Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF.
Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, beta-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [(3)H]NE, beta-receptor density by [(125)I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial beta-adrenoceptor density and beta-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial beta-adrenoceptor density and beta-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.
Liang
Chang-Seng
CS
Cardiology Unit, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. chang-seng_liang@urmc.rochester.edu
Himura
Yoshihiro
Y
Kashiki
Michihiro
M
Stevens
Suzanne Y
SY
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology; D007150:Immunohistochemistry; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000032:analysis; D009638:Norepinephrine / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D009929:Organ Size; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy* / Q000473:pathology
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D002316:Cardiotonic Agents; D009478:Neuropeptide Y; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D014446:Tyrosine 3-Monooxygenase; D003891:Desipramine; D009638:Norepinephrine