Central exogenous nitric oxide decreases cardiac sympathetic drive and improves baroreflex control of heart rate in ovine heart failure.
Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympathoexcitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from downregulation of neuronal NO synthase (nNOS). Therefore, we investigated the effects of increasing the levels of NO in the brain, or selectively in the paraventricular nucleus of the hypothalamus (PVN), on cardiac sympathetic nerve activity (CSNA) and baroreflex control of CSNA and heart rate in ovine pacing-induced HF. The resting level of CSNA was significantly higher in the HF than in the normal group, but the resting level of RSNA was unchanged. Intracerebroventricular infusion of the NO donor sodium nitroprusside (SNP; 500 μg · ml(-1)· h(-1)) in conscious normal sheep and sheep in HF inhibited CSNA and restored baroreflex control of heart rate, but there was no change in RSNA. Microinjection of SNP into the PVN did not cause a similar cardiac sympathoinhibition in either group, although the number of nNOS-positive cells was decreased in the PVN of sheep in HF. Reduction of endogenous NO with intracerebroventricular infusion of N(ω)-nitro-l-arginine methyl ester decreased CSNA in normal but not in HF sheep and caused no change in RSNA in either group. These findings indicate that endogenous NO in the brain provides tonic excitatory drive to increase resting CSNA in the normal state, but not in HF. In contrast, exogenously administered NO inhibited CSNA in both the normal and HF groups via an action on sites other than the PVN.
Department of Physiology, University of Auckland, Auckland, New ZealandFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; and r.ramchandra@auckland.ac.nz.
Rohit
R
Ramchandra
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; and.
Sally G
SG
Hood
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia; and.
Clive N
CN
May
D000818:Animals; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007276:Injections, Intraventricular; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology; D012756:Sheep; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester
baroreflex; heart failure; nitric oxide; sympathetic nerve activity