebo-treated patients reached the protocol defined systolic BP goal (P = .001). Both active treatment groups showed a trend of better systolic BP response in older patients (> or =65 years). Secondary efficacy measures including pulse pressure, standing systolic, diastolic, and the 24-h ambulatory BP were also statistically significantly improved for both active treatments at the end of treatment, except for chlorthalidone in standing diastolic BP. Adverse events that occurred during the study were as expected and were well tolerated. The results of this study support the efficacy and safety of amlodipine and chlorthalidone for the treatment of stage 1 ISH during 20 weeks of treatment.

Aged↗

PubMed1986

Inhibition of Ca absorptive flux by chlorthalidone in the rat duodenum and colon.

To evaluate the mode and intestinal sites of action of chlorthalidone on Ca transport, balance and flux studies by the Ussing technique were performed in rats fed a low Ca diet throughout the experiment to stimulate Ca absorption. Half of the rats received chlorthalidone (5 mg X kg-1 X day-1) orally for 18 wk, a duration of administration previously shown to yield consistent changes. Net Ca absorption was decreased by chlorthalidone (0.91 +/- 0.07 vs. 1.08 +/- 0.3 mg/day, P less than 0.05), which is similar to prior observations in rats fed a normal Ca diet. Ca balance was unchanged by chlorthalidone (0.34 +/- 0.08 vs. 0.36 +/- 0.05 mg/day) because of concomitant hypocalciuria of similar magnitudes. In the duodenum, chlorthalidone decreased mucosal-to-serosal flux (Jm----s) (96.7 vs. 111.5 nmol X cm-2 X h-1, P less than 0.05). Since serosal-to-mucosal flux (Js----m) was unchanged, net Ca flux (Jnet) was reduced (74.0 vs. 89.6 nmol X cm-2 X h-1, P less than 0.05). Similarly, chlorthalidone selectively inhibited Jm----s in the descending colon (27.0 vs. 36.2 nmol X cm-2 X h-1, P less than 0.01), reducing Jnet (14.3 vs. 23.2 nmol X cm-2 X h-1, P less than 0.005). Short-circuit current and tissue conductance were unaffected. These data suggest that chronic chlorthalidone treatment reduces Ca absorption by inhibiting active calcium transport in the small and large intestine.

Absorption↗

PubMedDate not supplied

Biliary excretion of chlorthalidone in humans.

A single oral dose of the diuretic chlorthalidone (100 or 200 mg) was given to six cholecystectomized patients with T-tube drainage of the common bile duct, and the 24 h bile and urine were collected during 3--7 days. Urinary recovery of chlorthalidone was 23--27 per cent of the dose, which is in the range of that in healthy volunteers. Chlorthalidone concentration in bile was 11--44 times lower than urine concentration in corresponding periods, and biliary recovery was only 0.6--1.4 per cent of the dose. When compared from equal periods of sampling of bile and urine, the same relative amount of drug was found in bile, whether the 100 or 200 mg dose had been given (viz., a fraction of 2.5--4.7 per cent and 2.5--5.7 per cent of corresponding urinary amounts respectively). It was concluded that excretion into bile constitutes only a minor route of elimination for unchanged chlorthalidone. Bile samples treated with glucuronidase and sulphatase showed no increase of chlorthalidone concentration. The open acid analogue of chlorthalidone, 3-(4-chloro-3-sulphamoylbenzoyl)-benzoic acid, was apparently not formed as a human metabolite, as evidenced by gas chromatographic analysis of both urine and bile.

Adult↗

PubMed1982

Relative bioavailability of chlorthalidone in humans: adverse influence of polyethylene glycol.

The bioavailability of two commercial preparations of chlorthalidone was studied in healthy male subjects. Reference solutions/suspensions for the two products were chlorthalidone dissolved in a solution of water-polyethylene glycol and a solution/suspension of chlorthalidone. Bioavailability of the chlorthalidone in water-polyethylene glycol solution was significantly reduced in comparison to one of the commercial preparations, and trends in the data suggested that it was less well absorbed than either the chlorthalidone in water solution/suspension or the other commercial preparation of chlorthalidone. These data, together with previous reports indicating that polyethylene glycol may retard the absorption of some drugs in vitro, suggest that this compound should not be used to aid dissolution of drug in a reference standard for bioavailability investigations.

Adult↗

PubMed1995

A randomized, double-masked, placebo-controlled trial of chlorthalidone and bone loss in elderly women.

Employing a double-masked, prospective design, bone loss at three skeletal sites has been monitored among 113 postmenopausal women participating in a placebo-controlled trial of the thiazide-like diuretic chlorthalidone for treatment of systolic hypertension. The mean duration of chlorthalidone use was 2.6 years, at doses of 12.5-25 mg/day. Compared with placebo use, chlorthalidone use was associated with significant reductions in annual bone loss rates. Non-use of chlorthalidone was associated with bone loss at the calcaneus (-0.56% per year) and the proximal radius (-0.91% per year); borderline bone gain was observed at the distal radius (+0.39%). In contrast, chlorthalidone use was associated with bone gain at the calcaneus (+0.44% per year) and the distal radius (+1.51% per year); proximal radius bone loss was significantly reduced to -0.32% per year. The average increment for three appendicular sites was +0.9% per year. These data support a causal relationship between chlorthalidone use and reduced bone loss.

Aged↗

PubMed1998

The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness.

BACKGROUND: It is unclear whether the carotid intima-media thickness can be influenced by antihypertensive treatment and whether some antihypertensive agents, such as calcium antagonists, may have a greater effect on this parameter than others, such as diuretics. The present paper reports the principal results of the ultrasound substudy of the randomized, prospective, controlled, Verapamil in Hypertension and Atherosclerosis Study (VHAS). DESIGN AND METHODS: In 498 hypertensive patients in eight Italian centres, randomized to either verapamil (240 mg once a day) or chlorthalidone (25 mg once a day), a B-mode ultrasound scan was performed according to a standardized procedure at baseline and after 3, 12, 24, 36 and 48 months of treatment. The maximum intima-media thicknesses of the far walls of common, bifurcation and internal carotid arteries were measured bilaterally, and the following indices calculated: the mean thickness at the six measured sites, the mean thickness at the common and bifurcation sites and the single maximum thickness. The primary endpoint for treatment efficacy was the slope of the change over 4 years (rate of change, mm/year), corrected by using the initial mean over the six sites (baseline + 3 months) as a covariate (mm/year per mm). The patients were also classified into three strata according to their baseline single maximum thickness: those with normal carotid arteries (single maximum ( 1 mm), those with thickened carotid arteries (single maximum > 1 and < or = 1.5 mm and those with carotid plaques (single maximum > 1.5 mm). RESULTS: Among the 456 patients with satisfactory baseline ultrasound readings, 33% were classified with normal carotid arteries, 27% with thickened carotid arteries and 40% with plaques. In the intention-to-treat population (377 patients with ultrasound measurements taken on at least three different occasions over a period of at least 2 years), the rate of change in the mean thickness at the six sites measured was rather small (0.015 mm/year), but significantly (P < 0.05) smaller in patients with plaques (0.003 mm/year) than in patients with thickened or with normal carotids (0.023 and 0.025 mm/year, respectively). When related to initial values, the rate of change in the mean thickness at the six sites had a negative slope (-0.059 mm/year per mm, P < 0.01). Although rates of change in the carotid intima-media thickness in unstratified patients were not different in those treated with verapamil or with chlorthalidone, when changes in the mean thickness of six sites were related to the initial value, the slope of this relationship was significantly different in the two treatment groups (verapamil -0.082 versus chlorthalidone -0.037 mm/year per mm, P < 0.02). The blood pressure-lowering effect of the two randomized treatments was similar. Taking fatal and nonfatal, major and minor cardiovascular events together, there were 19 events in the verapamil group and 35 in the chlorthalidone group, with a significantly (P < 0.01) greater incidence in patients with plaques, and among patients with plaques in those who were randomized to chlorthalidone (P < 0.05). CONCLUSIONS: In accord with evidence from animal models of atherosclerosis, the calcium antagonist verapamil was more effective than the diuretic chlorthalidone in promoting regression of thicker carotid lesions. Changes in the carotid intima-media thickness were small in both groups, and the differences between the changes under the two treatments were consequently small, but the observation that these small differences in carotid wall changes were paralleled by differences in the incidence of cardiovascular events (better intima-media thickness regression with verapamil paralleled by a lower cardiovascular event rate) suggests that even small effects on carotid plaques may have clinical and prognostic relevance.

Adult↗

PubMed1991

The combination of chlorthalidone with nifedipine does not exert an additive antihypertensive effect in essential hypertensives: a crossover multicenter study.

To evaluate whether the combination of nifedipine with chlorthalidone exerts an additive antihypertensive effect when compared to single-drug treatment, 66 uncomplicated essential hypertensives, whose diastolic blood pressure was greater than 100 and less than 115 mm Hg at the end of a 1-month washout placebo period, received, according to a randomized, double-blind, crossover design, nifedipine (20 mg b.i.d.), chlorthalidone (25 mg o.d.), the two drugs combined at the same doses, and the corresponding placebo. When compared to the randomized placebo the three active treatments significantly (p less than 0.001) reduced blood pressure without changing heart rate and body weight. However, blood pressure values were similarly reduced under nifedipine and the combination and were significantly lower (p less than 0.05) than those under chlorthalidone. Moreover, the percentage of responders and normalized patients under nifedipine and the two drugs combined were similar and significantly (normalized, p less than 0.0001; responders, p less than 0.02) greater than those under chlorthalidone. Under chlorthalidone and its combination with nifedipine, plasma potassium tended to decrease and blood glucose and serum uric acid were significantly (p less than 0.05) increased. These data show that the combination of nifedipine with chlorthalidone does not exert any additive antihypertensive effect when compared to nifedipine alone and that this combination increases both blood glucose and serum uric acid. Taken together these findings indicate that the combination of a dihydropyridine calcium antagonist with a thiazide diuretic is devoid of any clinical significance in the treatment of uncomplicated essential hypertensives.

Adult↗

PubMed1984

Analysis of chlorthalidone in biological fluids by high-performance liquid chromatography using a rapid column cleanup procedure.

A high-performance liquid chromatographic assay usable for clinical monitoring of chlorthalidone in biological fluids was developed. Extraction efficiency was greater than 80% for blood and urine using a rapid, disposable column cleanup procedure. Chlorthalidone could be reliably measured in the range of 100-4,000 ng/ml in biological fluids with excellent day-to-day reproducibility and within-day precision. Chlorthalidone was found to be stable at -20 degrees C in blood and urine for at least 1 year, permitting repeat assays and large clinical studies to be conducted. The pharmacokinetics of chlorthalidone was studied in 24 subjects over a 120-h time interval following a single dose. chlorthalidone has a long terminal half-life in whole blood of 49 h, with peak concentrations occurring 8-10 h after oral dosing. During the first 12 h after dosing, chlorthalidone was rapidly excreted into urine followed by a slower phase with a half-life of 49 h.

Adolescent↗

PubMed2006

Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.

Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients. Chlorthalidone has significantly reduced stroke and cardiovascular end points in several landmark trials; however, hydrochlorothiazide remains favored in practice. Most clinicians assume that the drugs are interchangeable, but their antihypertensive effects at lower doses have not been directly compared. We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. The main outcome, 24-hour ambulatory blood pressure (BP) monitoring, was assessed at baseline and week 8, along with standard office BP readings every 2 weeks. Thirty patients completed the first active treatment period, whereas 24 patients completed both. An order-drug-time interaction was observed with chlorthalidone; therefore, data from only the first active treatment period was considered. Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = -12.4+/-1.8 mm Hg versus -7.4+/-1.7 mm Hg; P=0.054; nighttime mean = -13.5+/-1.9 mm Hg versus -6.4+/-1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (-15.7+/-2.2 mm Hg versus -4.5+/-2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (-17.1+/-3.7 versus -10.8+/-3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.

Adult↗

PubMed1986

Low-dose atenolol-chlorthalidone combination for treatment of mild hypertension.

In a randomized, double-blind, within-patient study, 28 out-patients with mild to moderate hypertension were given, at the end of a 3-week placebo wash-out period, four different antihypertensive treatments for 3 weeks each. the treatments were 50 mg atenolol, 100 mg atenolol, 12.5 mg chlorthalidone and a fixed combination of 50 mg atenolol and 12.5 mg chlorthalidone. All treatments were given once daily. Visits were scheduled for the last day of each treatment period, 24-26 hours after the last dose, and there was an intermediary wash-out period between each pair of active treatments. Supine systolic/diastolic blood pressure was 165/102 on placebo, 153/93 mmHg on 50 mg atenolol, 155/91 mmHg on 100 mg atenolol, 148/93 mmHg on 12.5 mg chlorthalidone and 144/89 mmHg on the combination. All the changes in pressure were significant (p less than 0.01) versus placebo. Supine systolic blood pressure was lower on the combination than on 100 mg atenolol alone (p less than 0.05) and upright systolic pressure was lower on the combination than on 100 mg atenolol (p less than 0.05) or 50 mg atenolol (p less than 0.05) alone. The heart rate was lowered by atenolol alone or combined with chlorthalidone but did not fall below 56 bpm in any patient. Serum potassium levels were lower on 12.5 mg chlorthalidone than on placebo (3.88 mEq/l vs 4.09 mEq/l--p less than 0.05) but the difference was trivial; on the combination of atenolol-chlorthalidone there was no significant difference versus placebo (3.97 mEq/l vs 4.09 mEq/l--NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Half-strength atenolol-chlorthalidone combination (tenoretic mite) in the treatment of elderly hypertensive patients.

The antihypertensive efficacy and tolerance of a new fixed combination of 50 mg atenolol and 12.5 mg chlorthalidone (Tenoretic Mite, TM) was studied in 37 patients with arterial hypertension, aged 61-80 years (mean, 70.2 years), who had been randomized to either 50 mg atenolol or 12.5 mg chlorthalidone for a 4-week period. At the end of this period, the fixed combination of atenolol and chlorthalidone was given to all patients for 6 months at a dose of one tablet daily in the morning. In both atenolol- and chlorthalidone-pretreated patients, treatment with the fixed combination resulted in a further significant drop in blood pressure, whereas the heart rate decreased only in the latter group. The mean blood pressure reduction achieved by the fixed combination was 30/15 mmHg in the standing position. Serum potassium levels significantly increased with the fixed combination compared with values on chlorthalidone alone. Unwanted effects were rare, and their frequency tended to decrease over time. In conclusion, the fixed combination of 50 mg atenolol plus 12.5 mg chlorthalidone tested in this study proved highly effective in lowering elevated blood pressure values in a population of elderly hypertensive patients treated over a 6-month period without noticeable unwanted effects.

Age Factors↗

PubMed1980

Antihypertensive activity of a fixed combination of oxprenolol and chlorthalidone in mild to moderate arterial hypertension.

In a multicentre double-blind study, 92 out-patients with mild to moderate hypertension who had a resting blood pressure greater than or equal to 160/100 mmHg after a two-weeks' placebo wash-out were treated for 6 weeks with a fixed combination of oxprenolol 80 mg + chlorthalidone 10 mg per tablet or chlorthalidone alone (1 tablet = 10 mg). Five patients were drop-outs, 19 out of 44 patients on fixed combination and 7 out of 43 on chlorthalidone were given only 1 tablet b.i.d. throughout the study; the remaining doubled the corresponding dosage after the first 2 weeks. Resting and standing systolic and diastolic blood pressure decreased on both treatments, the reductions being significantly more marked on fixed combination in comparison to chlorthalidone alone (p < 0.01 and p < 0.05). The systolic blood pressure decrease was significantly greater on fixed combination from the first week of treatment (p < 0.05). Normalization of diastolic blood pressure was reached more frequently on fixed combination (73%) than on chlorthalidone (49%) (p < 0.05). Side-effects were recorded in 14 out of 44 patients treated with fixed combination and in 14 out of 43 treated with chlorthalidone. The advantages of treating patients with mild to moderate hypertension with a fixed combination of beta-blocker and diuretics are discussed.

Chlorthalidone↗

PubMed1995

Vascular effects of chlorthalidone in mild hypertensives.

In a randomized trial with chlorthalidone, 30 hypertensive outpatients of both genders, aged 50.4 +/- 8.6 years, having diastolic blood pressure between 95 and 110 mm HG were divided into 2 groups of 15, after a two-week placebo period. The A group received chlorthalidone in a single dose of 23 mg for one month, and the next month was given a 12.5 mg alternative dose, whereas the B group was given 12.5 mg in the first month and 25 mg in the second. Changes in vascular reactivity were measured by occlusive plethysmography (mercury strain-gauge) at the ends of the placebo period, the first and the second month of therapy. All the observed parameters, i.e. rest flow, peak flow, venous capacity, and maximal venous outflow, were found to have increased with 25 mg chlorthalidone, and similar findings were registered when 12.5 mg of the drug were given. Venous capacity increased significantly in both groups (from 2.6 to 3.2 and from 3.0 to 3.4 ml/100 ml). The peak-flow values augmented significantly only in the group where 25 mg of chlorthalidone were given first (from 18.6 to 23.9 ml/100 ml/min). Both doses had a similar antihypertensive effect, decreasing the mean arterial pressure by some 8% in the upright, sitting, and supine position. It is concluded that the antihypertensive effect of chlorthalidone is, at least partly, due to changes in vascular reactivity; vasodilation is more prominent on the venous side of the circulation. Low-dose chlorthalidone is equipotent as antihypertensive, its side-effects are rare, and the cost of such a therapy is by far the lowest.

Adult↗

PubMedDate not supplied

Bioavailability in man of atenolol and chlorthalidone from a combination formulation.

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drug as a fixed combination ('Tenoretic'), as a free combination, and individually, at doses of 100 mg atenolol, and 25 mg chlorthalidone. There were no statistically significant differences between the three formulations of atenolol in terms of individual blood levels, half-life, area-under-the-curve, and urinary excretion. The half-lives were between 5 and 6 h in agreement with other published data. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet. The chlorthalidone blood levels were slightly higher following the administration of the fixed combination when compared with the free combination or the chlorthalidone tablet. This observation was reflected in estimates of the area under the curves and the urinary recoveries. The half-lives of all three formulations were similar at about 60 h. It is concluded that combining chlorthalidone and atenolol in a single tablet does not reduce the systemic bioavailability of either component.

Adult↗

PubMed1985

Degradation of chlorthalidone in methanol: kinetics and stabilization.

The reaction of chlorthalidone with methanol to give the corresponding methyl ether was investigated. The kinetics are pseudo-first-order in chlorthalidone, but the observed pseudo-first-order rate constants show an unexpected dependence on the initial chlorthalidone concentration, attributable to the presence of trace catalytic impurities in commercial chlorthalidone. Evidence is presented to show that trace heavy metals are probably responsible for the primary catalytic effect. Trace quantities of acetic acid are also present and show a smaller secondary catalytic effect. Kinetics in the presence of added heavy metals and acetic acid were examined. EDTA and povidone reduce the degradation rate. Stabilization by EDTA is due to its ability to chelate heavy metals. Stabilization by povidone is also primarily due to its ability to complex heavy metals; complexation data of ferric and nickel ions with povidone and with 1-methyl-2-pyrrolidinone as a monomer model are presented. In addition, complexation constants were calculated for the interaction of povidone with chlorthalidone, which may also play a role in stabilization.

Chemical Phenomena↗

PubMed2000

The diuretic chlorthalidone normalizes baroreceptor and Bezold-Jarisch reflexes in DOCA-salt hypertensive rats.

The contributions of arterial baroreceptor and Bezold-Jarisch reflexes, and atrial natriuretic factor (ANF) to the anti-hypertensive effect of the diuretic chlorthalidone were investigated in rats with deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Chlorthalidone (8 mg rat(-1)day(-1)added to food) was given to one group during all 20 days of DOCA (8 mg kg(-1)s.c. twice per week) administration (preventive regimen) and, to another group, 20 days after DOCA treatment was initiated until the 40th day (therapeutic regimen). DOCA caused a significant increase in mean arterial pressure, reduced arterial baroreflex, and increased both the Bezold-Jarisch reflex and pro-ANF converting enzyme activity. Chlorthalidone reversed or prevented the DOCA-salt-induced hypertension, which was accompanied by the normalization of both the arterial baroreflex and the Bezold-Jarisch reflex. Additionally, both preventive and therapeutic regimens with chlorthalidone did cause normalization of the plasma sodium concentration and pro-ANF converting enzyme activity in the left atrium that follows DOCA-salt hypertension. Although it is difficult to determine the relative importance of each of the above regulatory mechanisms altered by chlorthalidone treatment, these data indicate that they may account for the prevention or decrease of DOCA-salt-induced hypertension in rats.

Animals↗