EFFECTS OF CALCIUM-RECEPTOR AND ET(A)-RECEPTOR ANTAGONISTS ON ENDOTHELIN-INDUCED VASOCONSTRICTION AND LEVELS OF ENDOTHELIN IN THE HUMAN INTERNAL MAMMARY ARTERY

1. The effects of the ET(A) receptor antagonist BQ123 and dihydropyridine calcium antagonists on the vasoconstrictor effect of endothlin-1 (ET-1) were studied in human isolated internal mammary artery (IMA). The effect of the calcium antagonist, nisoldipine, on ET-1 levels has also been examined in cultured IMA endothelial cells (IMAEC). 2. The results showed that BQ123 and the calcium antagonists nisoldipine, isradipine, nitrendipine and nifedipine fully relaxed IMA precontracted with 3 nmol/L ET-1 with the EC(50) values of 7.18+/-0.09 (-log mol/L) for BQ123, and 7.68+/-0.07, 7.02+/-0.12, 6.96+/-0.08 and 6.89+/-0.09 for the calcium antagonists, respectively. 3. Pretreatment of IMA with 10, 30, 100 and 300 nmol/L nisoldipine significantly depressed the maximal response (Max; 88.3+/-5.1, 75.2+/-4.9, 59.3+/-5.6 and 56.2+/-4.8% of maximal noradrenaline response versus 99.1+/-13.2% in control, P<0.01) of IMA to ET-1 without a significant change in the EC(50) values. 4. Pretreatment of IMA with 300 nmol/L BQ123 significantly increased both the EC(50) (7.97+/-0.09 vs 8.36+/-0.08 in the control, P<0.05) and the Max (138.1+/-10.2% vs the control, P<0.01) of IMA to ET-1. 5. Incubation of IMAEC with nisoldipine for 7h resulted in a dose-dependent (10(-8)-10(-5) mol/L) reduction up to 93.1% in ET levels in the conditioned media. 6. ET levels in the cell lysates were not detectable either in the absence or in the presence of nisoldipine, suggesting the reduction of ET levels in the media could be due to inhibition of ET synthesis. 7. In conclusion, these studies demonstrate that: (i) both BQ123 and the calcium antagonists are potent relaxant agents of human IMA precontracted with ET-1; (ii) BQ123 also increases the Max of IMA to ET-1 and the mechanism is unknown; (iii) the calcium antagonist nisoldipine reduces ET levels in the cultured human IMAEC.