title: Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries.
abstract: Parathyroid hormone (PTH) augments bone metabolism and bone mass when given intermittently. Enhanced blood flow is requisite to support high tissue metabolism. The bone arteries are responsive to all three PTH analogs, which may serve to augment skeletal blood flow during intermittent PTH administration.
  
  
  BACKGROUND
  PTH augments bone metabolism. Yet, mechanisms by which PTH regulates bone blood vessels are unknown. We deciphered (1) endothelium-dependent and endothelium-independent vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34, (2) the signaling pathways (i.e., endothelial nitric oxide synthase [eNOS], cyclooxygenase [COX], protein kinase C [PKC], and protein kinase A [PKA]), and (3) receptor activation.
  
  
  METHODS
  Femoral principal nutrient arteries (PNAs) were given cumulative doses (10(-13)-10(-8) M) of PTH 1-84, PTH 1-34, and PTHrP 1-34 with and without signaling pathway blockade. Vasodilation was also determined following endothelial cell removal (i.e., denudation), PTH 1 receptor (PTH1R) inhibition and to sodium nitroprusside (SNP; a nitric oxide [NO] donor).
  
  
  RESULTS
  Vasodilation was lowest to PTH 1-34, and maximal dilation was highest to PTHrP 1-34. Inhibition of eNOS reduced vasodilation to PTH 1-84 (-80 %), PTH 1-34 (-66 %), and PTHrP 1-34 (-48 %), evidencing the contribution of NO. Vasodilation following denudation was eliminated (PTH 1-84 and PTHrP 1-34) and impaired (PTH 1-34, 17 % of maximum), highlighting the importance of endothelial cells for PTH signaling. Denuded and intact PNAs responded similarly to SNP. Both PKA and PKC inhibition diminished vasodilation in all three analogs to varying degrees. PTH1R blockade reduced vasodilation to 1, 12, and 12 % to PTH 1-84, PTH 1-34, and PTHrP 1-34, respectively.
  
  
  CONCLUSIONS
  Vasodilation of femoral PNAs to the PTH analogs occurred via activation of the endothelial cell PTH1R for NO-mediated events. PTH 1-84 and PTHrP 1-34 primarily stimulated PKA signaling, and PTH 1-34 equally stimulated PKA and PKC signaling.
authors.affiliation: Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA.
authors.forename: T
authors.initials: T
authors.lastname: Benson
authors.affiliation: Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA.
authors.forename: T
authors.initials: T
authors.lastname: Menezes
authors.affiliation: Department of Kinesiology, University of Texas at Arlington, Arlington, TX, 76019, USA.
authors.forename: J
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Bone Vascular and Microcirculation Laboratory, Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, 19713, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bice
authors.affiliation: Bone Vascular and Microcirculation Laboratory, Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, 19713, USA.
authors.forename: B
authors.initials: B
authors.lastname: Hood
authors.affiliation: Bone Vascular and Microcirculation Laboratory, Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE, 19713, USA. prisby@udel.edu.
authors.forename: R
authors.initials: R
authors.lastname: Prisby
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005269:Femur / Q000098:blood supply*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D017208:Rats, Wistar; D019379:Teriparatide / Q000008:administration & dosage / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D014665:Vasodilator Agents; D019379:Teriparatide; C054296:parathyroid hormone-related protein (1-34); D009599:Nitroprusside
keywords: Bone resistance arteries; PTH; Vasodilation