1 7-[2-[4-(2-chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) produces tracheal relaxation, intracellular accumulation of cyclic nucleotides, inhibition of phosphodiesterases (PDEs) and activation of K þ channels. 2 KMUP-1 (0.01-100 mM) induced concentration-dependent relaxation responses in guinea-pig epithelium-intact trachea precontracted with carbachol. Relaxation responses were also elicited by the PDE inhibitors theophylline, 3-isobutyl-1-methylxanthine (IBMX), milrinone, rolipram and zaprinast (100 mM), and a K ATP channel opener, levcromakalim. 3 Tracheal relaxation induced by KMUP-1 was attenuated by epithelium removal and by pretreatment with inhibitors of soluble guanylate cyclase (sGC) (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 1 mM), nitric oxide synthase (N o -nitro-L-arginine methyl ester, 100 mM), K þ channels (tetraethylammonium, 10 mM), K ATP channels (glibenclamide, 1 mM), voltage-dependent K þ channels (4-aminopyridine, 100 mM) and Ca 2 þ -dependent K þ channels (charybdotoxin, 0.1 mM or apamin, 1 mM). 4 Both KMUP-1 (10 mM) and theophylline nonselectively and slightly inhibited the enzyme activity of PDE3, 4 and 5, suggesting that they are able to inhibit the metabolism of adenosine 3 0 ,5 0 -cyclic monophosphate (cyclic AMP) and guanosine 3 0 ,5 0 -cyclic monophosphate (cyclic GMP). Likewise, the effects of IBMX were also measured and its IC 50 values for PDE3, 4 and 5 were 6.571.2, 26.373.9 and 31.775.3 mM, respectively. 5 KMUP-1 (0.01-10 mM) augmented intracellular cyclic AMP and cyclic GMP levels in guinea-pig cultured tracheal smooth muscle cells. These increases in cyclic AMP and cyclic GMP were abolished in the presence of an adenylate cyclase inhibitor SQ 22536 (100 mM) and an sGC inhibitor ODQ (10 mM), respectively. 6 KMUP-1 (10 mM) increased the expression of protein kinase A (PKA RI ) and protein kinase G (PKG 1a1b ) in a time-dependent manner, but this was only significant for PKG after 9 h. 7 Intratracheal administration of tumour necrosis factor-a (TNF-a, 0.01 mg kg À1 ) induced bronchoconstriction and exhibited a time-dependent increase in lung resistance (R L ) and decrease in dynamic lung compliance (C dyn ). KMUP-1 (1.0 mg kg À1 ), injected intravenously for 10 min before the intratracheal TNF-a, reversed these changes in R L and C dyn . 8 These data indicate that KMUP-1 activates sGC, produces relaxation that was partly dependent on an intact epithelium, inhibits PDEs and increases intracellular cyclic AMP and cyclic GMP, which then increases PKA and PKG, leading to the opening of K þ channels and resulting tracheal relaxation.
1 KMUP-1 (1, 3, 5 mg kg 71 , i.v.), a xanthine derivative, produced dose-dependent sustained hypotensive and short-acting bradycardiac eects in anaesthetized rats. This hypotensive eect was inhibited by pretreatment with glibenclamide (5 mg kg 71 , i.v.). 2 In endothelium-intact or denuded aortic rings preconstricted with phenylephrine, KMUP-1 caused a concentration-dependent relaxation. This relaxation was reduced by endothelium removal, the presence of NOS inhibitor L-NAME (100 mM) and sGC inhibitors methylene blue (10 mM) and ODQ (1 mM). 3 The vasorelaxant eects of KMUP-1 was attenuated by pretreatment with various K + channel blockers TEA (10 mM), glibenclamide (1 mM), 4-AP (100 mM), apamin (1 mM) and charybdotoxin (ChTX, 0.1 mM). 4 Increased extracellular potassium levels (30 ± 80 mM) caused a concentration-related reduction of KMUP-1-induced vasorelaxations. Preincubation with KMUP-1 (1, 10, 100 nM) increased the AChinduced maximal vasorelaxations mediated by endogenous NO release, and enhanced the potency of exogenous NO-donor SNP. 5 The vasorelaxant responses of KMUP-1 (0.01, 0.05, 0.1 mM) together with a PDE inhibitor IBMX (0.5 mM) had an additive action. Additionally, KMUP-1 (100 mM) aected cyclic GMP metabolism since it inhibited the activity of PDE in human platelets. 6 KMUP-1 induced a dose-related increase in intracellular cyclic GMP levels in rat A10 vascular smooth muscle (VSM) cells, but not cyclic AMP. The increase in cyclic GMP content of KMUP-1 (0.1 ± 100 mM) was almost completely abolished in the presence of methylene blue (10 mM), ODQ (10 mM), and L-NAME (100 mM). 7 In conclusion, these results indicate that KMUP-1 possesses the following merits: (1) stimulation of NO/sGC/cyclic GMP pathway and subsequent elevation of cyclic GMP, (2) K + channels opening, and (3) inhibition of PDE or cyclic GMP breakdown. Increased cyclic GMP display a prominent role in KMUP-1-induced VSM relaxations.
1 In isolated endothelium-intact or denuded rabbit corpus cavernosum preconstricted with phenylephrine, KMUP-1 (0.001 ± 10 mM) caused a concentration-dependent relaxation. 2 This relaxation of KMUP-1 was attenuated by endothelium removed, high K + and pretreatments with a soluble guanylyl cyclase (sGC) inhibitor ODQ (1 mM), a NOS inhibitor L-NAME (100 mM), a K + channel blocker TEA (10 mM), a K ATP channel blocker glibenclamide (1 mM), a voltage-dependent K + channel blocker 4-AP (100 mM) and Ca 2+-dependent K + channel blockers apamin (1 mM) and charybdotoxin (ChTX, 0.1 mM). 3 The relaxant responses of KMUP-1 (0.01, 0.05, 0.1 mM) together with a PDE inhibitor IBMX (0.5 mM) had additive actions on rabbit corpus cavernosum smooth muscle (CCSM). 4 KMUP-1 (0.01 ± 10 mM) induced increase of intracellular cyclic GMP level in the primary cell culture of rabbit CCSM. This increase in cyclic GMP content was abolished in the presence of ODQ (10 mM). 5 Both KMUP-1 and sildena®l at 0.2, 0.4, 0.6 mg kg 71 caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. These in vivo activities of ICP for sildena®l and KMUP-1 are consistent with those of in vitro eects of cyclic GMP. 6 KMUP-1 has the following merits: (1) inhibition of PDE or cyclic GMP breakdown, (2) stimulation of NO/sGC/cyclic GMP pathway, and (3) subsequent stimulation of K + channels, in rabbit CCSM. We suggest that these merits play prominent roles in KMUP-1-induced CCSM relaxation-associated increases of ICP and penile erection.
Eugenosedin-A has been demonstrated to possess alpha/beta-adrenoceptor and serotonergic receptor blocking activities. We have investigated by what mechanisms eugenosedin-A prevents lipopolysaccharide (LPS)-induced hypotension, vascular hyporeactivity, hyperglycaemia, oxidative injury or inflammatory cytokines formation in rats. Intravenous administration of eugenosedin-A, trazodone, yohimbine (1 mg kg(-1)), aminoguanidine or ascorbic acid (15 mg kg(-1)) normalized LPS (10 mg kg(-1))-induced hypotension. Pretreatment with eugenosedin-A or the other agents 30 min before LPS injection reduced aortic hyporeactivity. LPS-induced increases in plasma interleukin-1beta (IL-beta), IL-6, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and blood glucose levels were significantly inhibited by eugenosedin-A (1 mg kg(-1), i. v.). The same dose of trazodone, a chloropiperazinylbenzene-type antidepressant, and yohimbine, an alpha(2)-adrenoceptor antagonist, reduced IL-1beta and TNF-alpha, but it could not inhibit hyperglycaemia. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, and ascorbic acid, an antioxidant, decreased IL-1beta, TNF-alpha contents and hyperglycaemia. Eugenosedin-A and the other agents inhibited Fe(2+)-ascorbic acid-induced peroxidation in rat cortex, indicating that those agents had antioxidant effects, with the exception of aminoguanidine. In free radical scavenged experiments, eugenosedin-A and ascorbic acid eliminated peroxyl radicals. All test agents inhibited the LPS-induced increase of malondialdehyde (MDA) content in rat brain homogenates. When mice were administered an intraperitoneal injection of LPS alone, mortality occurred from 4 to 16 h, after which time all were dead. However, eugenosedin-A significantly prolonged the survival time after LPS injection, suggesting that eugenosedin-A protected against LPS-induced cardiovascular dysfunction, hyperglycaemia, tissue injury and inflammatory cytokine production. This was attributable mainly to the antioxidant and peroxyl radical scavenged effects of eugenosedin-A, and which may be, at least in part, due to its blockade on alpha/beta-adrenergic and serotonergic receptors.
Eugenosedin-A is a newly synthesized compound with special serotonergic, α- and β1-adrenergic blocking actions. Intravenous injection of eugenosedin-A significantly caused dose-dependent decreases in the mean arterial blood pressure and heart rate in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The effects of eugenosedin-A-decreased blood pressure and heart rate in SHR were more potent than in WKY. In in vitro experiments, eugenosedin-A competitively antagonized the serotonin-, norepinephrine- and clonidine-induced vasocontraction in a concentration-dependent manner in isolated thoracic aorta of WKY and SHR. We also observed that eugenosedin-A competitively antagonized the isoproterenol-induced positive inotropic effects in a concentration-dependent manner in the isolated left atrium of WKY and SHR. These findings clearly suggested that eugenosedin-A possesses α1/α2, β1 and 5-HT2A receptor-blocking activities. The order of pA2 values in isolated tissues of WKY was 5-HT2A > α1/α2 > β1. However, the order of pA2 values in isolated tissues of SHR was α1/α2 >5-HT2A > β1. Similarly, we found that the in vitro functional activity of eugenosedin-A is quite different between WKY and SHR. On the other hand, in the isolated rabbit ear artery sensitized with 16 mmol/l K+, eugenosedin-A antagonized 5-nonyloxytryptamine- and serotonin-induced vasocontractions, indicating that it also blocked 5-HT1B and 5-HT2A receptors. In radioligand binding experiments, eugenosedin-A had significant binding affinities on α1/α2, β1, 5-HT1B and 5-HT2A receptors. Finally, we suggest that the hypotensive effects of eugenosedin-A can be attributed to its multiple actions on the blockade of 5-HT1B, 5-HT2A, α and β1 receptors in both WKY and SHR strains.
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