BLOOD PRESSURES AND CARDIOVASCULAR HOMEOSTASIS IN MICE HAVING REDUCEDOR ABSENT ANGIOTENSIN-CONVERTING ENZYME GENE-FUNCTION

We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivatio n of the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/- mice but was reduced by 51+/-4 mm Hg in -/- mice. Although the presser response to injected angiotensin II did not differ significantly in the three genotypic groups, the presse r response to angiotensin I was strongly affected by Ace genotype: Com pared with the response in the +/+ group (+26% of baseline), the respo nse to Ang I was close to half normal (+12%) in the +/- group and virt ually abolished (+1%) in the -/- group. The depressor response to inje cted bradykinin was significantly enhanced in the +/- and -/- groups c ompared with the +/+ group. Ace expression and ACE activity were direc tly related to functional Ace copy number, and renin and angiotensinog en mRNA levels were inversely related to Ace copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the /+, +/-, and -/- groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE aff ect the blood pressure responses to infused angiotensin I and bradykin in in vivo; and (3) compensations for inactivation of one Ace copy, wh ich include increased expression of renin, normalize blood pressure in heterozygotes.