Effects of chlorthalidone on ventricular hypertrophy in deoxycorticosterone acetate-salt hypertensive rats.

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.

Endothelium-dependent and endothelium-independent effects of adenosine diphosphate in renovascular hypertension.

Norepinephrine-induced responses in isolated perfused mesenteric vascular bed from normotensive and renovascular hypertensive rats were examined in the presence of adenosine diphosphate (ADP, 2 x 10(-6) M). Responses to norepinephrine were significantly greater in vessels from hypertensive rats. Norepinephrine-induced contractions increased after the removal of endothelium. N omega-Nitro-L-arginine (L-NOARG), a potent inhibitor of nitric oxide formation, similarly increased contractions. The greatest responses were obtained, however, after treatment of the vascular segments with methylene blue. The presence of ADP caused significant endothelium-dependent decreases in contractions. Although decreases caused by ADP in vessels with endothelium after treatment with L-NOARG were not statistically significant, a tendency to decreased responses seems to suggest that L-NOARG diminishes but does not completely prevent the effect of ADP in mesenteric vessels. Methylene blue partially reduced the endothelium-dependent ADP-induced relaxant effects in sham-operated nephrectomized rats. A tendency to increased contractions to norepinephrine was observed in the presence of ADP after removal of endothelium. Thus, in the mesenteric resistance arteries of the rat under stimulation by ADP, it appears that nitric oxide released from L-arginine and the activity of soluble guanylate cyclase account only in part for the endothelium-dependent decreased responses to norepinephrine. When nitric oxide formation or soluble guanylate cyclase activity are depressed simultaneously with endothelium damage, ADP released from platelets or red blood cells may be an important factor that acts synergically with vasoconstrictor stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorthalidone alters the vascular reactivity of DOC-salt hypertensive rats to norepinephrine.

Hypertension caused by deoxycorticosterone-salt (DOC-salt) may involve enhanced sympathetic tone and some diuretics may exert their antihypertensive action by modulating presynaptic adrenergic sensitivity. This study analyzes the noradrenergic sensitivity of the perfused mesentery isolated from DOC-salt hypertensive rats treated or not with chlorthalidone. Chlorthalidone treatment reduced arterial hypertension in DOC-salt treated rats (from 160 +/- 7 to 127 +/- 5 mmHg). The diuretic completely prevented the increase in sympathetic tone and blunted the decreased vagal tone observed in DOC-salt rats. Norepinephrine-induced vasoconstriction was enhanced in perfused mesenteries isolated from DOC-salt rats. This alteration was attenuated in preparations from chlorthalidone-treated DOC-salt animals. Blockade of neuronal catecholamine uptake using cocaine did not change these responses. These data suggest that chlorthalidone reduces the vascular hyperresponsiveness to catecholamines observed in DOC-salt treated hypertensive rats.

Chlorthalidone reduces vascular hyperresponsiveness in DOCA-salt hypertensive rats.

The mechanisms of anti-hypertensive effect of diuretics remain unknown. The purpose of this study was to test the hypothesis that long-term treatment with chlorthalidone decreases the responsiveness of resistance vessels to neurohormones. The study was performed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with and without treatment with chlorthalidone (Chlor. 8 mg/day, for 20 days). Resting mean arterial pressure in freely moving state was significantly reduced in DOCA-salt-Chlor rats when compared to DOCA-salt rats (116 +/- 3 vs 147 +/- 7 mmHg, respectively). Chlorthalidone treatment reduced the high plasma sodium content observed in DOCA-salt rats to the same levels observed in normotensive control groups. Results obtained in isolated perfused mesenteric arteries showed: a) the increase in perfusion pressure elicited by norepinephrine (NE), serotonin (SE) and vasopressin (VP) was significantly greater in DOCA-salt than in DOCA-salt + Chlor rats or control normotensive rats; b) the endothelium removal increased the pressor responses to NE, SE and VP in a similar way in all groups. These data provide evidence that long-term chlorthalidone treatment reduces vascular hyperresponsiveness to these neurohormones. In addition, these results indicate that this reduction in vascular hyperresponsiveness, associated with a decrease in extracellular sodium level, could be a possible mechanism by which the diuretics reduce the high blood pressure.

Chlorthalidone alters the vascular reactivity of doc-salt hypertensive rats to norepinephrine

Hypertension caused by deoxycorticosterone-salt (DOC-salt) may involve enhanced sympathetic tone and some diuretics may exert their antihypertensive action by modulating presynaptic adrenergic sensitivity. This study analyzes the noradrenergic sensitivity of the perfused mesentery isolated from DOC-salt hypertensive rats treated or not with chlorthalidone. Chlorthalidone treatment reduced arterial hypertension in DOC-salt treated rats (from 160 ñ 7 to 127 ñ 5 mmHg). The diuretic completely prevented the increase in sympathetic tone and blunted the decreased vagal tone observed in DOC-salt rats. Norepinephrine-induced vasoconstriction was wnhanced in perfused mesenteries isolated from DOC-salt rats. This alteration was attenuated in preparations from chlorthalidone-treated DOC-salt animals. Blockade of neuronal catecholamine uptake using cocaine did not change these responses. These data suggest that chlorthalidone reduces the vascular hyperresponsiveness to catecholamines observed in DOC-salt treated hypertensive rats