The study was aimed to examine the effects of three quaternary ammonium ions on both endothelial and exogenous nitric oxide (NO)-mediated relaxation in the rat aorta and to examine whether L-arginine could antagonize the inhibitory effects on endothelial NOdependent vascular responses. In endothelium-intact aortic rings, cyclopiazonic acid (CPA) induced relaxation with a pD2 of 6.40 ± 0.06. This relaxation was attenuated after treatment with tetrabutyalmmonium (TBA+ ), tetrapentylammonium (TPA+ ), or tetraoctylammonium (TOA+ ) ions, each at 3 µM or with NG-nitro-L-arginine methyl ester (L-NAME) at 100 µM. Larginine at 1 mM antagonized the inhibitory effect of TBA+ and L-NAME, but not of TPA+ and TOA+ . TPA+ and TOA+ , but not TBA+ , also inhibited endothelium-independent relaxation induced by a NO donor, hydroxylamine. The inhibitory effect of TPA+ was absent in 50 mM K+ -containing Krebs solution. These results indicate that (1) TBA+ inhibits endothelial NO-mediated relaxation probably through inhibition of NO production and/or release; (2) TPA+ -induced inhibition of endothelial and exogenous NO-dependent relaxation may be mediated through blockade of K+ channels in aortic smooth muscle; and (3) TOA+ may act on both endothelium and smooth muscle to inhibit NO-mediated vasorelaxant effect.

Many quaternary ammonium ions are pharmacological blockers of vascular K+ channels. NO was found to activate the vascular Ca2+-activated K+ channels. It is, therefore, possible that part of ammonium ions-induced effect on NO-dependent relaxation is mediated through inhibition of K+ channels on aortic smooth muscle cells. The inhibitory effect of TPA+ was lost in the aortic rings preconstricted by 50 mM K+. One of the principal effects of raising extracellular K+ concentration is to decrease the electrochemical gradient for K+ efflux, so that the influence of K+ channel activation by NO donors or inhibition by quaternary ammonium ions would have been blunted. These results indicate that TPA+ -induced inhibition of both endogenous and exogenous NO-mediated relaxation may be mediated via inhibition of K+ channels. However, TOA+ still attenuated NO donor-induced relaxation, indicating more complex actions on blood vessels. In summary, TBA+ , TPA+ , and TOA+ all reduced endothelial NO-mediated relaxation but via different mechanisms. TBA+ may act partly as an inhibitor of NO production in the endothelium and TPA+ may act as a putative blocker of cGMP-dependent K+ channels in vascular smooth muscle. Whilst, TOA+ acts in a more complex manner, which may target both endothelium and vascular smooth muscle leading to inhibition of NO-dependent aortic relaxation. In view of the complexity of the vascular actions, caution must be taken when employing quaternary ammonium ions even at their low concentrations as pharmacological tools in endothelium-intact blood vessels.

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