Burn-induced alterations in cardiac β-adrenergic receptors

Previous studies in our laboratory have demonstrated that burn injury (45% total body surface area, 3rd-degree scald burn) diminishes contractile and relaxation function in the isolated perfused guinea pig heart. The mechanisms responsible for the burn-mediated dysfunction are not well understood. Therefore the purpose of this study was to examine the inotropic response to isoproterenol, a β-adrenergic agonist, and burn-induced alterations in β- adrenergic receptors (β-AR) in adult guinea pig hearts. Isoproterenol dose- response curves were generated in isolated perfused hearts from sham-burned and burned guinea pigs. In addition, binding studies were performed using [¹²⁵I]iodocyanopindolol on hearts from sham-burned and burned guinea pigs. Both the functional response and sensitivity to isoproterenol were significantly diminished 24 h after burn injury. β-AR density (binding capacity, B(max)) and affinity were determined by Scatchard analysis. Agonist competition curves were performed in the presence or absence of 0.1 mM 5'- guanylyl imidodiphosphate. There was no difference in B(max) in membranes from sham-burned and burned hearts; however, the affinity of β-AR was significantly decreased after burn injury compared with sham burn [dissociation constant = 32.5 ± 1.9 (mean ± SE), n = 10, vs. 26.7 ± 1.7 pM, n = 10, P = 0.039]. Furthermore, the fraction of receptors in a high- affinity state (those functionally coupled to G(s) protein) was significantly decreased after burn injury compared with sham burn (41.2 ± 4.7%, n = 9, vs. 54 ± 2%, n = 9, P = 0.023). We conclude that burn-mediated alterations in the coupling of β-AR to G(s) protein contribute in part to the diminished functional response to isoproterenol in the guinea pig heart.