Vasoactive intestinal peptide receptor in failing human ventricular myocardium exhibits increased affinity and decreased density

Abstract

We investigated vasoactive intestinal peptide (VIP)-receptor pharmacology in failing and nonfailing human ventricular myocardium by examining [125I]VIP binding in membrane fractions of left ventricle and inotropic effects of VIP in isolated right ventricular trabeculae mounted in tissue baths. [125I]VIP binding demonstrated upwardly concave, curvilinear Scatchard plots consistent with two classes of binding sites. Only the high-affinity (dissociation constant [K(d)] 400-800 pM) site could be regulated by guanine nucleotides. Compared with nonfailing heart, membranes derived from failing heart exhibited a twofold reduction in the K(d) of the high-affinity VIP binding site, whereas the receptor density (B(max)) was decreased by 62%. In concordance with this decreased receptor density and increased affinity, the maximal contractile response of right ventricular trabeculae from failing right ventricles was decreased by 61%, and the dose-response curve to VIP was left-shifted approximately threefold. We conclude that the VIP receptor in failing human ventricular myocardium exhibits novel regulatory behavior consisting of increased receptor affinity and decreased receptor density.