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

1 Adult ventricular cardiomyocytes show an unusual structure-function relat ionship for cyclic AMP-dependent effects of PTHrP. We investigated whether PTHrP(1-16), void of biological activity on classical PTHrP target cells, i s able to mimic the positive contractile effect of PTHrP(1-34), a fully bio logical agonist on cardiomyocytes. 2 Adult ventricular cardiomyocytes were paced at a constant frequency of 0. 5 Hz and cell contraction was monitored using a cell-edge-detection system. TM itch amplitudes, expressed as per cent cell shortening of the diastolic cell length, and rate constants for maximal contraction and relaxation vel ocity were analysed. 3 PTHrP(1-16) (1 mu mol l(-1)) mimicked the contractile effects of PTHrP(1- 34) (1 mu mol 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. 4 PTH(1-34) (10 mu mol l(-1)) affected the positive contractile effect of P THrP(1-34), but not that of PTHrP(1-16). 5 RpcAMPS (10 mu mol l(-1)) inhibited the positive contractile effect of PT HrP(1-34), but not that of PTHrP(1-16). 6 The positive contractile effect of PTHrP(1-16) was antagonized by the ET receptor antagonist BQ123. 7 Sarafotoxin 6b and PTHrP(1-16), but not PTHrP(1-34), replaced H-3-BQ123 f rom cardiac binding sites. 8 We conclude that N-terminal PTHrP peptides void of a PTH/PTHrP-receptor b inding domain are able to bind to, and activate cardiac ETA receptors.