title: Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure.
abstract: Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation [muscle sympathetic nerve activity (MSNA)] during exercise in heart failure (HF) patients is heightened compared with that of healthy humans and that muscle mechanoreceptors are sensitized by metabolic by-products. We sought to determine whether cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip (RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control were infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control were infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise, consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 min of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 min of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of the very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which also appears to be mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.
authors.affiliation: Dept. of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. hmiddlekauff@mednet.ucla.edu
authors.forename: Holly R
authors.initials: HR
authors.lastname: Middlekauff
authors.forename: Josephine
authors.initials: J
authors.lastname: Chiu
authors.forename: Michele A
authors.initials: MA
authors.lastname: Hamilton
authors.forename: Gregg C
authors.initials: GC
authors.lastname: Fonarow
authors.forename: W Robb
authors.initials: WR
authors.lastname: Maclellan
authors.forename: Antoine
authors.initials: A
authors.lastname: Hage
authors.forename: Jaime
authors.initials: J
authors.lastname: Moriguchi
authors.forename: Jignesh
authors.initials: J
authors.lastname: Patel
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000628:Aminophylline / Q000008:administration & dosage; D001794:Blood Pressure; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D018737:Hand Strength; D006333:Heart Failure / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008875:Middle Aged; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D010543:Peroneal Nerve / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D012107:Research Design; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D016861:Cyclooxygenase Inhibitors; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D000628:Aminophylline; D011451:Prostaglandin-Endoperoxide Synthases; D000241:Adenosine; D007213:Indomethacin