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

Alan S. Maisel, MD; C. Michael Wright, MD; Steven M. Carter; Michael Ziegler, MD; and Harvey J. Motulsky, MD
[+] Article, Author, and Disclosure Information

Grant Support: Partial support by grants from the Veterans Administration, the National Institutes of Health, and the American Heart Association.

Requests for Reprints: Alan Maisel, MD, Division of Cardiology, 111-A, Veterans Administration Medical Center, 3550 La Jolla Village Drive, San Diego, CA 92161.

Current Author Addresses: Drs. Maisel and Wright: Division of Cardiology, Hl-A, Veterans Administration Medical Center, 3550 La Jolla Village Drive, San Diego, CA 92161.

Mr. Carter: M036 University of California, San Diego, La Jolla, CA 92093.

Dr. Ziegler: UCSD Medical Center, H-781-B, 225 W. Dickinson Street, San Diego, CA 92103.

Dr. Motulsky: Department of Pharmacology, M036, University of California, San Diego, La Jolla, CA 92093.

© 1989 American College of PhysiciansAmerican College of Physicians

Ann Intern Med. 1989;110(3):195-201. doi:10.7326/0003-4819-110-3-195
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Study Objective: To determine whether intravenous therapy with amrinone changes number, location or function of the β-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 µg/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 β-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 β-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.





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