EFFECTS OF NISOLDIPINE UPON VASOCONSTRICTOR RESPONSES AND BINDING OF ENDOTHELIN-1 IN ISCHEMIC AND REPERFUSED RAT HEARTS

Changes in the vascular response of isolated, perfused rat hearts to endothelin-1 (ET-1) and binding of [I-125]ET-1 to cardiac membranes were examined following ischemia (30 min, zero flow) and reperfusion (15 min). Infusion of ET-1 (0, 2.5, 5, 7.5, and 10 X 10(-10) M) increased the control heart perfusion pressure (61, 73, 88, 102, and 117 mm Hg, respectively). Ischemic and reperfused hearts were more sensitive to ET-1 infusion (p < 0.05 at all concentrations). Nisoldipine (NIS, 1 nM) prevented the rise in sensitivity to ET-1 following ischemia and reperfusion. Two binding sites for [I-125]ET-1 were identified in cardiac membranes. High-affinity (K(d) = 0.04 nM, B(max) = 0.46 pmol/mg of protein) and low-affinity (K(d) = 13.8 nM, B(max) = 5.4 pmol/mg of protein) sites were unchanged by ischemia and reperfusion, and NIS did not change binding constants in control or ischemic and reperfused hearts. Increased ET-1 sensitivity after ischemia may be due to other factors. Endothelium-dependent vasodilation and endothelium-independent vasodilation were significantly reduced following 30 min of ischemia. Inhibition of dilator responses may account for increased ET-1 responses following transient ischemia.