Anti-dopamine beta-hydroxylase immunotoxin-induced sympathectomy in adult rats.
Anti-dopamine beta-hydroxylase immunotoxin (DHIT) is an antibody-targeted noradrenergic lesioning tool comprised of a monoclonal antibody against the noradrenergic enzyme, dopamine beta-hydroxylase, conjugated to saporin, a ribosome-inactivating protein. Noradrenergic-neuron specificity and completeness and functionality of sympathectomy were assessed. Adult, male Sprague-Dawley rats were given 28.5, 85.7, 142 or 285 micrograms/kg DHIT i.v. Three days after injection, a 6% to 73% decrease in the neurons was found in the superior cervical ganglia of the animals. No loss of sensory, nodose and dorsal root ganglia, neurons was observed at the highest dose of DHIT. In contrast, the immunotoxin, 192-saporin (142 micrograms/kg), lesioned all three ganglia. To assess the sympathectomy, 2 wk after treatment (285 micrograms/kg), rats were anesthetized with urethane (1 g/kg) and cannulated in the femoral artery and vein. DHIT-treated animals' basal systolic blood pressure and heart rate were significantly lower than controls. Basal plasma norepinephrine levels were 41% lower in DHIT-treated animals than controls. Tyramine-stimulated release of norepinephrine in DHIT-treated rats was 27% of controls. Plasma epinephrine levels of DHIT animals were not reduced. DHIT-treated animals exhibited a 2-fold hypersensitivity to the alpha-adrenergic agonist phenylephrine. We conclude that DHIT selectively delivered saporin to noradrenergic neurons resulting in destruction of these neurons. Anti-dopamine beta-hydroxylase immunotoxin administration produces a rapid, irreversible sympathectomy.
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D004299:Dopamine beta-Hydroxylase / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006339:Heart Rate / Q000187:drug effects; D000922:Immunotoxins / Q000633:toxicity*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D017783:Superior Cervical Ganglion / Q000473:pathology; D013566:Sympathomimetics / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology
D018663:Adrenergic Agents; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; D013566:Sympathomimetics; C101397:anti-dopamine beta-hydroxylase immunotoxin; D010656:Phenylephrine; D004299:Dopamine beta-Hydroxylase; D000076985:Saporins; D009638:Norepinephrine; D014439:Tyramine