A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors.

Abstract

1. 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. 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. Twitch amplitudes, expressed as per cent cell shortening of the diastolic cell length, and rate constants for maximal contraction and relaxation velocity were analysed. 3. PTHrP(1 - 16) (1 micromol l(-1)) mimicked the contractile effects of PTHrP(1 - 34) (1 micromol 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 micromol l(-1)) affected the positive contractile effect of PTHrP(1 - 34), but not that of PTHrP(1 - 16). 5. RpcAMPS (10 micromol l(-1)) inhibited the positive contractile effect of PTHrP(1 - 34), but not that of PTHrP(1 - 16). 6. The positive contractile effect of PTHrP(1 - 16) was antagonized by the ET(A) receptor antagonist BQ123. 7. Sarafotoxin 6b and PTHrP(1 - 16), but not PTHrP(1 - 34), replaced (3)H-BQ123 from cardiac binding sites. 8. 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.