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Suppression of peripheral sympathetic activity underlies protease-activated receptor 2-mediated hypotension.

Kim YH, Ahn DS, Joeng JH, Chung S - Korean J. Physiol. Pharmacol. (2014)

Bottom Line: In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA).Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ω-CgTx.These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of ICa-N which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yonsei University College of Medicine, Seoul 120-752, Korea.

ABSTRACT
Protease-activated receptor (PAR)-2 is expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although some reports have suggested involvement of a neurogenic mechanism in PAR-2-induced hypotension, the accurate mechanism remains to be elucidated. To examine this possibility, we investigated the effect of PAR-2 activation on smooth muscle contraction evoked by electrical field stimulation (EFS) in the superior mesenteric artery. In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA). However, thrombin, a potent PAR-1 agonist, had no effect on EFS-evoked contraction. Additionally, ω-conotoxin GVIA (CgTx), a selective N-type Ca(2+) channel (ICa-N) blocker, significantly inhibited EFS-evoked contraction, and this blockade almost completely occluded the suppression of EFS-evoked contraction by PAR-2 agonists. Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ω-CgTx. These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of ICa-N which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.

No MeSH data available.


Related in: MedlinePlus

PAR-2 agonists inhibited ICa in rat SCG neurons (A) Left, a representative trace of ICa in the presence (●) and absence (○) of 30 nM typsin. Right, a representative trace of ICa in the presence (●) and absence (○) of 30 nM BT. (B) Left, a representative traces of ICa in the presence (●) and absence (○) of 100µM SL-NH2. Right, a representative trace of ICa in the presence (●) and absence (○) of 100µM LR-NH2. (C) left, a summary of ICa inhibition by trypsin (815.5±104.9 pA for control; 428.0±54.1 pA for trypsin, n=5) and BT (906.6±115.7 pA for control, 863.1±125.6 pA for BT, n=5, p>0.05). Right a summary of ICa inhibition by SL-NH2 (902.5±111.6 pA for control, 506.1±58.8 pA for SL-NH2, n=5) or LR-NH2 (786.8±67.1 pA for control, 727.1±71.2 pA for LR-NH2, n=5, p>0.01).
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Figure 5: PAR-2 agonists inhibited ICa in rat SCG neurons (A) Left, a representative trace of ICa in the presence (●) and absence (○) of 30 nM typsin. Right, a representative trace of ICa in the presence (●) and absence (○) of 30 nM BT. (B) Left, a representative traces of ICa in the presence (●) and absence (○) of 100µM SL-NH2. Right, a representative trace of ICa in the presence (●) and absence (○) of 100µM LR-NH2. (C) left, a summary of ICa inhibition by trypsin (815.5±104.9 pA for control; 428.0±54.1 pA for trypsin, n=5) and BT (906.6±115.7 pA for control, 863.1±125.6 pA for BT, n=5, p>0.05). Right a summary of ICa inhibition by SL-NH2 (902.5±111.6 pA for control, 506.1±58.8 pA for SL-NH2, n=5) or LR-NH2 (786.8±67.1 pA for control, 727.1±71.2 pA for LR-NH2, n=5, p>0.01).

Mentions: To determine the relationship between PAR-2 and N-type voltage-gated Ca2+ channels directly, we examined the effects of PAR-2 agonists on ICa using the conventional voltage-clamp method in dissociated SCG neurons. To measure ICa in rat SCG neurons, the current was evoked by 200 ms depolarizing step pulses to a test potential of 0 mV from a holding potential of -80 mV. The average membrane capacitance of the CG neurons was 30.6±0.3 pF (n=56). Fig. 5A shows a typical example of the effect of trypsin on the ICa in SCG neurons. Application of 30 nM trypsin diminished ICa by 45.5±1.7% in an irreversible manner (Fig. 5A and C). Likewise, 100µM SL-NH2 also decreased ICa by 43.6±2.2% in an irreversible (Fig. 5B and C). BT (30 nM) (Fig. 5A and C) did not affect the ICa (inhibition 5.6±1.9%). Similarly, 100µM LR-NH2 (Fig. 5B and C) did not affect ICa (inhibition 8.0±2.8%).


Suppression of peripheral sympathetic activity underlies protease-activated receptor 2-mediated hypotension.

Kim YH, Ahn DS, Joeng JH, Chung S - Korean J. Physiol. Pharmacol. (2014)

PAR-2 agonists inhibited ICa in rat SCG neurons (A) Left, a representative trace of ICa in the presence (●) and absence (○) of 30 nM typsin. Right, a representative trace of ICa in the presence (●) and absence (○) of 30 nM BT. (B) Left, a representative traces of ICa in the presence (●) and absence (○) of 100µM SL-NH2. Right, a representative trace of ICa in the presence (●) and absence (○) of 100µM LR-NH2. (C) left, a summary of ICa inhibition by trypsin (815.5±104.9 pA for control; 428.0±54.1 pA for trypsin, n=5) and BT (906.6±115.7 pA for control, 863.1±125.6 pA for BT, n=5, p>0.05). Right a summary of ICa inhibition by SL-NH2 (902.5±111.6 pA for control, 506.1±58.8 pA for SL-NH2, n=5) or LR-NH2 (786.8±67.1 pA for control, 727.1±71.2 pA for LR-NH2, n=5, p>0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4296038&req=5

Figure 5: PAR-2 agonists inhibited ICa in rat SCG neurons (A) Left, a representative trace of ICa in the presence (●) and absence (○) of 30 nM typsin. Right, a representative trace of ICa in the presence (●) and absence (○) of 30 nM BT. (B) Left, a representative traces of ICa in the presence (●) and absence (○) of 100µM SL-NH2. Right, a representative trace of ICa in the presence (●) and absence (○) of 100µM LR-NH2. (C) left, a summary of ICa inhibition by trypsin (815.5±104.9 pA for control; 428.0±54.1 pA for trypsin, n=5) and BT (906.6±115.7 pA for control, 863.1±125.6 pA for BT, n=5, p>0.05). Right a summary of ICa inhibition by SL-NH2 (902.5±111.6 pA for control, 506.1±58.8 pA for SL-NH2, n=5) or LR-NH2 (786.8±67.1 pA for control, 727.1±71.2 pA for LR-NH2, n=5, p>0.01).
Mentions: To determine the relationship between PAR-2 and N-type voltage-gated Ca2+ channels directly, we examined the effects of PAR-2 agonists on ICa using the conventional voltage-clamp method in dissociated SCG neurons. To measure ICa in rat SCG neurons, the current was evoked by 200 ms depolarizing step pulses to a test potential of 0 mV from a holding potential of -80 mV. The average membrane capacitance of the CG neurons was 30.6±0.3 pF (n=56). Fig. 5A shows a typical example of the effect of trypsin on the ICa in SCG neurons. Application of 30 nM trypsin diminished ICa by 45.5±1.7% in an irreversible manner (Fig. 5A and C). Likewise, 100µM SL-NH2 also decreased ICa by 43.6±2.2% in an irreversible (Fig. 5B and C). BT (30 nM) (Fig. 5A and C) did not affect the ICa (inhibition 5.6±1.9%). Similarly, 100µM LR-NH2 (Fig. 5B and C) did not affect ICa (inhibition 8.0±2.8%).

Bottom Line: In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA).Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ω-CgTx.These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of ICa-N which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Yonsei University College of Medicine, Seoul 120-752, Korea.

ABSTRACT
Protease-activated receptor (PAR)-2 is expressed in endothelial cells and vascular smooth muscle cells. It plays a crucial role in regulating blood pressure via the modulation of peripheral vascular tone. Although some reports have suggested involvement of a neurogenic mechanism in PAR-2-induced hypotension, the accurate mechanism remains to be elucidated. To examine this possibility, we investigated the effect of PAR-2 activation on smooth muscle contraction evoked by electrical field stimulation (EFS) in the superior mesenteric artery. In the present study, PAR-2 agonists suppressed neurogenic contractions evoked by EFS in endothelium-denuded superior mesenteric arterial strips but did not affect contraction elicited by the external application of noradrenaline (NA). However, thrombin, a potent PAR-1 agonist, had no effect on EFS-evoked contraction. Additionally, ω-conotoxin GVIA (CgTx), a selective N-type Ca(2+) channel (ICa-N) blocker, significantly inhibited EFS-evoked contraction, and this blockade almost completely occluded the suppression of EFS-evoked contraction by PAR-2 agonists. Finally, PAR-2 agonists suppressed the EFS-evoked overflow of NA in endothelium-denuded rat superior mesenteric arterial strips and this suppression was nearly completely occluded by ω-CgTx. These results suggest that activation of PAR-2 may suppress peripheral sympathetic outflow by modulating activity of ICa-N which are located in peripheral sympathetic nerve terminals, which results in PAR-2-induced hypotension.

No MeSH data available.


Related in: MedlinePlus