A LONG-TERM RECEPTOR STIMULATION IS REQUISITE FOR ANGIOTENSIN II-DEPENDENT DNA-SYNTHESIS IN VASCULAR SMOOTH-MUSCLE CELLS FROM SPONTANEOUSLYHYPERTENSIVE RATS

Angiotensin II stimulates DNA synthesis in aortic smooth muscle cells prepared from spontaneously hypertensive rats, with maximal levels det ected 20 h after stimulation. Angiotensin II receptor antagonists inhi bited the angiotensin II-induced DNA synthesis. In particular, the non competitive antagonist 2-ethoxy-1-[[2'(1 iphenyl-4-yl]methyl]-1H-benzi midazole-7-carboxylic acid (CV11974) was more effective than expected from its affinity for the angiotensin II receptor and its potency for inhibiting angiotensin II-induced increase in cytosolic free Ca2+ conc entration. -(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassiu m salt (losartan), one of the antagonists, inhibited angiotensin II-in duced DNA synthesis by 92% and 79%, even when added 2 and 4 h after an giotensin II stimulation, respectively. Angiotensin II also increases the mRNA of platelet-derived growth factor-A chain and basic fibroblas t growth factor. The increase was observed within 4 h after angiotensi n II stimulation. Tn this case, the addition of losartan at 4 h after angiotensin II stimulation hardly influenced the time course of the mR NA level of growth factors. Also, conditioned media of cells stimulate d with angiotensin II did not influence DNA synthesis in the presence of CV11974. These results suggest that sustained receptor stimulation with angiotensin II is required for DNA synthesis in addition to the e arly intracellular signaling following phospholipase C activation in a manner independent of the induction of growth factors such as platele t-derived growth factor-AA and basic fibroblast growth factor.