In the present study we searched for quantitative trait loci (QTLs) that affect neuroendocrine stress responses in a 20-min restraint stress paradigm using Brown-Norway (BN) and Wistar-Kyoto-Hyperactive (WKHA) rats. These strains differed in their hypothalamic-pituitary-adrenal axis (plasma ACTH and corticosterone levels, thymus, and adrenal weights) and in their renin-angiotensin-aldosterone system reactivity (plasma renin activity, aldosterone concentration). We performed a whole-genome scan on a F2 progeny derived from a WKHA x BN intercross, which led to the identification of several QTLs linked to plasma renin activity (Sr6, Sr8, Sr11, and Sr12 on chromosomes RNO2, 3, 19, and 8, respectively), plasma aldosterone concentration (Sr7 and Sr9 on RNO2 and 5, respectively), and thymus weight (Sr10, Sr13, and Srl4 on RNO5, 10, and 16, respectively). The type 1b angiotensin II receptor gene (Agtrlb) maps within the confidence intervals of QTLs on RNO2 linked to plasma renin activity (Sr6, highly significant; LOD = 5.0) and to plasma aldosterone level (Sr7, suggestive; LOD = 2.0). In vitro studies of angiotensin II-induced release of aldosterone by adrenal glomerulosa cells revealed a lower receptor potency (log EC50 = -8.16 +/- 0.11 M) and efficiency (Emax = 453.3 +/- 25.9 pg/3 x 10(4) cells/24 h) in BN than in WKHA (log EC50 = -10.66 +/- 0.18 M; Emax = 573.1 +/- 15.3 pg/3 x 10(4) cells/24 h). Moreover, differences in Agtr1b mRNA abundance and sequence reinforce the putative role of the Agtr1b gene in the differential plasma renin stress reactivity between the two rat strains.