Intrarenal angiotensin II generation and renal effects of AT1 receptor blockade.
The intrarenal renin-angiotensin system plays a critical role in the paracrine regulation of renal function and the pathophysiology of hypertension. Angiotensin II (AngII) is formed intrarenally from systemically delivered angiotensin I (AngI) and intrarenally formed AngI. Intrarenal AngII content, which is greater than can be explained by the circulating AngII concentrations, is compartmentalized such that proximal tubule concentrations of AngI and AngII greatly exceed plasma concentrations. Proximal tubule cells are thought to secrete AngII or precursors of AngII into the tubular fluid to activate luminal AngII receptors. Recent immunohistochemical studies have demonstrated an abundance of AT1 receptors on the luminal surface of proximal and distal tubule cells and on afferent and efferent arteriolar vascular smooth muscle cells and mesangial cells of glomeruli. Activation of luminal AT1 receptors stimulates tubular sodium reabsorption rate. To evaluate the direct effects of AT1 receptor blockade on renal function in AngII-dependent hypertension, experiments were performed on two-kidney, one-clip (2K1C) Goldblatt hypertensive rats. Although the nonclipped kidney is renin-depleted, the intrarenal AngII levels are not suppressed, and AngII concentrations in proximal tubular fluid remain high (10(-8) M). Candesartan was administered into the renal artery of nonclipped kidneys to avoid the confounding consequences of decreases in arterial pressure. Blockade of intrarenal AT1 receptors elicited significant increases in GFR, renal blood flow, sodium excretion, and fractional sodium excretion, suggesting synergistic actions on tubular transport and vascular smooth muscle cells.
Navar
L G
LG
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. Navar@mailhost.tcs.tulane.edu
Harrison-Bernard
L M
LM
Imig
J D
JD
Wang
C T
CT
Cervenka
L
L
Mitchell
K D
KD
D000803:Angiotensin I / Q000032:analysis / Q000502:physiology; D000804:Angiotensin II / Q000032:analysis / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D005919:Glomerular Filtration Rate; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism*; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011945:Receptors, Angiotensin / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000803:Angiotensin I; C081643:candesartan