Specific augmentation of plantar skin blood flow by lipo-PGE1 assessed in tetrodotoxin- and N(G)-nitro-L-arginine-treated rats.

1Vasodilating effects of prostaglandin E1 incorporated in lipid microspheres (lipo-PGE1) were compared with those of prostaglandin E1 (PGE1) or its cyclodextrin clathrated preparation (PGE1-CD) on plantar skin blood flow in rats treated with tetrodotoxin and N(G)-nitro-L-arginine (L-NNA). Tetrodotoxin (50 microg/kg, i.v.) could totally inhibit the pressor response to electrical stimulation of the spinal cord, and the reflex tachycardia due to the depressor response to acetylcholine. Furthermore, L-NNA (30 mg/kg, i.v.) was used to counteract the lowering of the systemic blood pressure and peripheral vascular tone by elimination of sympathetic nerve activity, and to maintain the arterial blood pressure at the control level. Lipo-PGE1 increased plantar skin blood flow 4 to 6 times more potently than PGE1-CD or PGE1 in the treated rats. Furthermore, lipo-PGE1 increased plantar skin blood flow about 3 times more selectively than PGE1-CD. We also assessed several vasodilators, including terbutaline, nitroprusside, nicardipine, and papaverine in tetrodotoxin- and L-NNA-treated rats. However, none of them could selectively increase plantar blood flow despite the prominent depressor responses achieved. These results suggest that PGE1 preparations, especially lipo-PGE1 could potently and selectively increase plantar skin blood flow in rats treated with tetrodotoxin and L-NNA.

Glibenclamide-sensitive hypotension produced by helodermin assessed in the rat.

The effects of helodermin, a basic 35-amino acid peptide isolated from the venom of a lizard salivary gland, on arterial blood pressure and heart rate were examined in the rat, focusing on the possibility that activation of ATP sensitive K+ (K(ATP)) channels is involved in the responses. The results were also compared with those of vasoactive intestinal polypeptide (VIP). Helodermin produced hypotension in a dose-dependent manner with approximately similar potency and duration to VIP. Hypotension induced by both peptides was significantly attenuated by glibenclamide, which abolished a levcromakalim-produced decrease in arterial blood pressure. Oxyhemoglobin did not affect helodermin-induced hypotension, whereas it shortened the duration of acetylcholine (ACh)-produced hypotension. These findings suggest that helodermin-produced hypotension is partly attributable to the activation of glibenclamide-sensitive K+ channels (K(ATP) channels), which presumably exist on arterial smooth muscle cells. EDRF (endothelium-derived relaxing factor)/nitric oxide does not seem to play an important role in the peptide-produced hypotension.

Glibenclamide-sensitive mechanism is involved in helodermin-produced vasodilatation in rat mesenteric artery.

Helodermin-caused vascular relaxation was simultaneously measured with intracellular Ca2+ concentration ([Ca2+]i) in rat mesenteric artery. Helodermin caused concentration-dependent relaxation in the mesenteric artery preconstricted with norepinephrine (NE). Helodermin-caused relaxation was accompanied by decrease in [Ca2+]i, D-cis-Diltiazem, a Ca2+ channel blocker, also lowered the [Ca2+]i and tension increased by NE. However, helodermin relaxed the artery more efficiently than D-cis-diltiazem, suggesting that the peptide decreased myofilament Ca2+ sensitivity. The vascular relaxation and the corresponding decrease in [Ca2+]i induced by helodermin were partly, but significantly attenuated by glibenclamide. Helodermin-induced vascular responses were mimicked by vasoactive intestinal polypeptide (VIP) or forskolin. Furthermore, helodermin increased cAMP contents in the mesenteric artery. These findings show that vasodilatation induced by helodermin is attributable to lowered [Ca2+]i of arterial smooth muscle partly through the activation of glibenclamide-sensitive K+ channels, and to decrease in the myofilament Ca2+ sensitivity. The increase in the cellular cAMP content probably plays a key role in the peptide-induced vasorelaxation.