title: Inflammatory cell-derived NO modulates cardiac allograft contractile and electrophysiological function.
abstract: We previously demonstrated that inhibition of inducible nitric oxide (NO) synthase (iNOS) ameliorated acute cardiac allograft rejection. This study used a rat cardiac transplant model to characterize contractile and electrophysiological dysfunction during early acute rejection, further examine the role of NO and iNOS in this process, and determine which cells expressed iNOS during early rejection. During early acute rejection, before significant myocyte necrosis, allograft papillary muscles had reduced tension development and rates of tension development and decline during beta-adrenergic, adenylate cyclase, and calcium stimulation compared with isograft and normals [e.g., tension of 36 (allograft) vs. 73 (isograft) mN/mm2 during calcium stimulation, P < 0.001]. Allografts had resting membrane potential depolarization and reduced action potential amplitude and upstroke velocity. iNOS mRNA was expressed in infiltrating inflammatory cells but not in allograft myocytes, endothelial cells, or isografts. Corticosteroids attenuated allograft contractile and electrophysiological dysfunction and inhibited iNOS enzyme activity. Direct iNOS inhibition with aminoguanidine inhibited NO production and prevented allograft contractile and electrophysiological dysfunction (e.g., tension of 64 mN/mm2 during calcium stimulation, P < 0.001). We conclude that 1) early allograft rejection caused contractile and electrophysiological dysfunction that was largely mediated by iNOS expression in infiltrating inflammatory cells, 2) corticosteroid-mediated amelioration of allograft contractile and electrophysiological dysfunction may reflect inhibition of iNOS, and 3) iNOS inhibition may offer an alternative in management of immune-mediated myocardial dysfunction.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis 63110, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Worrall
authors.forename: R T
authors.initials: RT
authors.lastname: Pyo
authors.forename: M D
authors.initials: MD
authors.lastname: Botney
authors.forename: T P
authors.initials: TP
authors.lastname: Misko
authors.forename: P M
authors.initials: PM
authors.lastname: Sullivan
authors.forename: D G
authors.initials: DG
authors.lastname: Alexander
authors.forename: W D
authors.initials: WD
authors.lastname: Lazenby
authors.forename: T B
authors.initials: TB
authors.lastname: Ferguson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology / Q000379:methods; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation / Q000502:physiology*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008775:Methylprednisolone / Q000494:pharmacology; D009200:Myocardial Contraction; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology*; D015347:RNA Probes; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D014158:Transcription, Genetic; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000502:physiology; D014185:Transplantation, Isogeneic / Q000502:physiology
chemical_list: D000305:Adrenal Cortex Hormones; D006146:Guanidines; D015347:RNA Probes; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000262:Adenylyl Cyclases; C004479:pimagedine; D002118:Calcium; D008775:Methylprednisolone