A MOUSE VIEW OF HYPERTENSION

Essential hypertension probably results from combinations of genetic v ariations, not necessarily the same in all afflicted persons, which in dividually may not cause sufficient deviation from normality to be sig nificantly harmful. We have used gene targeting to vary the amounts of angiotensinogen and angiotensin-converting enzyme (ACE) synthesized f rom their genes (Agt and Ace). These ''gene titration'' experiments es tablish that changes in Agt gene expression cause changes in the blood pressures of mice. Surprisingly, quantitative changes in Ace gene exp ression over a threefold range do not affect blood pressures. Computer simulations with a simple version of the renin-angistensin system pre dict that changes in Agt function alter the steady state levels of bot h angiotensin I (Ang I) and angiotensin II (Ang II). In contrast, mode st changes in Ace function alter Ang I levels considerably but scarcel y affect Ang II levels. Simulations over the ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II levels will d ecrease only when Ang I levels have plateaued. Comparisons of the comp uter simulations with our genetic experiments and with prior work of o thers using wide dose ranges of ACE inhibitor show a satisfactory agre ement and help reconcile the apparent contradictions between the genet ic and pharmacological experiments.