title: Regulation of β-adrenergic control of heart rate by GTP-cyclohydrolase 1 (GCH1) and tetrahydrobiopterin.
abstract: OBJECTIVE
  Clinical markers of cardiac autonomic function, such as heart rate and response to exercise, are important predictors of cardiovascular risk. Tetrahydrobiopterin (BH4) is a required cofactor for enzymes with roles in cardiac autonomic function, including tyrosine hydroxylase and nitric oxide synthase. Synthesis of BH4 is regulated by GTP cyclohydrolase I (GTPCH), encoded by GCH1. Recent clinical studies report associations between GCH1 variants and increased heart rate, but the mechanistic importance of GCH1 and BH4 in autonomic function remains unclear. We investigate the effect of BH4 deficiency on the autonomic regulation of heart rate in the hph-1 mouse model of BH4 deficiency.
  
  
  RESULTS
  In the hph-1 mouse, reduced cardiac GCH1 expression, GTPCH enzymatic activity, and BH4 were associated with increased resting heart rate; blood pressure was not different. Exercise training decreased resting heart rate, but hph-1 mice retained a relative tachycardia. Vagal nerve stimulation in vitro induced bradycardia equally in hph-1 and wild-type mice both before and after exercise training. Direct atrial responses to carbamylcholine were equal. In contrast, propranolol treatment normalized the resting tachycardia in vivo. Stellate ganglion stimulation and isoproterenol but not forskolin application in vitro induced a greater tachycardic response in hph-1 mice. β1-adrenoceptor protein was increased as was the cAMP response to isoproterenol stimulation.
  
  
  CONCLUSIONS
  Reduced GCH1 expression and BH4 deficiency cause tachycardia through enhanced β-adrenergic sensitivity, with no effect on vagal function. GCH1 expression and BH4 are novel determinants of cardiac autonomic regulation that may have important roles in cardiovascular pathophysiology.
authors.affiliation: Department of Cardiovascular Medicine,  University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU,  UK.
authors.forename: David
authors.initials: D
authors.lastname: Adlam
authors.forename: Neil
authors.initials: N
authors.lastname: Herring
authors.forename: Gillian
authors.initials: G
authors.lastname: Douglas
authors.forename: Joseph P
authors.initials: JP
authors.lastname: De Bono
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Danson
authors.forename: Amy
authors.initials: A
authors.lastname: Tatham
authors.forename: Cheih-Ju
authors.initials: CJ
authors.lastname: Lu
authors.forename: Katie A
authors.initials: KA
authors.lastname: Jennings
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.forename: David J
authors.initials: DJ
authors.lastname: Paterson
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001919:Bradycardia / Q000503:physiopathology; D004195:Disease Models, Animal; D006136:GTP Cyclohydrolase / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D055536:Vagus Nerve Stimulation
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D001708:Biopterins; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D007545:Isoproterenol