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Platelet free intracellular calcium levels were measured during a double-blind, placebo-controlled parallel study to investigate the antihypertensive activity of 50 μg, 125 μg, and 500μg cyclopenthiazide, in mild essential hypertension. Cytosolic free calcium levels were significantly higher in established hypertensive patients (135 ± 28 nmol/l, P< 0.001) but not in borderline hypertensive patients (123 ± 26 nmol/l) compared with normotensive controls (111 ± 9 nmol/l). A positive correlation between platelet free calcium level and systolic and diastolic blood pressure was confirmed (n = 68; r = 0.309 P = 0.01; r = 0.405 P < 0.001, respectively). The 125-μg and 500-μg doses of cyclopenthiazide produced mean decrements in blood pressure of 18/10mmHg and 23/8 mmHg, respectively, (P < 0.05 for both), after 8 weeks of therapy. The 50-μg dose displayed no useful antihypertensive activity. Platelet free calcium levels fell by a similar amount in the four groups. The fall in blood pressure produced by the 125 and 500-μg doses of cyclopenthiazide did not correlate with changes in platelet [Ca2+] (r = 0.166 systolic and r = 0.169 diastolic). These findings do not support the hypothesis that changes in platelet cytosolic calcium levels are determined by the same factors that control blood pressure.