ISOLATED PRESYNAPTIC INOTROPIC BETA-ADRENERGIC SUPERSENSITIVITY OF THE TRANSPLANTED DENERVATED HUMAN HEART INVIVO

Background. The regulation of contractility of the transplanted heart depends on circulating catecholamines resulting from cardiac denervation. Supersensitivity to circulating catecholamines may result from loss of presynaptic neuronal uptake or upregulation of postsynaptic beta-adrenergic receptors. Methods and Results. Dose-response curves using the beta-adrenergic receptor agonists isoprenaline (no neuronal uptake) and epinephrine (neuronal uptake) were performed in vivo. The inotropic response was measured echocardiographically as the increase of fractional shortening (DELTA-FS) and the increase of the systolic pressure/dimension ratio (DELTA-P/D). The inotropic response to increasing doses of isoprenaline (5-20 ng/kg.min) was identical in 36 heart transplant recipients compared with 13 control subjects: DELTA-FS during 20 ng/kg.min isoprenaline amounted to 18.2 +/- 6.2% versus 17.4 +/- 4.0% (NS) and DELTA-P/D to 2.3 +/- 1.2 mm Hg/mm versus 2.2 +/- 0.5 mm Hg/mm (NS), respectively. A vagally mediated indirect negative inotropic effect in the innervated hearts was excluded by identical inotropic responses to isoprenaline in control subjects without and after atropine pretreatment. The inotropic response to increasing doses of epinephrine (10-40 ng/kg.min) was significantly augmented in 13 heart transplant recipients compared with 11 control subjects: DELTA-FS during 40 ng/kg.min epinephrine amounted to 19.9 +/- 2.6% versus 8.6 +/- 2.0% (p < 0.001) and DELTA-P/D to 2.3 +/- 0.9 mm Hg/mm versus 0.6 +/- 0.3 mm Hg/mm (p < 0.001), respectively. Pretreatment with desipramine (blockade of neuronal uptake) in control subjects resulted in a significantly increased inotropic response: DELTA-FS during 40 ng/kg.min epinephrine amounted to 17.6 +/- 3.6% (p < 0.001 versus untreated controls, NS versus heart transplant recipients) and DELTA-P/D to 1.7 +/- 0.8 mm Hg/mm (p < 0.001 versus untreated controls, NS versus heart transplant recipients). Conclusions. These findings provide evidence against a postsynaptic inotropic supersensitivity or subsensitivity of the beta-adrenergic receptor-effector system of the transplanted denervated human heart in vivo. However, a marked presynaptic inotropic supersensitivity is present because of denervation-associated loss of neuronal catecholamine uptake.