title: Systemic inhibition of nitric oxide synthase unmasks neural constraint of maximal myocardial blood flow in humans.
abstract: BACKGROUND
  Nitric oxide (NO) is an endothelial mediator that regulates vascular smooth muscle tone, but it may exert its cardiovascular action also by modulating the autonomic control of vasomotor tone. We assessed the effect of simultaneous inhibition of both endothelial (eNOS) and neuronal (nNOS) NO synthase isoforms on myocardial blood flow (MBF) and coronary flow reserve (CFR) in volunteers and in (denervated) transplant recipients.
  
  
  RESULTS
  MBF (mL x min(-1) x g(-1)) was measured at rest and during adenosine-induced hyperemia with positron emission tomography and 15O-labeled water. CFR was calculated as adenosine/resting MBF. Measurements were repeated during one of the following intravenous infusions: group 1 (n=12), saline; group 2 (n=9), 3 mg/kg N(G)-monomethyl-L-arginine (L-NMMA), which crosses the blood-brain barrier and inhibits both eNOS and nNOS; group 3 (n=13), 10 mg/kg L-NMMA; group 4 (n=8), phenylephrine titrated to simulate the hemodynamic changes in group 3; and group 5 (n=6), 10 mg/kg L-NMMA infused into the heart transplant recipients. After intervention, hyperemic MBF and CFR were unchanged in groups 1, 2, and 4. By contrast, both hyperemic MBF (+53%, P<0.0001 versus baseline) and CFR (+52%, P<0.0001 versus baseline) increased in group 3, whereas they remained unchanged in group 5, which suggests that an intact cardiac innervation was required for the increase in MBF and CFR observed in group 3.
  
  
  CONCLUSIONS
  The results of the present study suggest that maximal adenosine-induced hyperemia and CFR in humans are constrained by neurally mediated vasoconstriction, which can be relieved by systemic NOS inhibition with L-NMMA.
authors.affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Kaufmann
authors.forename: Ornella
authors.initials: O
authors.lastname: Rimoldi
authors.forename: Tomaso
authors.initials: T
authors.lastname: Gnecchi-Ruscone
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bonser
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Camici
mesh_terms: D000241:Adenosine; D000328:Adult; D017763:Autonomic Denervation; D001794:Blood Pressure; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000000981:diagnostic imaging / Q000294:innervation; D006339:Heart Rate; D016027:Heart Transplantation; D006801:Humans; D006940:Hyperemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D049268:Positron-Emission Tomography; D011184:Postoperative Period; D012146:Rest; D014661:Vasoconstriction / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D009419:Nerve Tissue Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D000241:Adenosine