Extrarenal contributions to indapamide's antihypertensive mechanism of action

Autonomic responses in heart rate and blood pressure to Valsalva maneuvers and changes in vascular reactivity to pressor doses of phenylephrine and angiotensin II were studied before and after treatment with indapamide, a new antihypertensive diuretic. Six healthy male volunteers, placed on a daily diet consisting of 100 mEq of sodium, 80 mEq of potassium, and a fluid intake of 2500 ml, participated in this single-blind, placebo-controlled study. During active treatment, 5 mg of indapamide was administered once daily for 14 days. On the mornings of hemodynamic testing, samples of blood, 24-hour urine, and plasma were obtained and analyzed for hematocrit, catecholamines and their metabolites, plasma renin activity, and aldosterone levels. Since each subject served as his own control, the results were analyzed by the paired t-test method. Plasma renin activity and 24-hour urinary aldosterone levels increased (p less than 0.05), and serum potassium and chloride levels decreased (p less than 0.05). No other significant laboratory changes were noted after treatment, including changes in the plasma and urinary catecholamine levels. Following treatment, responses in heart rate and blood pressure to Valsalva maneuvers were unaltered. During the control period the doses of phenylephrine and angiotensin II required to raise the systolic pressure 25 to 35 mm Hg and the diastolic pressure 20 to 30 mm Hg were 5.03 +/- 0.72 micrograms/kg and 16.7 +/- 2.1 ng/kg, respectively. After treatment, the doses of phenylephrine and angiotensin II were significantly (p less than 0.05) greater: 10.72 +/- 1.02 micrograms/kg and 31.7 +/- 4.8 ng/kg, respectively. Dose-response relationships to these pressor agents were shifted in parallel to the right after treatment. A small but significant decrease in body weight, which may have reflected a decrease in plasma volume, was observed. However, no orthostatic changes between the supine and erect mean arterial blood pressures or incremental increases in heart rates were noted between the two periods. An increase in hematocrit and blunting of the diastolic overshoot during the Valsalva maneuvers that were used as indexes of plasma volume contraction were also not observed. In summary, our results indicate that changes in vascular responsiveness occurred by mechanisms independent of changes in the autonomic nervous system, since plasma norepinephrine levels did not change and responsiveness to Valsalva maneuvers was unaltered. Furthermore, it appears that this effect on the vasculature was probably not related to changes in plasma volume.