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To study cellular calcium metabolism in hypertension, we investigated the effects of human serum, and of the circulating pressor substance, parathyroid hypertensive factor (PHF), on the cytosolic free calcium (Cai-f) content of erythrocytes from normotensive and essential hypertensive subjects. In their own serum, basal Cai-f was higher in hypertensive than in normotensive subjects (mean ± SEM; 39.4 ± 4.0 vs. 23.4 ± 2.7 nM; p < 0.05). Without serum, Cai-f was lower and not significantly different (23.0 ± 3.1 vs. 18.2 ± 2.7 nM; p = not significant). Addition of serum to serum-free erythrocytes increased Cai-f, and reestablished the Cai-f gradient in hypertensive cells (31.4 ± 0.8 vs. 23.0 ± 2.3 nM; p < 0.05). PHF levels were directly related to basal Cai-f (r = −0.648; p < 0.05) and to the serum-induced rise in Cai-f (r = 0.600; p < 0.05). Furthermore, semipurified PHF, but not similarly prepared normotensive serum, increased Cai-f in normal human erythrocytes (PHF: +83.9 ± 37.3% vs. + 14.5 ± 27.5%; p < 0.05). We conclude that circulating factors in general, and PHF in particular, may account for the increased basal Cai-f of hypertension, and thus at least partially contribute to the pathophysiology of the hypertensive process.