Signaling mechanisms for the selective vasoconstrictor effect of norbormide on the rat small arteries.
Norbormide (NRB) is a selective vasoconstrictor agent of the rat small vessels. The mechanisms underlying the selective vasoconstrictor effect of NRB are unknown. To investigate whether phospholipase C (PLC) signaling pathway plays a role in NRB-induced vasoconstriction, we performed experiments in NRB-contracted tissues, namely, rat caudal arteries (RCA) and smooth muscle cells derived from rat mesenteric arteries (MVSMCs). An NRB-insensitive vessel, namely rat aorta (RA), served as a control tissue. In RCA and RA we measured either isometric tension or formation of inositol phosphates (IPs), the latter taken as an index of PLC activation. In MVSMCs, we measured intracellular free calcium concentration ([Ca2+]cyt). In the presence of external Ca2+, NRB (2-50 microM) stimulated IPs formation in RCA but not in RA, and increased [Ca2+]cyt in MVSMCs. In the absence of external Ca2+, NRB (50 microM) increased IPs formation in RCA but was unable to increase [Ca2+]cyt in MVSMCs. In RCA, in the presence of external Ca2+, NRB-induced contraction was inhibited by calphostin C (0.2-1 microM), an inhibitor of protein kinase C (PKC), and by SK&F 96365 (30 microM), an inhibitor of the store-operated calcium channels, but was poorly affected by verapamil, an L-type calcium channel blocker. However, verapamil was much more effective when external Ca2+ was substituted by Sr2+. These results suggest that NRB elicits its tissue and species-selective vasoconstrictor effect by stimulating PLC-PKC pathway and increasing Ca2+ influx through both verapamil-sensitive and -insensitive calcium channels. Ca2+ release from sarcoplasmic reticulum seems not involved in NRB vasoconstriction.
Bova
S
S
Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy. bova@ux1.unipd.it
Trevisi
L
L
Cima
L
L
Luciani
S
S
Golovina
V
V
Cargnelli
G
G
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001158:Arteries / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009636:Norbornanes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013324:Strontium / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D007093:Imidazoles; D007295:Inositol Phosphates; D009281:Naphthalenes; D009636:Norbornanes; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014700:Verapamil; C058819:calphostin C; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; C005321:norbormide; D002118:Calcium; D013324:Strontium