Abstract-The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points. To determine the impact of strain (BPH/2 versus BPL/1), age (juvenile versus adult), and the interaction of strain and age on gene expression levels, we performed standard 2-factor ANOVA and computed a concordance coefficient to assess the reproducibility of gene expression measurements among replicates. Of genes with significant (PϽ0.05) differential expression, 2647 showed strain differences, 982 showed age differences, and 757 exhibited strain-by-age interaction. Fold-changes in gene expression assayed by microarray were confirmed in a subset by real-time polymerase chain reaction (Rϭ0.739, Pϭ0.0094). We used a systems biology approach to evaluate alterations in contributing biochemical pathways and we statistically quantified these global pathway disturbances using the Kolmogorov-Smirnov goodness-of-fit test. We found widespread, indeed global, alterations in patterns of gene expression in diverse systems of BPH/2: in sympathochromaffin transcripts suggesting increased sympathetic stimulation; in vasoconstrictor/vasodilator systems; global reductions in carbohydrate intermediary metabolism; and increases in oxidative stress, with changes in oxygen radical forming and disposition enzymes. These analyses highlight widespread derangements in diverse physiological pathways, providing multiple avenues for further investigation into the pathogenesis of genetic hypertension. Key Words: hypertension Ⅲ genetics Ⅲ adrenal gland Ⅲ gene expression Ⅲ metabolism Ⅲ lipids Ⅲ oxidative stress H ypertension displays substantial genetic influence, with heritability estimates for blood pressure ranging from Ϸ30% to 50%. 1 The multifactorial nature of this condition, however, has made it difficult to elucidate the underlying genetic components. With the advent of gene expression microarray technology, it has become possible to study large numbers of genes in parallel, which is ideal for studying polygenic diseases such as hypertension. 2 High-throughput microarray studies of hypertension are well complemented by the use of genetic models of hypertension. The genetically/hereditary hypertensive "blood pressure high" (BPH/2) mouse was developed by Schlager in a selection program to develop a strain of hypertensive mice inbred to homozygosity. 3 The BPH/2 strain parallels human hypertension, with elevated blood pressure, higher heart rate, and early mortality. 4 Schlager's selection program also included concurrent development of a hypotensive mouse strain, the "blood pressure low" (BPL/1). 3 Although not...