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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., (Copyright 2000 Academic Press.)

We have reported that chlorthalidone (Chlor) prevents the development of heart hypertrophy in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The present study was carried out to determine whether Chlor (8 mg/day per animal, added to the food, for 20 days) affects kidney and heart hypertrophy in DOCA-salt (8 mg/kg, sc, twice a week) rats by causing alterations in protein and peptide hydrolysis. Heart (left ventricle) and kidney enzyme activities were measured in tissue homogenates from normal-control, salt-control, DOCA-salt and DOCA-salt-Chlor male Wistar rats (N = 6 for each group), using azocasein as the substrate for proteolytic enzymes and specific peptides for prolylendopeptidase (PEP) and multicatalytic proteinase (MCP). The tissue weight/body weight ratio increased in parallel to elevation of blood pressure. The left ventricular muscle hypertrophy (26%, P < 0.05) present in the DOCA-salt hypertensive group was completely prevented by simultaneous Chlor treatment. Chlor treatment did not change the kidney hypertrophy (+79%, P < 0.;05) observed in the salt-control (+57%, P < 0.05) and DOCA-salt (+74%, P < 0.05) groups. The hydrolysis of peptides by PEP and MCP was similar in the normal and salt-control groups. The heart PEP activity was 24% higher (P < 0.01) in DOCA-salt rats, whereas MCP activity was not different when compared to control groups. DOCA-salt treatment increased MCP activity in the kidney by 44% while PEP activity did not differ from that of control groups. The hydrolysis of proteins by heart enzymes was increased by salt by 47%. Chlor treatment restored the reduction in protein hydrolysis induced by DOCA-salt (a 21% decrease, P < 0.05) to a level similar to that of the normal-control group. Similarly, Chlor coadministration prevented the 30% reduction in renal proteolytic activity elicited by DOCA-salt treatment. Although Chlor treatment prevented the DOCA-salt-induced reduction in protein hydrolysis, this response did not interfere with kidney hypertrophy. The mechanism by which hypertension produces hypertrophy is unclear, but our results suggest that this structural modification is not related to the activities of some peptidases, e.g. protein and peptide hydrolases.

Diuretics have been the mainstay of long-term treatment of hypertension, but there is no evidence suggesting that diuretics may be effective in reducing cardiac hypertrophy associated with hypertension. Thus, the present study was carried out to elucidate if long-term treatment with chlorthalidone (8 mg per animal per day added to food) affects the development of and reverses the ventricular hypertrophy in deoxycorticosterone acetate (DOCA) (8 mg/kg SC twice a week)-salt hypertensive rats. Chlorthalidone was given to one group during all 20 days of DOCA administration (preventive regimen) and to another group 20 days after DOCA treatment was initiated until the 40th day (therapeutic regimen). Chlorthalidone was found to reduce or prevent the development of ventricular hypertrophy, as assessed by a reduction in ventricular mass and cardiac protein as well as arterial hypertension. Both chlorthalidone regimens prevented the increase or induced a significant decrease in the plasma concentration of sodium and in cardiac sympathetic tone, which were both increased in DOCA-salt-treated rats. These data provide evidence that long-term chlorthalidone treatment is effective in preventing or reducing ventricular hypertrophy along with arterial hypertension. However, whether this is due to a reduction in plasma sodium or other additional mechanisms, such as a reduction in cardiac sympathetic tone, remains to be determined.