Tachyphylaxis with Amrinone Therapy: Association with Sequestration and Down-Regulation of Lymphocyte Beta-Adrenergic Receptors

STUDY OBJECTIVE: To determine whether intravenous therapy with amrinone changes number, location or function of the beta-adrenergic receptors on lymphocytes. DESIGN: Case series. SETTING: Veterans hospital coronary care unit. PATIENTS: Eleven patients with decompensated class III or IV heart failure. INTERVENTIONS: A bolus of intravenous amrinone followed by a continuous infusion at 10 micrograms/kg.min for 72 hours. MEASUREMENTS AND MAIN RESULTS: At 24 to 36 hours there was a reduction in pulmonary capillary wedge pressure (35%), right atrial pressure (20%), and systemic vascular resistance (25%) with an increase in cardiac output (30%). By 72 hours all these parameters had returned nearly to baseline levels. This partial cardiovascular tolerance to amrinone was accompanied by a 126% increase in the plasma epinephrine, a 182% increase in norepinephrine, a 31% decrease in the number of beta-adrenergic receptors on lymphocytes, and a 36% decrease in isoproterenol-stimulated cyclicadenosine monophosphate on lymphocytes. The number of sequestered receptors doubled during the treatment, and the extent of sequestration correlated well with the extent of receptor down-regulation. CONCLUSIONS: The hemodynamic responses to amrinone had virtually returned to baseline by 72 hours. This tolerance was accompanied by increased plasma catecholamines, and a down-regulation, desensitization, and sequestration of beta-adrenergic receptors on lymphocytes. We suggest that these receptor changes also occur in cardiovascular tissues and may in part account for the tolerance to amrinone.