Decreased digitalis receptor activity in acute rejecting canine transplanted heart

Abstract

In the course of acute rejection, myocardial tissue undergoes massive transformation and we hypothetized that for digitalis-like substances, receptor binding characteristics might be altered. Ten canine heterotopic cardiac allografts were carried out and were harvested once rejection had developed (8-10 days post-transplant). Microsomal membrane fractions of those grafts and of native hearts were isolated. Radioligand binding studies were carried out in a medium containing 5 mM Tris PO4, 50 mM Tris HCl, 5 mM MgCl2, pH 7.4 at 37 degrees C, using 3H-ouabain as the ligand. Saturation experiments (n = 10) indicate the presence of one homogeneous population of high affinity binding sites with an affinity constant (Kd) of 8-13 nM and a maximum binding capacity (Bmax) of 47 +/- 3.5 pmol/mg protein. Both saturation and competition binding studies illustrate the fact that acute rejection resulted in a significant decrease in Bmax (43%) without significant alteration in Kd value. These studies indicate that digitalis-like substances might not exert significant inotropic activity during rejection, but this hypothesis must be confirmed by in vivo haemodynamic experiments.

Acute Hypercalcemia and Increased Work Load in Canine Transplanted Heart

“…In most cases, without evi dence of rejection, the transplanted heart's function is considered normal as well as he modynamic adjustments to vasodilator or inotropic drugs [17][18][19], When rejection is detectable, multiple abnormalities have been identified; the myocardial function might be severely depressed and the transmural myo cardial blood flow significantly impaired [4][5][6]11]. In addition, experimental studies car ried out during acute rejection have demon strated that atypical drug responses are re lated to transmembrane calcium-handling defects, reduction of membrane receptor population, or enzyme profile abnormalities [20][21][22], The present study indicates that the absence of coronary blood flow adjustments might explain abnormal drug responses.…”