Glomerular losartan (DuP 753)-sensitive angiotensin II receptor density is increased in young spontaneously hypertensive rats.
There is increasing evidence that an activated intrarenal renin-angiotensin system (RAS) alters renal hemodynamics and fluid balance and that such events may lead to the development of hypertension. To examine the role of the glomerular RAS in the development of hypertension in the spontaneously hypertensive (SHR) rat, we studied angiotensin (ANG) II receptors in isolated glomeruli from young (4- to 5-wk-old) and adult (10- to 12-wk-old) SHR and from age-matched, normotensive Wistar-Kyoto (WKY) rats. Glomerular ANG II receptor density in young SHR is 3-fold higher than in age-matched WKY rats (2033 +/- 154 versus 742 +/- 151 receptors/microns2; p < 0.05) and 1.5-fold higher than in adult SHR and WKY rats (1128 +/- 85 and 1198 +/- 181 receptors/microns2, respectively; p < 0.05). Additional studies demonstrated that the differences in receptor density are not related to disparity in receptor occupancy and that they are also independent of systemic ANG levels. Suppression of RAS by ANG converting enzyme inhibitors resulted in a 3-fold increase in receptor density in young SHR rats and a 4.5-fold increase in young WKY rats; receptor density remained greater in young SHR rats (5915 +/- 318 versus 3358 +/- 234 receptors/microns2, p < 0.05). Furthermore, competitive binding experiments using the nonpeptide ANG II antagonists losartan (AT1) and PD 123319 (AT2) indicate that the greater ANG II receptor density in the young SHR rats represents an increase in the number of a single population of AT1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Haws
R M
RM
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063.
Shaul
P W
PW
Arant
B S
BS
Atiyeh
B A
BA
Seikaly
M G
MG
D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011945:Receptors, Angiotensin / Q000145:classification / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan