Differential regulation of angiotensin peptide levels in plasma and kidney of the rat.
We compared the effects of the converting enzyme inhibitor perindopril on components of the renin-angiotensin system in plasma and kidney of male Sprague-Dawley rats administered perindopril in their drinking water at two doses (1.4 and 4.2 mg/kg) over 7 days. Eight angiotensin peptides were measured in plasma and kidney: angiotensin-(1-7), angiotensin II, angiotensin-(1-9), angiotensin I, angiotensin-(2-7), angiotensin III, angiotensin-(2-9), and angiotensin-(2-10). In addition, angiotensin converting enzyme activity, renin, and angiotensinogen were measured in plasma, and renin, angiotensinogen, and their respective messenger RNAs were measured in kidney; angiotensinogen messenger RNA was also measured in liver. In plasma, the highest dose of perindopril reduced angiotensin converting enzyme activity to 11% of control, increased renin 200-fold, reduced angiotensinogen to 11% of control, increased angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels 25-, 9-, 10-, and 13-fold, respectively; angiotensin II levels were not significantly different from control. By contrast, for the kidney, angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels did not increase; angiotensin II levels fell to 14% of control, and angiotensinogen fell to 12% of control. Kidney renin messenger RNA levels increased 12-fold, but renal renin content and angiotensinogen messenger RNA levels in kidney and liver were not influenced by perindopril treatment. These results demonstrate a differential regulation of angiotensin peptides in plasma and kidney and provide direct support for the proposal that the cardiovascular effects of converting enzyme inhibitors depend on modulation of tissue angiotensin systems. Moreover, the failure of kidney angiotensin I levels to increase with perindopril treatment, taken together with the fall in kidney angiotensinogen levels, suggests that angiotensinogen may be a major rate-limiting determinant of angiotensin peptide levels in the kidney.
Campbell
D J
DJ
St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Lawrence
A C
AC
Towrie
A
A
Kladis
A
A
Valentijn
A J
AJ
D000808:Angiotensinogen / Q000032:analysis; D000809:Angiotensins / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D020913:Perindopril; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000032:analysis; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors
D000809:Angiotensins; D000959:Antihypertensive Agents; D007211:Indoles; D012333:RNA, Messenger; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D020913:Perindopril