Potentiation by aminoethylisothiourea of the extra-cellular Ca2+ componentof norepinephrine-induced contraction in rat femoral arteries

Aminoethylisorhiourea (AET) is a potent inhibitor of inducible nitric oxide synthase (NOS). The present study was performed to investigate whether AET and its rearrangement products might modulate vascular contraction indepen dently of its effects as a NOS inhibitor in rat small femoral arteries. AET caused an endothelium-independent increase in contraction induced by norep inephrine (NE). This effect was not affected by either N-omega-nitro-L-argi nine methyl ester, nitro-L-arginine, indomethacin or propanolol, but it was suppressed in Ca2+-free medium. AET enhanced extracellular Ca2+ component of NE-induced contraction, and this effect was prevented by the receptor-me diated Ca2+ entry blocker, 1-{beta-[3-(p-methoxyphenyl)-propyloxy]-p-methox yphenetyl}-1H-imidazole hydrochloride (SK&F 96365), but not by the voltage- dependent Ca2+ channel blocker, nitrendipine, AET did not alter the respons e to CaCl2 in vessels exposed to KCl depolarization. The protein kinase C ( PKC) inhibitor, 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) (GF 109203X), prevented the potentiating effect of AET on the NE response. AET failed to produce an increase in tone in the presence of NE and GTP in perm eabilized arteries. Among the AET rearrangement products, mercaptoethylguan idine produced an endothelium-independent increase in the NE response. 2-am inothiazoline had no effect, and guanidinoethyldisulphide produced relaxati on. The effect of mercaptoethylguanidine was dependent on extracellular Ca and was prevented by GF 109203X. These results indicate that AET is able t o potentiate the contraction to NE in rat femoral resistance arteries indep endently of its inhibitory effect on either NOS or cyclo-oxygenase. Its eff ect occurs via an enhancement of SK&F 96365-sensitive Ca2+ entry. A PKC inh ibitor-sensitive mechanism also appears to be involved in the AET effect. M ercaptoethylguanidine potentiates NE response through a mechanism similar t o AET, (C) 2000 Elsevier Science Inc. All rights reserved.