Abstract
Angiotensin II (AII), an important hypertrophic factor in the cardiovascular system, exerts most of its known effects in vivo through the AII receptor type 1 (AT1) subclass of AII receptors. These receptors are also responsible for the growth-related effects of AII in cultured vascular smooth muscle cells (VSMCs). We presently investigated the effects of BAY 10–6734 (Embusartan), a new orally active AT1 antagonist, on VSMC growth and proliferation of cultured VSMCs isolated from the aortae of Wistar Kyoto rats and spontaneously hypertensive rats. BAY 10–6734 and losartan (considered as AT1 receptor antagonist of reference), as well as their respective active metabolites, were studied for their inhibition of: 1) [125I]AII binding to its receptors, 2) AII-induced DNA and protein synthesis (by measuring the incorporation of 5-bromo-2′-deoxyuridine and [3H]l-leucine, respectively), and 3) AII-induced variations in intracellular Ca2+ concentration, using cells labeled with Fura-2. All of the tested compounds inhibited the aforementioned parameters in a concentration-dependent manner. Half-maximal inhibitory concentration values indicated that BAY 10–6734 was significantly more potent than losartan and that spontaneously hypertensive rat-derived VSMCs were more sensitive than Wistar Kyoto rat-derived ones. Neither BAY 10–6734 nor losartan affected the intracellular Ca2+ concentration of unstimulated VSMCs but both compounds inhibited both AII-induced Ca2+ mobilization from internal stores and Ca2+influx. Neither compound affected arginine-vasopressin-, basic fibroblast growth factor-, or serum-induced DNA and protein synthesis. BAY 10–6734 appears therefore as a potent and specific new inhibitor of AII-induced growth-related events in VSMCs.
Footnotes
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Send reprint requests to: Dr P. Marche, Pharmacologie, CNRS URA 1482, Université René Descartes, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France. E-mail: marche{at}necker.fr
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↵1 This study was partially supported by a research collaboration agreement between Bayer AG and CNRS.
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↵2 Part of this work was presented at the 13th Scientific Meeting of the American Society of Hypertension (New York, NY, May 13–16, 1998).
- Abbreviations:
- VSMC
- vascular smooth muscle cell
- AII
- angiotensin II
- AT1
- angiotensin II type 1 receptor
- [Ca2+]i
- cystolic calcium concentration
- SHR
- spontaneously hypertensive rat
- WKY
- Wistar-Kyoto rat
- DMEM
- Dulbecco’s modified Eagle’s medium
- FCS
- fetal calf serum
- BrdU
- 5-bromo-2′-deoxyuridine
- bFGF
- basic fibroblast growth factor
- TCA
- trichloroacetic acid
- Received July 6, 1998.
- Accepted November 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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