A N-terminal PTHrP peptide fragment void of a PTH/PTHrP-receptor binding domain activates cardiac ET(A) receptors.
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.
Schlüter
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KD
Physiologisches Institut, Aulweg 129, 35392 Giessen, Germany. Klaus-Dieter.Schlueter@physiologie.med.uni-giessen.de
Katzer
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Piper
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D002469:Cell Separation; D065128:Endothelin Receptor Antagonists; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein; D010456:Peptides, Cyclic / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects*; D018016:Receptors, Parathyroid Hormone / Q000187:drug effects / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D065128:Endothelin Receptor Antagonists; D044162:Parathyroid Hormone-Related Protein; D010456:Peptides, Cyclic; D011506:Proteins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D018016:Receptors, Parathyroid Hormone; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D010656:Phenylephrine; D001262:Atenolol; D007545:Isoproterenol; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D011224:Prazosin