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  • Title: Inhibition of smooth muscle cell calcium mobilization and aortic ring contraction by lactone vastatins.
    Author: Escobales N, Crespo MJ, Altieri PI, Furilla RA.
    Journal: J Hypertens; 1996 Jan; 14(1):115-21. PubMed ID: 12013483.
    Abstract:
    OBJECTIVE: To determine the effects of vastatins on the contraction of rat aortic rings and to assess their effects on calcium mobilization using cultured smooth muscle cells from rat aorta. METHODS: Aortic rings from Sprague-Dawley rats were mounted on stainless steel wires to determine the generation of tension using force-displacement transducers. The tension (g) developed by angiotensin II (100 nmol/l) was measured under basal conditions and after 45 min incubation with 20 micromol/l simvastatin. The effect of 20 mol/l simvastatin, lovastatin, mevastatin and pravastatin on noradrenaline concentration-response curves and the angiotensin II-induced calcium mobilization was also evaluated. RESULTS: Addition of angiotensin II to aortic rings incubated in Krebs' Ringer bicarbonate medium produced tension generation (0.9 +/- 0.12 g = 100%). Treatment of aortic rings with simvastatin inhibited the angiotensin II-induced contraction 58 +/- 0.06%. To evaluate this effect further, dose-response curves with noradrenaline were measured in the presence and absence of 20 micromol/l simvastatin, lovastatin, mevastatin and pravastatin. The results indicate that simvastatin, lovastatin and mevastatin inhibited the contraction induced by noradrenaline (10 micromol/l) by about 50%. Pravastatin did not inhibit aortic ring contraction. Furthermore, the concentration required for 50% of the maximal contraction (EC50) by noradrenaline (6.2 +/- 0.1 nmol/l) was significantly increased by simvastatin, lovastatin, mevastatin and pravastatin. The inhibition of vascular contraction by vastatins appears to involve inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity because the inhibitory effect of simvastatin was reduced 50% by 10 mmol/l mevalonic acid. To determine whether the depression of vascular contraction by these agents was correlated with cell calcium changes, the angiotensin II-induced calcium mobilization was determined in Fura-2 loaded cells, before and after treatment with these inhibitors. Simvastatin, lovastatin and mevastatin significantly reduced the angiotensin II-induced calcium mobilization. The concentration that induced 50% inhibition was 3.3 micromol/l for simvastatin, 17.4 micromol/l for mevastatin and 21.7 micromol/l for lovastatin. No effect of pravastatin on calcium mobilization was observed. CONCLUSIONS: These findings suggest that lactone vastatins depress vascular contraction by reducing cytosolic calcium release in vascular smooth muscle cells. These agents also appear to exert competitive and non-competitive type antagonisms on noradrenaline action.
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