ANGIOTENSIN-I-CONVERTING-ENZYME INHIBITION BUT NOT ANGIOTENSIN-II SUPPRESSION ALTERS ANGIOTENSIN-I-CONVERTING-ENZYME GENE-EXPRESSION IN VESSELS AND EPITHELIA

The concentration of angiotensin-converting enzyme (ACE) increases dur ing chronic treatment with ACE inhibitors for unknown reasons. We inve stigated whether alterations in ACE mRNA and ACE concentration occur i n the different tissues during ACE inhibition and the role of angioten sins in these regulations by comparing ACE inhibitors with other block ers of the renin-angiotensin system. Enalapril, an ACE inhibitor, in t he range of 0.3 to 10 mg/kg/day in rats induced dose-and time-dependan t increases in plasma ACE up to two to three times control values. The re were significant increases in the steady state ACE mRNA in the lung (32%), duodenum (64%) and aorta (324%) and 40% to 140% increases in m embrane-bound enzyme concentration in these tissues and in the heart a nd kidney. The ACE content of purified duodenal brush border was incre ased by 80%, but the enzyme and its mRNA in the testis were not altere d. The angiotensin II receptor antagonist losartan at several regimens of up to 30 mg/kg twice a day for 14 days produced no change in plasm a ACE level or lung ACE mRNA. The human renin inhibitor ciprokiren was tested in guinea pigs, a species sensitive to this compound. Both ena lapril and cilazapril induced 2-fold increases in plasma ACE, but cipr okiren (24 mg/kg/day for 12 days) had no effect. Enalapril treatment o f BN/Kat rats (lacking circulating kininogens) caused a similar increa se in ACE as in other rats. This study documents a general increase in ACE gene expression and enzyme concentration in tissues during ACE in hibition, with the exception of the testis, most probably reflecting a n activation of the 5', so-called somatic promoter of the ACE gene. An giotensins are not involved in this regulation and do not seem to cont rol ACE gene expression in normal rodents.