title: Effect of propranolol as antiadhesive therapy in sickle cell disease.
abstract: Sickle red blood cells (SSRBCs) adhere to both endothelial cells (ECs) and the extracellular matrix. Epinephrine elevates cyclic adenosine monophosphate in SSRBCs and increases adhesion of SSRBCs to ECs in a β-adrenergic receptor and protein kinase A-dependent manner. Studies in vitro as well as in vivo have suggested that adrenergic stimuli like epinephrine may contribute to vaso-occlusion associated with physiologic stress. We conducted both animal studies and a Phase I dose-escalation study in sickle cell disease (SCD) patients to investigate whether systemically administered propranolol inhibits SSRBC adhesion and to document the safety of propranolol in SCD. Systemically administered propranolol prevented SSRBC adhesion and associated vaso-occlusion in a mouse model. In patients receiving a single oral dose of 10, 20, or 40 mg propranolol, SSRBC adhesion to ECs was studied before and after propranolol, with and without stimulation with epinephrine. Propranolol administration significantly reduced epinephrine-stimulated SSRBC adhesion in a dose dependent manner (p = 0.03), with maximum inhibition achieved at 40 mg. Adverse events were not severe, did not show dose dependence, and were likely unrelated to drug. No significant heart rate changes occurred. These results imply that β-blockers may have a role as antiadhesive therapy for SCD.
authors.affiliation: Duke Comprehensive Sickle Cell Center, Division of Hematology, Department of Medicine, Duke University, Durham, North Carolina, USA. decas004@mc.duke.edu
authors.forename: Laura M
authors.initials: LM
authors.lastname: De Castro
authors.forename: Rahima
authors.initials: R
authors.lastname: Zennadi
authors.forename: Jude C
authors.initials: JC
authors.lastname: Jonassaint
authors.forename: Milena
authors.initials: M
authors.lastname: Batchvarova
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004837:Epinephrine / Q000494:pharmacology / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D011433:Propranolol / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000986:Antisickling Agents; D011433:Propranolol; D004837:Epinephrine