A N‐terminal PTHrP peptide fragment void of a PTH/PTHrP‐receptor binding domain activates cardiac ET A receptors

Adult ventricular cardiomyocytes show an unusual structure‐function relationship for cyclic AMP‐dependent effects of PTHrP. We investigated whether PTHrP(1 – 16), void of biological activity on classical PTHrP target cells, is able to mimic the positive contractile effect of PTHrP(1 – 34), a fully biological agonist on cardiomyocytes. Adult ventricular cardiomyocytes were paced at a constant frequency of 0.5 Hz and cell contraction was monitored using a cell‐edge‐detection system. Twitch amplitudes, expressed as per cent cell shortening of the diastolic cell length, and rate constants for maximal contraction and relaxation velocity were analysed. PTHrP(1 – 16) (1 μmol l −1 ) mimicked the contractile effects of PTHrP(1 – 34) (1 μmol l −1 ). It increased the twitch amplitude from 5.33±0.72 to 8.95±1.10 (% dl l −1 ) without changing the kinetic of contraction. PTH(1 – 34) (10 μmol l −1 ) affected the positive contractile effect of PTHrP(1 – 34), but not that of PTHrP(1 – 16). RpcAMPS (10 μmol l −1 ) inhibited the positive contractile effect of PTHrP(1 – 34), but not that of PTHrP(1 – 16). The positive contractile effect of PTHrP(1 – 16) was antagonized by the ET A receptor antagonist BQ123. Sarafotoxin 6b and PTHrP(1 – 16), but not PTHrP(1 – 34), replaced 3 H‐BQ123 from cardiac binding sites. We conclude that N‐terminal PTHrP peptides void of a PTH/PTHrP‐receptor binding domain are able to bind to, and activate cardiac ET A receptors.British Journal of Pharmacology (2001) 132 , 427–432; doi: 10.1038/sj.bjp.0703830