title: PTH-receptors regulate norepinephrine release in human heart and kidney.
abstract: Recent data suggests that chronic renal failure and hyperparathyroidism are associated with sympathetic overactivity. Since peptide hormones are known to modulate norepinephrine (NE) release by activating prejunctional receptors, this study investigates whether parathyroid hormone fragment (1-34) (hPTH(1-34)) increases neuronal NE release in human heart and kidney. Using specific PTH-receptor agonists and antagonists, this study furthermore highlights functional differences between PTH1 and PTH2 receptors. Human atrial and renal tissues were incubated with [(3)H]-NE and superfused. Three electrical stimulations (5Hz, 1min) induced a stable [(3)H]-NE release which was taken as an index of endogenous NE release. RT-PCR with specific primers for PTH1- and PTH2-receptor was performed in heart and kidney. hPTH(1-34) (0.01-0.1μmol/L) and a stable analog of its second messenger cAMP (8-bromo-cAMP) increased [(3)H]-NE release in human atria. This facilitatory effect of PTH was also observed in human renal cortex. The PTH1-receptor antagonist (D-Trp(12), Tyr(34))-pTH-(7-34) (0.5μmol/L) abolished the effect of hPTH(1-34). This data was verified using isolated perfused mouse kidneys. Tuberoinfundibular peptide of 39 residues (TIP-39) (0.1nmol/L-0.1μmol/L) decreased [(3)H]-NE release in atria. PTH1- and PTH2-receptor expressions were demonstrated in human heart and kidney. Moreover, a splice variant of the PTH2-receptor was detected in human kidney. In conclusion, PTH is able to facilitate NE release in human atria and renal cortex by activation of PTH1-receptors. The highly increased PTH levels that can be observed in chronic renal failure might be one contributor for the elevated sympathetic nerve activity and the associated cardiovascular mortality in patients with end stage renal disease.
authors.affiliation: Department of Nephrology, Medical Faculty Heinrich-Heine University of Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. sebastian.potthoff@med.uni-duesseldorf.de
authors.forename: S A
authors.initials: SA
authors.lastname: Potthoff
authors.forename: A
authors.initials: A
authors.lastname: Janus
authors.forename: H
authors.initials: H
authors.lastname: Hoch
authors.forename: M
authors.initials: M
authors.lastname: Frahnert
authors.forename: P
authors.initials: P
authors.lastname: Tossios
authors.forename: D
authors.initials: D
authors.lastname: Reber
authors.forename: M
authors.initials: M
authors.lastname: Giessing
authors.forename: H M
authors.initials: HM
authors.lastname: Klein
authors.forename: E
authors.initials: E
authors.lastname: Schwertfeger
authors.forename: I
authors.initials: I
authors.lastname: Quack
authors.forename: L C
authors.initials: LC
authors.lastname: Rump
authors.forename: O
authors.initials: O
authors.lastname: Vonend
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology; D006321:Heart / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000209:etiology; D051379:Mice; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D009479:Neuropeptides; C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; D044183:Receptor, Parathyroid Hormone, Type 2; C094316:parathyroid hormone (1-37); C400136:tuberoinfundibular peptide 39; D003042:Cocaine; D003345:Corticosterone; D009638:Norepinephrine