EFFECTS OF THE DIVALENT-CATIONS NICKEL AND CADMIUM ON CONTRACTIONS OF RAT AORTA TO ENDOTHELIN-1

1 The effects of inorganic and organic calcium channel antagonists on the contractile responses of rat isolated aortic rings to endothelin-1 (ET-1) were studied. 2 ET-1 (0.1-100 nM) evoked concentration-related contractile responses of the rat aorta (EC50 1.65 +/- 0.22 nM, E(max) 125.8 +/- 4.5 %KCl(max) n = 20). In Ca2+-free modified Krebs solution (containing 1 mM EGTA) aortic rings failed to contract to ET-1 (0.1-30 nM). 3 Nickel chloride (0.2-0.8 mM) attenuated the ET-1 (1-100 nM)-induced contraction of rat aorta (response (%KCl(max)) to 10 nM ET-1: control 132.0 +/- 8.7 and after 0.2 mM Ni2+ 90.3 +/- 14.8, 0.4 mM Ni2+ 54.7 +/- 12.3, 0.8 mM Ni2+ 10.3 +/- 4.4, n = 6/group). Cadmium chloride (10-30-mu-M) depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 15.4 +/- 1.5-mu-M (n = 6). 4 The ET-1 evoked contractile responses were not modified by the dihydropyridine calcium channel antagonist, nicardipine (0.1-mu-M), or by omega-conotoxin (1.0-mu-M). Cinnarizine (10-mu-M), however, significantly attenuated the maximum response to ET-1 (96.9 +/- 6.0 vs 128.0 +/- 5.8 %KCl(max) for control), but failed to modify the EC50 value. 5 Amiloride, a Na+-Ca2+ exchange inhibitor, also depressed the maxima of the concentration-response curves to ET-1 with an IC50 of 0.45 +/- 0.05 mM (n = 4). 6 In conclusion, endothelin-1-induced contractions of the rat aorta are dependent on the influx of extracellular calcium into the cytosol via a Ni2+/Cd2+ sensitive pathway that is distinct from the slow (L-type) calcium channel.