Pharmacological study on the mechanism underlying the development of NO-tolerance

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To attempt to clarify the possible role of superoxide on the mechanism underlying nitrate-tolerance, we examined this by a use of a nitrate-tolerance rabbit. This model was made by an application of transdermal glyceryl trinitrate (GTN) patches continuously for 10 days (GTN-treated rabbit). To examine the possible role of type 1 angiotensin II receptor (AT_1R) on this mechanism, AT_1R blocker valsartan (GTN+Valsartan-treated rabbit) or the antioxidant ascorbate (GTN+Ascorbate-treated rabbits) was co-administered with the NTG in some rabbits.1) In endothelium-denuded mesenteric resistant arteries, the relaxation ability of GTN, as well as the nitric oxide donor NOC-7, was significantly reduced in GTN-treated rabbits. In B-escin-skinned smooth muscles, the relaxing ability of 8-Br-cGMP was also downregulated in GTN-treated rabbits. Neither the conventional and/or novel PKCs inhibitor GF109203X (0.6 μM) nor a PKC activator phorbol 12,13-dibutyrate (PDBu, 0.1 μM) modified this downregulati … More on of cGMP-mediated relaxation seen in GTN-treated rabbits. These results suggest that the conventional and/or novel PKCs do not play a major role in the maintaining downregulation of cGMP-mediated relaxation in smooth muscle of mesenteric resistance arteries in GTN-treated rabbits.2) We examined to determine whether long-term in vivo administration of GTN downregulates the endothelium-dependent relaxation induced by acetylcholine (ACh) in rabbit intrapulmonary veins and, if so, whether the AT1R blocker valsartan normalizes this downregulation. In the rabbit intrapulmonary vein, ACh produces an endothelium-dependent relaxation mainly through an action mediated by endothelium-derived nitric oxide. The ACh-induced relaxation was downregulated and the production of superoxide by the endothelial cells was increased in GTN-treated rabbits, and these were normalized in GTN+Valsartan-treated rabbits. It is suggested that the increased superoxide in the endothelial cell through an action mediated by AT_1R contributes to the downregulation of the endothelium-dependent relaxation in rabbit pulmonary veins.3) We examined to determine whether long-term in vivo administration of GTN downregulates the hyperpolarization induced by ACh in rabbit aortic valve endothelial cells (AVECs) and, if so, whether antioxidant agents can normalize this downregulated hyperpolarization. In rabbit AVECs application of ACh produces a hyperpolarization due to co-activations of CTX-sensitive and apamin-sensitive K_<Ca> channels. The ACh-induced hyperpolarization is downregulated in GTN-treated rabbits and these are normalized when the antioxidant ascorbate was in vivo co-administered with the NTG (but not by its in vitro application). It is suggested that superoxide plays a pathophysiological role in the development and/or maintenance of the downregulation of ACh-induced hyperpolarization in AVECs in NTG-treated rabbits. Less