Thrombin receptor activation peptide induces pulmonary vasoconstriction.
We investigated the involvement of the 14-residue thrombin receptor activating peptide SFLLRNPNDKYEPF (TRAP-14) in mediating the pulmonary vasoconstriction in response to alpha-thrombin. Isolated guinea pig lungs were uniformly perfused with Ringer-albumin solution at a constant flow of 28 ml/min. Addition of TRAP-14 or human alpha-thrombin to the perfusate caused dose-dependent increases of pulmonary arterial pressure within 1 min. TRAP-14 at 1 microM increased pulmonary arterial pressure to a similar extent as 10 nM alpha-thrombin (i.e., increase of 7.7 +/- 0.8 and 7.4 +/- 0.9 cmH2(0) from baseline, respectively). The increases in pulmonary venous resistance induced by TRAP-14 and alpha-thrombin were two- to fivefold greater than the increases in pulmonary arterial resistance, indicating that both agonists mediated pulmonary hypertension secondary to pulmonary venoconstriction. Stimulation of cultured guinea pig pulmonary artery smooth muscle cells with 100 microM TRAP-14 or 10 nM alpha-thrombin increased cytosolic Ca2+ concentration about five- to sevenfold over baseline. The increase in cytosolic Ca2+ concentration in smooth muscle cells was not observed with a subsequent challenge with either agonist, indicating desensitization. In the perfused lungs, an initial stimulation with alpha-thrombin or TRAP-14 desensitized the lungs to either agonist. The alpha-thrombin-desensitized lungs remained refractile to alpha-thrombin after 1 h of perfusion with fresh Ringer solution, whereas the TRAP-14-desensitized lungs recovered 79% of the vasoconstrictor response by 10 min and 93% of the response by 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Lum
H
H
Department of Pharmacology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612.
Andersen
T T
TT
Fenton
J W
JW
Malik
A B
AB
D000595:Amino Acid Sequence; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C072032:thrombin receptor peptide (42-55); D013917:Thrombin