Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides

evidence for receptor heterogeneity

Samir S. Roy, Mahmoud Saifeddine, Rodger Loutzenhiser, Christopher Triggle, Morley D. Hollenberg

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The vascular actions of the proteinase-activated receptor-2-activating peptides (PAR2APs), SLIGRL-NH2 (SL-NH2) and SLIGKV-NH2 (KV-NH2) as well as the reverse-sequence peptide, LSIGRL-NH2 (LS-NH2) and an N-acylated PAR2AP derivative, trans-cinnamoyl-LIGRLO-NH2 (tcLI-NH2), were studied in rat intact and endothelium-denuded artery ring preparations, primarily from the pulmonary artery (RPA). 2 In RPA rings with but not without a functional endothelium, SL-NH2 (but not LS-NH2) caused either an endothelium-dependent relaxation (at concentrations: <10 μM) or (at higher concentrations: >10 μM), an endothelium-dependent contraction. No contractile response was observed in endothelium-denuded preparations, that otherwise contracted in response to the PAR1AP, TFLLR-NH2. 3 The endothelium-dependent contractile response to SL-NH2 was not blocked by the α-adrenoceptor antagonist prazosin, the endothelin antagonist BQ123, the angiotensin II antagonist DuP753, by tetrodotoxin; nor by the enzyme inhibitors, Nω-nitro-L-arginine-methylester (NO-synthase), indomethacin (cyclo-oxygenase), SKF-525A (epoxygenase) and MK886 (leukotriene synthesis inhibitor). 4 In the relaxation assay, KV-NH2, was 5 fold less potent than SL-NH2, whereas in the contractile assay KV-NH2, was about equipotent with SL-NH2. However, the maximal contractile response to KV-NH2 was lower than that of SL-NH2. 5 The PAR2AP analogue, tcLI-NH2, was as active as SL-NH2 in the relaxation assay but was inactive as a contractile agonist in the endothelium-intact RPA. 6 The relaxant responses caused by SL-NH2 and trypsin, as well as the contractile response caused by SL-NH2, did not desensitize in the course of repeated exposures of the tissue to agonist; whereas the contractile response to trypsin, only observed at concentrations greater than 30 u ml-1, was desensitized by previous exposure of the tissue to either thrombin or trypsin. 7 In a contractile assay, where the tissue was desensitized to a concentration of trypsin that would otherwise cause a relaxant response, the preparation still contracted in response to SL-NH2. However, the trypsin-desensitized preparations were no longer contracted by thrombin. 8 From the cross-desensitization by thrombin of the contractile response to trypsin (and vice versa), we concluded that the contractile effect of trypsin was due to activation of the thrombin receptor and not PAR2. 9 We concluded that the endothelium-dependent contraction caused by high concentrations of SL-NH2 is due to an as yet unidentified contracting factor; whereas the endothelium-dependent relaxation response observed at low concentrations of SL-NH2 (≤10 μM) is mediated by nitric oxide. 10 The distinct structure activity profiles for the contractile response (potency of KV-NH2≤ SL-NH2) compared with the relaxant response (potency of KV-NH2< <SL-NH2); the contractile responsiveness to SL-NH2, of an endothelium-intact RPA preparation, that did not contract in response to trypsin; and the lack of contractile activity of the PAR2AP analogue tcLI-NH2, that was as active as SL-NH2 in the relaxation assay all argue in favour of receptor heterogeneity in the vasculature for the PAR2APs. It remains to be determined if the distinct endothelial receptor responsible for the contractile action of SL-NH2 can be proteolytically activated, like PAR1 and PAR2.

Original languageEnglish
Pages (from-to)1434-1440
Number of pages7
JournalBritish Journal of Pharmacology
Volume123
Issue number7
DOIs
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

PAR-2 Receptor
Peptide Receptors
Vascular Endothelium
Endothelium
Trypsin
Peptides
Thrombin
seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
Proadifen
Thrombin Receptors

Keywords

  • Endothelium
  • Par
  • Par
  • Protease-activated receptor
  • Pulmonary artery
  • Thrombin receptor
  • Trypsin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides : evidence for receptor heterogeneity. / Roy, Samir S.; Saifeddine, Mahmoud; Loutzenhiser, Rodger; Triggle, Christopher; Hollenberg, Morley D.

In: British Journal of Pharmacology, Vol. 123, No. 7, 1998, p. 1434-1440.

Research output: Contribution to journalArticle

Roy, Samir S. ; Saifeddine, Mahmoud ; Loutzenhiser, Rodger ; Triggle, Christopher ; Hollenberg, Morley D. / Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides : evidence for receptor heterogeneity. In: British Journal of Pharmacology. 1998 ; Vol. 123, No. 7. pp. 1434-1440.
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T1 - Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides

T2 - evidence for receptor heterogeneity

AU - Roy, Samir S.

AU - Saifeddine, Mahmoud

AU - Loutzenhiser, Rodger

AU - Triggle, Christopher

AU - Hollenberg, Morley D.

PY - 1998

Y1 - 1998

N2 - The vascular actions of the proteinase-activated receptor-2-activating peptides (PAR2APs), SLIGRL-NH2 (SL-NH2) and SLIGKV-NH2 (KV-NH2) as well as the reverse-sequence peptide, LSIGRL-NH2 (LS-NH2) and an N-acylated PAR2AP derivative, trans-cinnamoyl-LIGRLO-NH2 (tcLI-NH2), were studied in rat intact and endothelium-denuded artery ring preparations, primarily from the pulmonary artery (RPA). 2 In RPA rings with but not without a functional endothelium, SL-NH2 (but not LS-NH2) caused either an endothelium-dependent relaxation (at concentrations: <10 μM) or (at higher concentrations: >10 μM), an endothelium-dependent contraction. No contractile response was observed in endothelium-denuded preparations, that otherwise contracted in response to the PAR1AP, TFLLR-NH2. 3 The endothelium-dependent contractile response to SL-NH2 was not blocked by the α-adrenoceptor antagonist prazosin, the endothelin antagonist BQ123, the angiotensin II antagonist DuP753, by tetrodotoxin; nor by the enzyme inhibitors, Nω-nitro-L-arginine-methylester (NO-synthase), indomethacin (cyclo-oxygenase), SKF-525A (epoxygenase) and MK886 (leukotriene synthesis inhibitor). 4 In the relaxation assay, KV-NH2, was 5 fold less potent than SL-NH2, whereas in the contractile assay KV-NH2, was about equipotent with SL-NH2. However, the maximal contractile response to KV-NH2 was lower than that of SL-NH2. 5 The PAR2AP analogue, tcLI-NH2, was as active as SL-NH2 in the relaxation assay but was inactive as a contractile agonist in the endothelium-intact RPA. 6 The relaxant responses caused by SL-NH2 and trypsin, as well as the contractile response caused by SL-NH2, did not desensitize in the course of repeated exposures of the tissue to agonist; whereas the contractile response to trypsin, only observed at concentrations greater than 30 u ml-1, was desensitized by previous exposure of the tissue to either thrombin or trypsin. 7 In a contractile assay, where the tissue was desensitized to a concentration of trypsin that would otherwise cause a relaxant response, the preparation still contracted in response to SL-NH2. However, the trypsin-desensitized preparations were no longer contracted by thrombin. 8 From the cross-desensitization by thrombin of the contractile response to trypsin (and vice versa), we concluded that the contractile effect of trypsin was due to activation of the thrombin receptor and not PAR2. 9 We concluded that the endothelium-dependent contraction caused by high concentrations of SL-NH2 is due to an as yet unidentified contracting factor; whereas the endothelium-dependent relaxation response observed at low concentrations of SL-NH2 (≤10 μM) is mediated by nitric oxide. 10 The distinct structure activity profiles for the contractile response (potency of KV-NH2≤ SL-NH2) compared with the relaxant response (potency of KV-NH2< <SL-NH2); the contractile responsiveness to SL-NH2, of an endothelium-intact RPA preparation, that did not contract in response to trypsin; and the lack of contractile activity of the PAR2AP analogue tcLI-NH2, that was as active as SL-NH2 in the relaxation assay all argue in favour of receptor heterogeneity in the vasculature for the PAR2APs. It remains to be determined if the distinct endothelial receptor responsible for the contractile action of SL-NH2 can be proteolytically activated, like PAR1 and PAR2.

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