Proteinase-activated receptors 1 and 2 and the regulation of porcine coronary artery contractility: a role for distinct tyrosine kinase pathways

Br J Pharmacol. 2014 May;171(9):2413-25. doi: 10.1111/bph.12593.


Background and purpose: Because angiotensin-II-mediated porcine coronary artery (PCA) vasoconstriction is blocked by protein tyrosine kinase (PYK) inhibitors, we hypothesized that proteinase-activated receptors (PARs), known to regulate vascular tension, like angiotensin-II, would also cause PCA contractions via PYK-dependent signalling pathways.

Experimental approach: Contractions of intact and endothelium-free isolated PCA rings, stimulated by PAR1 /PAR2 -activating peptides, angiotensin-II, PGF2α , EGF, PDGF and KCl, were monitored with/without multiple signalling pathway inhibitors, including AG-tyrphostins AG18 (non-specific PYKs), AG1478 (EGF-receptor kinase), AG1296 (PDGF receptor kinase), PP1 (Src kinase), U0126 and PD98059 (MEK/MAPKinase kinase), indomethacin/SC-560/NS-398 (COX-1/2) and L-NAME (NOS).

Key results: AG18 inhibited the contractions induced by all the agonists except KCl, whereas U0126 attenuated contractions induced by PAR1 /PAR2 agonists, EGF and angiotensin-II, but not by PGF2α , the COX-produced metabolites of arachidonate and KCl. PP1 only affected the responses to PAR1 /PAR2 -activating peptides and angiotensin-II. The EGF-kinase inhibitor, AG1478, attenuated contractions initiated by the PARs (PAR2 >> PAR1 ) and EGF itself, but not by angiotensin-II, PGF2α or KCl. COX-1/2 inhibitors blocked the contractions induced by all the agonists, except KCl and PGF2α .

Conclusion and implications: PAR1/2 -mediated contractions of the PCA are dependent on Src and MAPKinase and, in part, involve EGF-receptor-kinase transactivation and the generation of a COX-derived contractile agonist. However, the PYK signalling pathways used by PARs are distinct from each other and from those triggered by angiotensin-II and EGF. These signalling pathways may be therapeutic targets for managing coagulation-proteinase-induced coronary vasospasm.

Keywords: EGF; MAPKinase; PARs; PGF2α; angiotensin-II; coronary contraction; cyclooxygenase; protease; proteinase-activated receptors; tyrosine kinase signalling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coronary Vessels / drug effects
  • Coronary Vessels / enzymology*
  • Organ Culture Techniques
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / physiology*
  • Receptor, PAR-1 / physiology*
  • Receptor, PAR-2 / physiology*
  • Swine
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology*


  • Protein Kinase Inhibitors
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Protein-Tyrosine Kinases