Mechanisms of enhanced angiotensin II-stimulated signal transduction in vascular smooth muscle by aldosterone.
We tested the hypothesis that mineralocorticoids potentiate angiotensin II-stimulated phospholipase C activation through an increased number of angiotensin II receptors in cultured rat aortic vascular smooth muscle cells. Exposure of cells to aldosterone for 24 h resulted in concentration-dependent increases in angiotensin II receptor binding. Via studies of angiotensin II displacement by non-peptide receptor antagonists, both basal and upregulated angiotensin II receptors were found to be of the AT1 subtype. Incubation with 1 microM aldosterone resulted in 50-100% enhancement of angiotensin II (100 nM)-stimulated diacylglycerol formation and intracellular calcium mobilization. Exposure to 100 nM 1,25-(OH)2VitD3, which did not upregulate angiotensin II receptors, did not potentiate stimulated inositol phosphate formation. Incubation with aldosterone resulted in potentiation of inositol phosphate formation upon receptor occupation (100 nM angiotensin II) but not upon post-receptor stimulation (25 mM NaF/10 microM AlCl3). Aldosterone did not increase basal phospholipase C activity or content of the inositol trisphosphate precursor phosphatidylinositol-4,5-bisphosphate. These data are consistent with the hypothesis that aldosterone potentiates angiotensin II-stimulated, phospholipase C-dependent intracellular signals solely by coupling to an increased number of angiotensin II receptors. This mechanism may contribute to the sensitized vascular responses to angiotensin II observed in states of mineralocorticoid excess.
Department of Medicine, Medical University of South Carolina, Charleston 29425.
M E
ME
Ullian
J J
JJ
Fine
D000450:Aldosterone / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D007295:Inositol Phosphates / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013256:Steroids / Q000494:pharmacology; D015854:Up-Regulation
D007295:Inositol Phosphates; D011945:Receptors, Angiotensin; D013256:Steroids; D000804:Angiotensin II; D000450:Aldosterone