Blood pressures and cardiovascular homeostasis in mice having reduced or absent angiotensin-converting enzyme gene function.
We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivation 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 pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by Ace genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/- group and virtually abolished (+1%) in the -/- group. The depressor response to injected bradykinin was significantly enhanced in the +/- and -/- groups compared with the +/+ group. Ace expression and ACE activity were directly related to functional Ace copy number, and renin and angiotensinogen 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 affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one Ace copy, which include increased expression of renin, normalize blood pressure in heterozygotes.
Tian
B
B
Department of Medicine, University of Alabama at Birmingham, 35294-0007, USA.
Meng
Q C
QC
Chen
Y F
YF
Krege
J H
JH
Smithies
O
O
Oparil
S
S
D000704:Analysis of Variance; D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D001920:Bradykinin / Q000008:administration & dosage / Q000494:pharmacology; D002319:Cardiovascular System; D018076:DNA, Complementary; D004587:Electrophoresis, Agar Gel; D005260:Female; D018390:Gene Targeting; D006339:Heart Rate; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011945:Receptors, Angiotensin / Q000235:genetics
D018076:DNA, Complementary; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000804:Angiotensin II; D012313:RNA; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin