Moduretic has been reported to inhibit the suppression of plasma norepinephrine (NE) levels by the alpha 2 adrenoceptor agonist, clonidine. To determine whether plasma volume reduction by hydrochlorothiazide (HCTZ) or antagonism of Na+/H+ exchange by amiloride (the constituents of Moduretic) is responsible, the authors performed a modified clonidine suppression test (CST) in nine normal volunteers (aged 25 +/- 2 years), pretreated for 1 week with HCTZ 50 mg daily, amiloride 10 mg daily, or placebo, in a randomized, double-blind, crossover study. Baseline characteristics were identical on all study days, except serum [K+] and weight, which were lowest on HCTZ (3.6 +/- 0.2 mEq/L and 78.7 +/- 2.5 kg), compared with amiloride (4.2 +/- 0.1 mEq/L and 79.9 +/- 2.4 kg) and placebo (4.0 +/- 0.1 mEq/L and 80.2 +/- 2.7 kg, P less than .05). Oral clonidine (0.3 mg) produced a reduction in mean blood pressure by about 20%. Plasma norepinephrine levels were similar in patients receiving placebo, HCTZ, and amiloride (205 +/- 18, 272 +/- 40 and 277 +/- 44 pg/mL, P greater than .20), and decreased significantly during CST. The maximal reduction for each subject averaged 72.7 +/- 12.4%, 87.9 +/- 3.8%, and 82.9 +/- 5.7% for placebo, HCTZ, and amiloride. Clonidine also produced a four to seven-fold increase in plasma growth hormone levels, reduced salivary flow by about 75%, and increased the level of sedation. There were no differences among the three pretreatment regimens in the effects of clonidine, indicating that diuretic therapy does not need to be systematically discontinued in patients undergoing CST.