title: Converting enzyme inhibitors differentially affect expression of genes of the renin-angiotensin system.
abstract: There is considerable evidence from clinical and experimental studies that blood pressure is lowered by converting enzyme inhibitors (CEIs) irrespective of whether the plasma renin-angiotensin system (RAS) is stimulated. New insights into the molecular biology of the RAS--in particular, the gene expression of renin and angiotensinogen in various tissues--support the view that the antihypertensive properties of CEIs may be mediated, at least in part, by interaction with tissue RAS. To investigate this possibility further, stroke-prone spontaneously hypertensive male rats (SHRSP) were treated orally for 28 days with different CEIs or a peripheral vasodilator to study the effects of the various drug treatments on the gene expression of the RAS in selected tissues. Different effects of different CEIs on tissue gene expression suggest localized action and some degree of organ specificity of the drugs. The experiments involved: (1) untreated controls; and rats treated with either (2) 50 mg/kg of captopril; (3) 10 mg/kg of lisinopril; (4) 10 mg/kg of cilazapril; (5) or 30 mg/kg of the vasodilator hydralazine with 10 rats/group. All of the study drugs reduced systolic blood pressure to normotension. Cardiac hypertrophy and the heart:body weight ratio were significantly decreased only in the CEI-treated animals, and kidney renin mRNA was increased by the CEIs whereas hydralazine had no effect on heart weight or kidney renin mRNA. Plasma renin activity increased in parallel with kidney renin mRNA levels. Liquid hybridization and Northern blotting assays revealed drug-specific regulation of the angiotensinogen mRNA level in the adrenal gland, with cilazapril producing the most marked stimulation of adrenal angiotensinogen gene expression. Both lisinopril and cilazapril suppressed hypothalamic angiotensinogen mRNA. There were no significant changes in angiotensinogen gene expression observed in the kidney or liver with any of the CEIs. In conclusion, these data show that CEIs interact differentially and drug-specifically with tissue RAS, and have class-specific effects on cardiac hypertrophy.
authors.affiliation: German Institute for High Blood Pressure Research, University of Heidelberg.
authors.forename: C
authors.initials: C
authors.lastname: Keuneke
authors.forename: R
authors.initials: R
authors.lastname: Yacullo
authors.forename: M
authors.initials: M
authors.lastname: Sugiura
authors.forename: G
authors.initials: G
authors.lastname: Mall
authors.forename: R
authors.initials: R
authors.lastname: Metzger
authors.forename: D
authors.initials: D
authors.lastname: Ganten
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000097:blood / Q000187:drug effects; D000809:Angiotensins / Q000097:blood / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D005786:Gene Expression Regulation; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D000959:Antihypertensive Agents; D012333:RNA, Messenger; D000808:Angiotensinogen; D012083:Renin