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We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

Wild-type ( Agt ϩ / ϩ ) and homozygous angiotensinogen deletion mutant ( Agt Ϫ / Ϫ ) littermates were placed on normal (NS) or low Na diet (LS) for 2 weeks. Plasma aldosterone levels (P aldo ) were comparable during NS, and similarly elevated during LS in Agt ϩ / ϩ and Agt Ϫ / Ϫ . Moreover, in both, the elevation in P aldo was accompanied by marked increase in adrenal zona glomerulosa cells and adrenal P450aldo mRNA. Agt Ϫ / Ϫ mice were distinguished from Agt ϩ / ϩ mice by their higher plasma K level, by ‫ف‬ 1.5 and ‫ف‬ 3.8 mEq/liter during NS and LS, respectively. Within the Agt Ϫ / Ϫ group, P aldo was directly proportional to plasma K. The importance of K for the hyperaldosteronism during dietary Na restriction was verified by the observation that superimposition of K restriction led to hypotension in Agt ϩ / ϩ and uniform death in Agt Ϫ / Ϫ mice along with a reduction in P aldo by 75 and 90%, respectively. Thus, suppression of potassium, but not angiotensin, led to a marked attenuation of hyperaldosteronism during dietary Na restriction. Therefore, ( a ) a powerful angiotensin-independent mechanism exists for the hyperaldosteronism during LS; ( b ) high K is a central component of this mechanism; ( c ) contrary to current belief, the tonic effect of high K on aldosterone synthesis and release does not require an intact renin-angiotensin system; and ( d ) normally, intermediary feedback signals for hyperaldosteronism, i.e., both hypotension and high K, are effectively masked by aldosterone actions. ( J. Clin. Invest. 1997. 99:855-860.)

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