Effects Of Higenamine Research Articles

Effects of the Higenamine, a Potent Compound from Aconitum, on UVB-Induced Photoaging in Hairless Mice.

Aim Higenamine [1-[(4-hydroxyphenyl) methyl]-1, 2, 3, 4-tetrahydroisoquinoline-6, 7-diol], a potent cardiotonic compound from Aconitum, contributes to vascular relaxation and bronchodilation. However, the effects and mechanisms of action of higenamine on skin aging remain poorly understood. In this study, the effects of higenamine on UVB-induced photoaging were examined in the hairless mouse model. Methods The dorsal skin of hairless mice (CrlOri : SKH1) was exposed to chronic UVB irradiation (100–300 mJ/cm2 for 6 weeks), with subsequent administration of higenamine (1–20 mg/kg, p.o.) for 2 weeks. TGF-β, Smad3 DNA-binding phosphorylation, and COL1A1 levels were analyzed by immunohistochemistry, and histological analysis of the skin was performed via H&E and MT staining. Results Higenamine increased TGF-β, Smad3 DNA-binding phosphorylation, and COL1A1 expression in primary human fibroblast cells and mouse skin. Higenamine suppressed UVB-induced photoaging via skin recovery, improved epidermal thickness, and prevented Smad3, DNA-binding phosphorylation, and COL1A1 depletion via TGF-β signaling. Conclusion Higenamine enhances collagen production in the skin through TGF-β/Smad3 signaling and potentially suppresses UVB-induced skin aging.

Metabolomics coupled with integrated approaches reveal the therapeutic effects of higenamine combined with [6]-gingerol on doxorubicin-induced chronic heart failure in rats

BackgroundThis study was aimed to investigate the therapeutic effects and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX)—induced chronic heart failure (CHF) in rats.Materials and methodsTherapeutic effects of HG/[6]-GR on hemodynamics indices, serum biochemical indicators, histopathology and TUNEL staining of rats were assessed. Moreover, a UHPLC-Q-TOF/MS-based serum metabolic approach was performed to identify the metabolites and possible pathways of HG/[6]-GR on DOX-induced CHF.ResultsHG/[6]-GR had effects on regulating hemodynamic indices, alleviating serum biochemical indicators, improving the pathological characteristics of heart tissue and reducing the apoptosis of myocardial cells. Serum metabolisms analyses indicated that the therapeutic effects of HG and [6]-GR were mainly associated with the regulation of eight metabolites, including acetylphosphate, 3-Carboxy-1-hydroxypropylthiamine diphosphate, coenzyme A, palmitic acid, PE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, lysoPC(18:1(9Z)), and PC(16:0/16:0). Pathway analysis showed that HG/[6]-GR on CHF treatment was related to twelve pathways, including glycerophospholipid metabolism, fatty acid metabolism, pantothenate and CoA biosynthesis, citrate cycle (TCA cycle), pyruvate metabolism, and arachidonic acid metabolism. Serum metabolites and metabolic pathways regulated by HG/[6]-GR appear to be related to energy metabolism.ConclusionMultivariate statistical analysis has provided new insights for understanding CHF and investigating the therapeutic effects and mechanisms of HG/[6]-GR, which influencing the metabolites and pathways related to energy metabolism pathway.

Effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on platelet TXA 2 synthesis and aggregation

The effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on thromboxane A 2 (TXA 2) formation from arachidonic acid (AA) and aggregation in platelets, were investigated. YS-49 and YS-51 (IC 50; 32.8 and 39.4 μM respectively) exhibited much stronger inhibitory effects on TXA 2 formation than higenamine (IC 50; 2.99 mM). The higher inhibitory potencies of YS-49 and YS-51 (IC 50: 3.3 and 5.7 μM respectively) than higenamine (IC 50: 140 μM) on AA induced rat platelet aggregation was presumed to be the result of low inhibitory effect of higenamine than YS-49 and YS-51 on TXA 2 production from AA. Among the present three compounds, the more hydrophobic naphthylmethyl groups were supposed to be more favorable than p-hydroxybenzyl moiety, at 1-position of the tetrahydroisoquinoline ring, to display the inhibitory effects on TXA 2 production and AA induced aggregation of platelets. In addition, higenamine, YS-49 and YS-51 were observed directly antagonistic on TXA 2 receptor (TP receptors) by displaying inhibitory effects to U46619 (TXA 2 mimetic) induced platelet aggregation, however all of the three compounds showed similar order of inhibitory potencies. The present results are suggestive that YS-49 and YS-51 exert their inhibitory effects on AA-induced platelet aggregation partly by inhibiting the production of TXA 2 from AA and partly by directly blocking the TP receptor, in addition to the previously reported effects on α 2-adrenergic receptor. On the other hand, higenamine is supposed to antagonize AA-induced platelet aggregation by mostly directly blocking the TP receptor.

The effects of higenamine on LPS-induced experimental disseminated intravascular coagulation (DIC) in rats.

The effect of higenamine, a benzyl-tetrahydroisoquinoline alkaloid of the roots of Aconitum spp. (Ranunculaceae), on disseminated intravascular coagulation (DIC), was investigated using an experimental DIC rat model. The oral administration of higenamine (10 mg/kg or 50 mg/kg), significantly ameliorated the decrease of fibrinogen level in plasma, the increase of fibrinogen/fibrin degradation product (FDP) level, and the prolongation of prothrombin time (PT) induced by the i. v. infusion of lipopolysaccharide (LPS). The prolongation of activated partial thrombin time (aPTT) and the decrease of platelet count were suppressed. The increase in serum aspartate aminotransferase (AST) and blood urea nitrogen (BUN) were also significantly prevented with higenamine. The above results are suggestive that higenamine has therapeutic potential for DIC and/or accompanying multiple organ failure (MOF).

Counter Effects of Higenamine and Coryneine, Components of Aconite Root, on Acetylcholine Release from Motor Nerve Terminal in Mice

The counter effects of higenamine and coryneine, components of aconite root, on acetylcholine (ACh) release from motor nerve terminals in the mouse phrenic nerve–diaphragm muscle preparation were studied by a radioisotope method. Both nerve-evoked release and spontaneous release of [3H]-ACh from the preparation preloaded with [3H]-choline were measured. The change in the tetanic tension of muscle was simultaneously recorded in the same preparation. Higenamine (10 μM) augmented both the nerve-evoked and spontaneous ACh releases, and the muscle tension. The effects were inhibited by pretreatment with propranolol (10 μM), a β-adrenoceptor antagonist. Coryneine reduced the nerve-evoked release of ACh, accelerated the decay of tetanic tension (tetanic fade) at 30 μM, and it depressed the peak amplitude of tetanic tension at a higher concentration of 100 μM. These results suggest that of the two components contained in aconite root, higenamine increases ACh release via activation of β-adrenoceptor, and conversely coryneine depresses ACh release by preferentially acting at motor nerve terminal.

Effects of higenamine on the regulation of electrolyte transport in the guinea pig distal colonic mucosa

Effects of higenamine on the regulation of electrolyte transport in the guinea pig distal colonic mucosa

Effects of Higenamine on Regulation of Ion Transport in Guinea Pig Distal Colon

Effects of higenamine on Na+, K+ and Cl- transport were studied on stripped guinea pig distal colonic mucosa in vitro using Ussing chambers. Addition of 10(-5) M higenamine induced a biphasic change in short circuit current (Isc): a transient increase followed by a long-lasting decrease that was accompanied by an increase in transepithelial conductance (Gt). The initial phase with an increase in Isc was partially inhibited by serosal bumetanide and abolished by mucosal diphenylamine-2-carboxylate, a chloride channel blocker, indicating transient induction of Cl- secretion. The second phase with a decrease in Isc was composed of two effects: the inhibition of the amiloride-sensitive electrogenic Na+ absorption and the stimulation of the bumetanide-sensitive K+ secretion. However, the initial transient increase was not observed at the lower concentration of higenamine (10(-8)-10(-6) M). All the changes in Isc and Gt induced by higenamine were suppressed by the non-selective beta-adrenergic receptor antagonist propranolol and by the beta2-adrenergic receptor antagonist ICI-118,551, but not by the beta1-adrenergic-receptor-selective antagonist atenolol or by the alpha-antagonists phentolamine, prazosin and yohimbine. These results suggest that higenamine inhibits electrogenic Na+ absorption and stimulates electrogenic K+ and Cl- secretion through beta2-adrenergic receptors in guinea pig distal colon.

Inhibition of lipopolysaccharide-induced inducible nitric oxide (iNOS) mRNA expression and nitric oxide production by higenamine in murine peritoneal macrophages.

Nitric oxide synthesized by inducible nitric oxide synthase (iNOS) has been implicated as a mediator of inflammation in rheumatic and autoimmune diseases. The effects of higenamine, a tetrahydroisoquinoline compound, on induction of NOS by bacterial lipopolysaccharide (LPS) were examined in murine peritoneal macrophages. LPS-induced nitrite/nitrate production was markedly inhibited by higenamine which at 0.01 mM, decreased nitrite/nitrate levels by 48.7+/-4.4%. This was comparable to the inhibition of LPS-induced nitrite/nitrate production by tetrandrin (49.51+/-2.02%) at the same concentration. Northern and Western blot analysis of iNOS expression demonstrated that iNOS expression was significantly attenuated following co-incubation of peritoneal macrophages with LPS (10 microg/ml; 18 hrs) and higenamine (0.001, 0.01 mM; 18 hrs). These results suggest that higenamine can inhibit LPS-induced expression of iNOS mRNA in murine peritoneal macrophages. The clinical implications of these findings remain to be established.

Study on the mechanism for the positive inotropic effects of higenamine (II)

Study on the mechanism for the positive inotropic effects of higenamine (II)

Aconitine‐induced bradycardia, centrally acting muscarinic effects are inhibited peripherally by higenamine in conscious mice

AbstractThe effects of aconitine, higenamine and coryneine derived from processed aconite, a Sino‐Japanese medicine on pulse rate were examined in unanaesthetized mice. The intraperitoneal (i.p.) administration of the water extract (3 mg/kg) of processed aconite produced a bradycardia, like bigeminy, within 15 min which was prolonged for 30 min. Aconitine (30 μg/kg, i.p.) produced a similar bradycardia. Higenamine induced tachycardia at doses of 30 and 100 μg/kg, i.p. The aconitine‐induced bradycardia was antagonized completely by higenamine (10 μg/kg, i.p.), isoproterenol (1 μg/kg. s.c.), or scopolamine (10 μg/kg. s.c.). The anti‐aconitine effect of higenamine was prevented by propranolol (1 mg/kg, i.p.). Centrally administered aconitine (1 and 3μg) also induced bradycardia. The aconitine (i.c.v.)‐induced bradycardia was prevented by centrally administered atropine (1 μg, i.c.v.). These results demonstrated that aconitine (i.p.)‐induced bradycardia is mainly due to a central muscarinic action. As higenamine has a peripheral β1‐adrenergic action, like isoproterenol, the inhibition by higenamine of aconitine‐induced bradycardia is due to physiological antagonism.

Determination of blood concentration of higenamine by high pressure liquid chromatography

A procedure utilizing high pressure liquid chromatography coupled with UV detection is described for the determination of blood concentration of higenamine. Deproteinized serum was pretreated with C18 (Sep-pak C18 cartridge) and the 70% EtOH eluent was applied onto a reversed-phase column (μ Bondapak C18) with a 15% acetonitrile in 0.05 N NaH2 PO4-trichloroacetic acid mixed buffer (pH 2.8) as a mobile phase. With the UV detection at 232 nm, the retention times of higenamine and 1,2,3,4-tetrahydropapaveroline, an internal standard, were 5.2 min and 3.9 min respectively. The blood concentration of higenamine was measured at regular intervals afteri.v. injection of higenamine to rabbit. A drastic decrease in higenamine concentration to 30% of the maximum value obtained immediately after the injection, was observed during the first 1–2 min period and thereafter the rate of decrease was slowed down. The analytical result seemed to coincide with the pharmacological effect of higenamine exerting the maximum chronotropic and hypotensive effect at the completion of the injections which were progressively recovered.

Effect of higenamine on action potential of ventricular myocardial cells

Action potentials of isolated ventricular myocardial fibers of pigs and the electrophysiological actions of dl-demethylcoclaurine (DMC) or higenamine on the porcine myocardial cells were studied by glass microelectrodes. The action potentials of porcine ventricular myocardial fibers were similar to those of other mammalian hearts. Amplitude of the action potential was 115 +/- 9 mV, duration of action potential 242 +/- 30 ms, resting membrane potential -85 +/- 5 mV and the maximum rise of depolarization of action potential 151 +/- 27 V/s. After perfusion with normal Tyrode's solution containing DMC 5 micrograms/ml, the amplitude of action potential was increased and the duration of action potential was prolonged, the amplitude and duration of the plateau of action potential were increased and the slope of phase 2 of action potential was reduced (p less than 0.05). The resting potential, the slope of phase 3 and the maximum depolarization rate of phase 0 of action potential did not change. In Tyrode's solution containing Mn++ 3 mM, these electrophysiological actions of DMC disappeared. DMC may abolish the conduction block induced by K+-rich solution. In Tyrode's solution containing K+ 32 mM, the upstroke of action potential showed 2 phases under influence of DMC. The second phase disappeared when Mn++ was added. All findings indicate that DMC can be considered as an activator of the slow channel. The electrophysiological mechanism and clinical significance of DMC were discussed.