We have previously described a subset of subjects with essential hypertension who fail to appropriately modulate renal vascular and adrenal reactivity with changes in dietary sodium and in response to infused angiotensin II (Ang II). In this paper, we studied these responses in 13 unselected hypertensive subjects in whom the family history of hypertension had been carefully detailed. Nine of these 13 subjects had a positive family history (FH+) for hypertension and had significantly smaller decrements in renal blood flow with Ang II infusion than the four subjects who had a negative family history (FH-) (-84 +/- 16 ml/min/1.73 m2 for FH+ vs. -149 ml/min/1.73 m2 for FH-, p = 0.024). These FH+ subjects also showed smaller increases in renal blood flow with increases in dietary sodium than FH- subjects (7 +/- 10 ml/min/1.73 m2 vs. 72 +/- 24 ml/min/1.73 m2, respectively; p = 0.014). When classified as modulators or non-modulators by previously established criteria, all seven non-modulators were FH+, and seven of nine FH+ subjects were non-modulators. This association between non-modulation and family history of hypertension is significant (p = 0.021). To further clarify the association between non-modulation and family history of hypertension, we have studied the renal blood flow response to Ang II in 31 hypertensive siblings from 14 sibships. Twenty-five of these 31 subjects (81%) behaved as non-modulators (p = 0.008 compared with expected value in an unselected hypertensive population). Additionally, strong concordance of non-modulation between sibling pairs was observed (p = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)