Differential modulation of the renal and myocardial endothelin system by angiotensin II in Vivo. Effects of chronic selective ETA receptor blockade.
Angiotensin II (Ang II) stimulates endothelin-1 (ET-1) production in glomerular endothelial and mesangial cells and in cardiac fibroblasts in vitro. We investigated the effects of Ang II in vivo (200 ng/kg/min for 2 weeks) with or without the ETA receptor antagonist LU135252 (50 mg/kg/day) on blood pressure, renal and myocardial ET-1 protein expression, and [125I]ET-1 uptake in male Wistar-Kyoto (WKY) rats. ET-1 was extracted from whole kidneys and ventricular myocardium and was measured by radioimmunoassay (pg ET-1/g tissue). Organ tissue uptake was calculated as percentage of total DPM recovered after i.v. administration of radiolabeled [125I]ET-1. Ang II treatment increased blood pressure by 35 +/- 3 mm Hg, which was partly reduced by LU135252 (15 +/- 2 mm Hg, p < 0.05). LU135252 in part prevented the impaired weight gain induced by Ang II (p < 0.05). Ang II induced a threefold increase in expression of ET-1 (pg/g tissue) in kidneys (from 19 +/- 2 to 58 +/- 10, p < 0.05), which was normalized by LU135252 (20 +/- 9, p < 0.05). In myocardial tissue, Ang II had only minor effects (5 +/- 1 vs. 3.6 +/- 1, n.s.). However, concomitant LU135252 treatment reduced myocardial ET-1 levels (1.4 +/- 0.4, p < 0.05 vs. Ang II and control). Ang II increased uptake of [125I]ET-1 in kidneys (from 6.9 +/- 0.1% to 10.9 +/- 0.9% of total DPM, p < 0.05) but not in myocardium (1.45 +/- 0.26% vs. 1.59 +/- 0.18% of total DPM), which was unaffected by LU135252 treatment. These data suggest that the kidney, but not the ventricular myocardium, is a target for Ang II-mediated activation of the ET system in vivo, leading to expression and uptake of ET-1. ETA antagonists may provide a new approach to inhibit production and effects of ET-1 in diseases associated with increased activity of the renin-angiotensin system.
Barton
M
M
Cardiology, University Hospital Zürich, Switzerland.
Shaw
S
S
d'Uscio
L V
LV
Moreau
P
P
Lüscher
T F
TF
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D000804:Angiotensin II; C107831:darusentan