• Journal of Ginseng Research
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• v.40 no.3
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• pp.285-291
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• 2016

Background: Ginsenosides have been shown to exert beneficial pharmacological effects on the central nervous, cardiovascular, and endocrine systems. We sought to determine whether total ginsenosides (TG) inhibit monocrotaline (MCT)-induced pulmonary hypertension and to elucidate the underlying mechanism. Methods: MCT-intoxicated rats were treated with gradient doses of TG, with or without $N^G$-nitro-$\small{L}$-arginine methyl ester. The levels of molecules involving the regulation of nitric oxide and mitogen-activated protein kinase pathways were determined. Results: TG ameliorated MCT-induced pulmonary hypertension in a dose-dependent manner, as assessed by the right ventricular systolic pressure, the right ventricular hypertrophy index, and pulmonary arterial remodeling. Furthermore, TG increased the levels of pulmonary nitric oxide, endothelial nitric oxide synthase, and cyclic guanosine monophosphate. Lastly, TG increased mitogen-activated protein kinase phosphatase-1 expression and promoted the dephosphorylation of extracellular signal-regulated protein kinases 1/2, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase 1/2. Conclusion: TG attenuates MCT-induced pulmonary hypertension, which may involve in part the regulation of nitric oxide and mitogen-activated protein kinase pathways.

• Korean Journal of Veterinary Research
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• v.44 no.3
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• pp.389-397
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• 2004

The therapeutic efficacy of xylamine in the field of psychological medicine has been recognized for years and the drug is used to treat depression and some other conditions, but little is known about its mechanism of action on vascular system. Therefore, the present study was designed to investigate the influence of xylamine on the contractile responses of isolated rat thoracic arteries to phenylephrine(PE) and potassium chloride(KCl). Xylamine produced a concentration-dependent relaxation in PE-precontracted endothelium intact(+E) rat aortic rings, but not in a KCl-precontracted aortic rings. Also, xylamine inhibited the PE-induced contraction in concentration-dependent manner, but not in the high KCl-induced contraction in +E rings. This concentration-dependent inhibition was suppressed by the removal of the endothelium (-E). The inhibitory effects of xylamine($0.3{\mu}M$) on the PE-induced contractions were suppressed by N(G)-nitro-L-arginine(L-NNA), N(omega)-nitro-L-arginine methyl ester(L-NAME), aminoguanidine, dexamethasone, methylene blue, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one(ODQ), indomethacin, ryanodine, tetrabutylammonium(TBA), lidocaine, procaine and 0 mM extracellular $Na^+$, but not by 2-nitro-4-carboxyphenyl-n,n-diphenylcarbamate(NCDC), lithium, nifedipine, verapamil, 0 mM extracellular $Ca^{2+}$, glibenclamide and clotrimazole. These findings suggest that xylamine could act as a vasorelaxant and direct inhibitor of arterial contraction. This vasorelaxation involves an endothelial nitric oxide (NO)/cGMP (guanosine 3',5'-cyclic monophosphate) pathway or cyclooxygenase system, and an interference with $Ca^{2+}$ release, TBA-sensitive $Ca^{2+}$-activated $K^+$ channels and $Na^+$$ channels.

• The Korean Journal of Pain
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• v.20 no.1
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• pp.21-25
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• 2007

Background: Intrathecal sildenafil has produced antinociception by increasing the cGMP through inhibition of phosphodiesterase 5. Spinal opioid receptor has been reported to be involved in the modulation of nociceptive transmission. The aim of this study was to examine the role of opioid receptor in the effect of sildenafil on the nociception evoked by formalin injection. Methods: Rats were implanted with lumbar intrathecal catheters. Formalin testing was used as a nociceptive model. Formalin-induced nociceptive behavior (flinching response) was observed. To clarify the role of the opioid receptor for the analgesic action of sildenafil, naloxone was administered intrathecally 10 min before sildenafil delivery, and formalin was then injected 10 min later. Results: Intrathecal sildenafil produced dose-dependent suppression of flinches in both phases during the formalin test. Intrathecal naloxone reversed the analgesic effect of sildenafil in both phases. Conclusions: Sildenafil is active against the nociceptive state that's evoked by a formalin stimulus, and the opioid receptor is involved in the analgesic action of sildenafil at thespinal level.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.5
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• pp.273-277
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• 2011

Nitric oxide (NO) and atrial natriuretic peptide (ANP) may induce vascular relaxation by increasing the production of cyclic guanosine monophosphate (cGMP), an important mediator of vascular tone during sepsis. This study aimed to determine whether regulation of NO and the ANP system is altered in lipopolysaccharide (LPS)-induced kidney injury. LPS (10 $mg{\cdot}kg^{-1}$) was injected in the tail veins of male Sprague-Dawley rats; 12 hours later, the kidneys were removed. Protein expression of NO synthase (NOS) and neutral endopeptidase (NEP) was determined by semiquantitative immuno-blotting. As an index of synthesis of NO, its stable metabolites (nitrite/nitrate, NOx) were measured using colorimetric assays. mRNA expression of the ANP system was determined by real-time polymerase chain reaction. To determine the activity of guanylyl cyclase (GC), the amount of cGMP generated in response to sodium nitroprusside (SNP) and ANP was calculated. Creatinine clearance decreased and fractional excretion of sodium increased in LPS-treated rats compared with the controls. Inducible NOS protein expression increased in LPS-treated rats, while that of endothelial NOS, neuronal NOS, and NEP remained unchanged. Additionally, urinary and plasma NOx levels increased in LPS-treated rats. SNP-stimulated GC activity remained unchanged in the glomerulus and papilla in the LPS-treated rats. mRNA expression of natriuretic peptide receptor (NPR)-C decreased in LPS-treated rats, while that of ANP and NPR-A did not change. ANP-stimulated GC activity reduced in the glomerulus and papilla. In conclusion, enhancement of the NO/cGMP pathway and decrease in ANP clearance were found play a role in the pathogenesis of LPS-induced kidney injury.

• Integrative Medicine Research
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• v.6 no.2
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• pp.149-155
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• 2017

Background: Naringenin (NRG) is a common dietary polyphenolic constituent of fruits. NRG has diverse pharmacological activities, and is used in traditional medicine to treat various diseases including gastrointestinal (GI) disorders. Interstitial cells of Cajal (ICCs) are pacemaker cells of the GI tract. In this study, the authors investigated the effects of NRG on ICCs and on GI motility in vitro and in vivo. Methods: ICCs were dissociated from mouse small intestines by enzymatic digestion. The whole-cell patch clamp configuration was used to record pacemaker potentials in cultured ICC clusters. The effects of NRG on GI motility were investigated by calculating percent intestinal transit rates (ITR) using Evans blue in normal mice. Results: NRG inhibited ICC pacemaker potentials in a dose-dependent manner. In the presence of tetraethylammonium chloride or iberiotoxin, NRG had no effect on pacemaker potentials, but it continued to block pacemaker potentials in the presence of glibenclamide. Preincubation with SQ-22536 had no effect on pacemaker potentials or on their inhibition by NRG. However, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one blocked pacemaker potential inhibition by NRG. In addition, L-NG-nitroarginine methyl ester blocked pacemaker potential inhibition by NRG. Furthermore, NRG significantly suppressed murine ITR enhancement by neostigmine in vivo. Conclusion: This study shows NRG dose-dependently inhibits ICC pacemaker potentials via a cyclic guanosine monophosphate/nitric oxide-dependent pathway and $Ca^{2+}$-activated $K^+$ channels in vitro. In addition, NRG suppressed neostigmine enhancement of ITR in vivo.

• Journal of Applied Biological Chemistry
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• v.62 no.3
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• pp.305-313
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• 2019

Men's climactic syndrome, andropause, or testosterone deficit syndrome, is one of the new problems with the health of older men in the age of aging. This phenomenon is a natural phenomenon occurring in men as they age, clinically characterized by a decrease in blood testosterone levels and a marked decrease in physical and mental activity. The purpose of this study was to investigate the effect of hydrothermal extract of Taraxacum coreanum by comparing the levels of nitric oxide (NO) in the cavernosum and the levels of male hormone in the blood. Taraxacum coreanum extract increased NO production in vitro and in vivo in a dose-dependent manner. Levels of dihydrotestosterone and 17-hydroxyysteroid dehydrogenases, as well as levels of neurogenic nitric oxide synthase and cGMP, increased significantly in elderly rats (22 weeks) after 4 weeks of daily intake of Taraxacum coreanum extract. However, prostaglandin $E_2$, testosterone, and sexually-hormone-binding globulin levels were not different among all groups. Furthermore, total sperm and motile sperm counts were also no significant difference. Overall, these results suggest the possibility of Taraxacum coreanum extract as a safe and effective natural substance for enhancing NO, cGMP and free testosterone.

• Journal of Animal Science and Technology
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• v.62 no.6
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• pp.765-776
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• 2020

The retinal degenerative disease, progressive retinal atrophy (PRA) is a major reason of vision impairment in canine population. Canine PRA signifies an inherently dissimilar category of retinal dystrophies which has solid resemblances to human retinis pigmentosa. Even though much is known about the biology of PRA, the knowledge about the intricate connection among genetic loci, genes and pathways associated to this disease in dogs are still remain unknown. Therefore, we have performed a genome wide association study (GWAS) to identify susceptibility single nucleotide polymorphisms (SNPs) of PRA. The GWAS was performed using a case-control based association analysis method on PRA dataset of 129 dogs and 135,553 markers. Further, the gene-set and pathway analysis were conducted in this study. A total of 1,114 markers associations with PRA trait at p < 0.01 were extracted and mapped to 640 unique genes, and then selected significant (p < 0.05) enriched 35 gene ontology (GO) terms and 5 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways contain these genes. In particular, apoptosis process, homophilic cell adhesion, calcium ion binding, and endoplasmic reticulum GO terms as well as pathways related to focal adhesion, cyclic guanosine monophosphate)-protein kinase G signaling, and axon guidance were more likely associated to the PRA disease in dogs. These data could provide new insight for further research on identification of potential genes and causative pathways for PRA in dogs.

• Journal of Pharmacopuncture
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• v.27 no.2
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• pp.82-90
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• 2024

Objectives: Nitric oxide is the most important mediator of penile erection after the onset of sexual excitement. It activates cyclic guanosine monophosphate (cGMP), increasing penile blood flow. Most pharmaceutical medications prevent enzyme phosphodiesterase type 5 (PDE-5) from breaking down cGMP, thus keeping its level high. However, due to the adverse effects of pharmacological therapies, herbal drugs that improve sexual function have gained attention recently. This study aimed to investigate the combined effects of ginseng, Tribulus terrestris, and L-arginine amino acid on the sexual performance of individuals with erectile dysfunction (ED) using the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Methods: Over three months, 98 men with erectile dysfunction were randomly assigned to receive either 500 mg of herbal supplements or placebo pills. Each herbal tablet contained 100 mg of protodioscin, 35 mg of ginsenosides, and 250 mg of L-arginine. Results: The results showed that the changes in the average scores of ILEF-5 within each group before and after the intervention indicated that all parameters related to the improvement of sexual function in patients with erectile dysfunction improved in the herbal treatment group (p < 0.001). The herbal group significantly improved IIEF-5 scores in nondiabetics (p < 0.05). However, there was no significant difference in the changes of IIEF-5 scores between the two intervention and control groups in diabetic patients. Conclusion: In conclusion, ginseng, Tribulus terrestris, and L-arginine have properties that increase energy and strengthen sexual function, making them suitable for patients with sexual disorders.

• The Korean Journal of Physiology
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• v.28 no.2
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• pp.181-190
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• 1994

Endothelium-derived relaxing factor (EDRF) activates guanylate cyclase which mediates the formation of cGMP from GTP in vascular smooth muscle. It is well known that endothelium-dependent relaxation is impaired in spontaneously hypertensive rats (SHR). However, it is still unknown whether the impaired endothelium-dependent relaxation in SHR results from the reduced release of EDRF or from the decrease of vascular response to EDRF. We investigated the effects of cGMP on the contractility and Ca movement in the aorta of SHR and Wistar-Kyoto rats (WKY). The amplitude of the endothelium-dependent relaxation to actylcholine (ACh) was significantly less in SHR than in WKY. L-arginine $(10^{-3}M)$ did not increase endothelium-dependent relaxation in both strains. Sodium nitroprusside (SNP), an activator of guanylate cyclase, relaxed the 40 mM $K^+-induced$ contraction in a dose-dependent manner $(10^{-10}{\sim}10^{-6}\;M)$ in the endothelium-rubbed aortic strips of both strains. However, there was no significant difference in these relaxations between WKY and SHR. 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP), a cell membrane-permeable derivative of cGMP relaxed the 40 mM $K^+-induced$ contraction in a dose-dependent manner $(10^{-6}{\sim}10^{-4}\;M)$ in the endothelium-rubbed aortic strips of both strains. Also norepinephrine $(10^{-6}\;M)-induced$ contractions in normal and Ca-free Tyrode's solution were suppressed by the pretreatment with 8-Br-cGMP $(10^{-4}\;M)$ in either strain. However, the amplitudes of suppression induced by 8-Br-cGMP were greater in SHR than that in WKY. Basal $^{45}Ca$ uptake and 40mM $K^+-stimulated\;^{45}Ca$ uptake were not suppressed by pretreatment with 8-Br-cGMP $(10^{-4}\;M)$ in single aortic smooth muscle cells of both SHR and WKY. From the above results, it is suggested that cGMP decreases Ca sensitivity in vascular smooth muscle cells and that the impaired endothelium-dependent relaxation in the aortic strips of SHR is not the result of a reduced vascular response to EDRF.

• Journal of Society of Preventive Korean Medicine
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• v.22 no.1
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• pp.107-127
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• 2018

Objectives : The present study investigated the anti-obese and blood flow improvement activities of aqueous extracts of ginseng berry (GBe) on the mild diabetic obese mice as compared with metformin. Methods : After end of 56 days of continuous oral administrations of GBe 150, 100 and 50 mg/kg, or metformin 250 mg/kg, anti-obese and blood flow improvement effects - the changes of body weights, body and abdominal fat density by in live dual-energy x-ray absorptionmetry (DEXA), tail bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) levels, aorta and serum cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and endothelin (ET)-1 levels, aorta phosphorylated PI3K (pPI3K), phosphorylated Akt (pAkt) and phosphorylated p38 MAPK (pp38 MAPK) levels were systemically analyzed. In addition, aorta vascular dilation and constriction related gene mRNA expressions - PI3K, Akt, eNOS, p38 MAPK and ET-1 were also analyzed by realtime RT-PCR. Results : The obesity and related blood flow impairment, induced by 84 days of continuous HFD supply, were significantly inhibited by 56 days of continuous oral treatment of GBe 150, 100 and 50mg/kg, dose-dependently, and they also dramatically normalized the changes of the aorta vascular dilation and constriction related gene mRNA expressions, also dose-dependently. Especially, GBe 150 mg/kg constantly showed favorable inhibitory activities against type II diabetes related obesity and vascular disorders through PI3K/Akt pathway and p38 MAPK mediated cGMP, NO and ET-1 expression modulatory activities, as comparable to those of metformin 250 mg/kg in HFD mice. Conclusion : By assessing the key parameters for anti-obese and blood flow improvement activities on the HFD-induced mild diabetic obese mice, the present work demonstrated that GBe 150, 100 and 50 mg/kg showed favorable anti-obese and blood flow improvement effects in HFD-induced type II diabetic mice, through PI3K/Akt pathway and p38 MAPK mediated cGMP, NO and ET-1 expression modulatory activities.