Adrenal angiotensin: origin and site of generation.
BACKGROUND
Circulating angiotensin (Ang) II accumulates in adrenal tissue via binding to Ang II type 1 (AT1) receptors, reaching levels that are 15 to 20 times higher than in blood. Adrenal tissue contains a second renin transcript that gives rise to a truncated prorenin representing a cytosolic form of renin. Here we investigated what percentage of adrenal Ang II originates at adrenal tissue sites, and whether intracellular renin contributes to adrenal angiotensin production.


METHODS
Concentrations of endogenous and iodine-125 (125I)-labeled Ang I and II were measured in adrenal tissue and blood from pigs after 125I-Ang I infusion.


RESULTS
In the adrenal tissue in all animals, 125I-Ang I was undetectable. In untreated pigs, adrenal 125I-Ang II was 17 +/- 1 times arterial 125I-Ang II, and tissue Ang I and II were 5 +/- 1 and 388 +/- 40 times higher than plasma Ang I and II. The AT1 receptor antagonist eprosartan reduced adrenal 125I-Ang II accumulation by 80%, and increased plasma Ang II to a greater degree than tissue Ang II. As a consequence, eprosartan equally reduced the tissue/plasma concentration ratios of both Ang II and 125I-Ang II. Captopril did not alter 125I-Ang II accumulation, and acutely, but not chronically, reduced the adrenal Ang II/I ratio.


CONCLUSIONS
More than 90% of adrenal Ang II originates at adrenal tissue sites. Local adrenal Ang II generation occurs extracellularly and is followed by internalization via AT1 receptor-mediated endocytosis. Enhanced angiotensin generation, combined with incomplete AT1 receptor blockade and the large adrenal AT1 receptor reserve, explains why eprosartan increased rather than decreased adrenal Ang II. Our data do not support angiotensin generation by truncated prorenin.
van Kats
Jorge P
JP
Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
Chai
Wenxia
W
Duncker
Dirk J
DJ
Schalekamp
Maarten A D H
MA
Danser
A H Jan
AH
D000179:Acrylates / Q000494:pharmacology; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000803:Angiotensin I / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D007457:Iodine Radioisotopes; D008297:Male; D008954:Models, Biological; D012084:Renin-Angiotensin System / Q000187:drug effects; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology
D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D007457:Iodine Radioisotopes; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; D000803:Angiotensin I; D002216:Captopril