Dual effect mediated by protease-activated receptors on the mechanical activity of rat colon - PubMed (original) (raw)

Dual effect mediated by protease-activated receptors on the mechanical activity of rat colon

Flavia Mulè et al. Br J Pharmacol. 2002 Jun.

Abstract

1. The present study examined the mechanical effects of agonist enzymes and receptor-activating peptides for protease-activated receptor (PAR)-1 and PAR-2 on longitudinal and circular muscle of rat isolated colonic segments in the attempt to clarify the PAR functional role in intestinal motility. 2. The responses to PAR-1 and PAR-2 activation were examined in vitro by recording simultaneously the changes of endoluminal pressure (index of circular muscle activity) and of isometric tension (index of longitudinal muscle activity). 3. Both PAR-1 agonists, thrombin (0.1 nM - 3 microM) and SFLLRN-NH2 (1 nM - 3 microM), and PAR-2 agonists, trypsin (0.1 nM - 10 microM) and SLIGRL-NH2 (1 nM - 10 microM), induced different effects in the two muscular layers: a reduction of the spontaneous contractions in the circular muscle and a contractile effect or biphasic, relaxation followed by contraction, depending on the concentration, in the longitudinal muscle. 4. The inhibitory effects were greatly reduced or abolished by apamin (0.1 microM) indicating that they mainly occur via activation of Ca2+-dependent small conductance, K+-channels. 5. The responses to PAR-1 and PAR-2 were unaffected by tetrodotoxin (1 microM) or indomethacin (1 microM) suggesting that are independent by products of cyclooxygenase or by neural action potentials. 6. These findings indicate that both PAR-1 and PAR-2 are functionally expressed in rat colon. PARs mediate changes of the mechanical activity of longitudinal and circular muscle which might explain the alterations of colonic motility observed during inflammatory conditions.

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Figures

Figure 1

Figure 1

Experimental set-up used for the simultaneous recording of the intraluminal pressure and the isometric tension of the rat intestinal segments.

Figure 2

Figure 2

Representative recordings of the effects induced by thrombin and PAR-1 related peptides on the pressure waves (upper tracings) and on the tension oscillations (lower tracings) of an isolated segment of rat colon. The arrow indicates the application of the agonist. Only the more significant concentrations are shown. The PAR-1 agonist, SFLLRN-NH2, and the PAR-1 inactive control peptide, FSLLRN-NH2, were cumulatively added to the bath.

Figure 3

Figure 3

Representative recordings of the effects induced by trypsin and PAR-2 related peptides on the pressure waves (upper tracings) and on the tension oscillations (lower tracings) of an isolated segment of rat colon. The arrow indicates the application of the agonist. Only the more significant concentrations are shown. The PAR-2 agonist, SLIGRL-NH2, and the PAR-2 inactive control peptide, LSIGRL-NH2, were cumulatively added to the bath.

Figure 4

Figure 4

Concentration-response curves for effects evoked by PAR-1 and PAR-2 agonists on the pressure waves (left panel) and on the tension oscillations (right panel) of an isolated segment of rat colon. The inhibitory responses on circular muscle are expressed as the per cent change from the resting spontaneous activity (−100% corresponds to the abolition of spontaneous activity). The contractile effects on longitudinal muscle are expressed as a percentage of the maximal response to carbachol (10 μ

M

). Each value is the mean±s.e.mean of 5 – 9 experiments.

Figure 5

Figure 5

Concentration-response curves to PAR-1 and PAR-2 activating peptides, SFLLRN-NH2 and SLIGRL-NH2, respectively, in rat colonic segments in the absence or in the presence of apamin (0.1 μ

M

). The suppression of spontaneous contractions of circular muscle (left panel) is expressed as the percent change from the resting spontaneous activity (−100% corresponds to the abolition of spontaneous activity). The contractile response on longitudinal muscle (right panel) is expressed as a percentage of the contraction to carbachol (10 μ

M

). Each value is the mean±s.e.mean of six experiments. Apamin significantly antagonized the inhibitory responses and significantly enhanced the contractile effects induced by the highest concentration of PAR-1 agonist. *P<0.05, compared to the control value.

Figure 6

Figure 6

Histograms showing the suppression of spontaneous contractions of circular muscle (left panel) and the contractile effects on longitudinal muscle (right panel) exerted by the PAR-1 agonist, SFLLRN-NH2 (10 μ

M

), or by the PAR-2 agonist, SLIGRL-NH2 (10 μ

M

), in the absence or in the presence of TTX (1 μ

M

) or indomethacin (1 μ

M

). The inhibitory responses were expressed as the percent change from the resting spontaneous activity (−100% corresponds to the abolition of spontaneous activity). The contractile responses are expressed as a percentage of the maximal response to carbachol (10 μ

M

). Each value is the mean±s.e.mean of five experiments. TTX and indomethacin failed to affect the inhibitory and the contractile responses to PAR-1 or PAR-2 activation at all concentrations tested (data not shown).

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