seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide and Hypotension

The protease-activated receptor (PAR)-2 is highly 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 several mechanisms have been suggested to explain PAR-2-induced hypotension, the precise mechanism remains to be elucidated. To investigate this possibility, we investigated the effects of PAR-2 activation on N-type Ca(2+) currents (I(Ca-N)) in isolated neurons of the celiac ganglion (CG), which is involved in the sympathetic regulation of mesenteric artery vascular tone. PAR-2 agonists irreversibly diminished voltage-gated Ca(2+) currents (I(Ca)), measured using the patch-clamp method, in rat CG neurons, whereas thrombin had little effect on I(Ca). This PAR-2-induced inhibition was almost completely prevented by ω-CgTx, a potent N-type Ca(2+) channel blocker, suggesting the involvement of N-type Ca(2+) channels in PAR-2-induced inhibition. In addition, PAR-2 agonists inhibited I(Ca-N) in a voltage-independent manner in rat CG neurons. Moreover, PAR-2 agonists reduced action potential (AP) firing frequency as measured using the current-clamp method in rat CG neurons. This inhibition of AP firing induced by PAR-2 agonists was almost completely prevented by ω-CgTx, indicating that PAR-2 activation may regulate the membrane excitability of peripheral sympathetic neurons through modulation of N-type Ca(2+) channels. In conclusion, the present findings demonstrate that the activation of PAR-2 suppresses peripheral sympathetic outflow by modulating N-type Ca(2+) channel activity, which appears to be involved in PAR-2-induced hypotension, in peripheral sympathetic nerve terminals.

Topics: Action Potentials; Animals; Calcium Channels, N-Type; Ganglia, Sympathetic; Hypotension; Male; Mesenteric Arteries; Neurons; Oligopeptides; Rats; Rats, Sprague-Dawley; Receptor, PAR-2

1. Agonists for protease-activated receptor-2 (PAR-2) cause hypotension and an increase in gastric mucosal blood flow (GMBF) in vivo. We thus studied the mechanisms underlying the circulatory modulation by PAR-2 activation in vivo, especially with respect to involvement of endothelium-derived hyperpolarizing factor (EDHF). 2. Arterial blood pressure and GMBF were measured in anesthetized rats in vivo. Vascular relaxation was assessed in the precontracted rat gastric arterial rings in vitro. 3. The PAR-2-activating peptide SLIGRL-NH2 and/or trypsin, administered i.v., produced largely NO-independent hypotension and increase in GMBF accompanied by decreased gastric mucosal vascular resistance (GMVR) in rats. 4. Combined administration of apamin and charybdotoxin, but not each of them, specifically abolished the hypotension, increased GMBF and decreased GMVR caused by the PAR-2 agonists. 5. In the isolated rat gastric artery, SLIGRL-NH2 elicited endothelium-dependent relaxation even in the presence of an NO synthase inhibitor and indomethacin, which was abolished by apamin plus charybdotoxin. 6. Our data suggest involvement of apamin/charybdotoxin-sensitive K+ channels in the PAR-2-triggered hypotension and increased GMBF, predicting a role of EDHF-like factors.

Topics: Anesthesia; Animals; Apamin; Biological Factors; Blood Pressure; Charybdotoxin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gastric Mucosa; Hypotension; Male; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oligopeptides; Rats; Rats, Wistar; Receptor, PAR-2; Regional Blood Flow; Trypsin; Vascular Resistance