• Journal of Physiology & Pathology in Korean Medicine
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• v.21 no.5
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• pp.1271-1277
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• 2007

This study was designed to investigate the effects of Sagunja-tang Extract & Zingiberis rhizoma recens Juice (SEZJ) and Zingiberis rhizoma recens Juice (ZRJ) on the changes in regional cerebral blood flow (rCBF) and mean arterial blood pressure (MABP) in normal rats. The results were as follows ; SEZJ and ZRJ significantly increased rCBF in a dose-dependent manner, while it did not change MABP. This results suggest that SEZJ and ZRJ significantly increased rCBF by dilating pial arterial diameter. Increase of SEZJ-induced rCBF was significantly inhibited by pretreatment with methylene blue (10 ${\mu}g/kg$, i.p.), an inhibitor of guanylate cyclase, and indomethacin (1 mg/kg, i.p.), an inhibitor of cyclooxygenase. SEZJ-induced MABP was significantly increased by pretreatment with indomethacin but was not changed by methylene blue. These results suggested that the action of SEZJ was mediated by cyclic 3',5'-guanosine monophosphate.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.6
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• pp.337-341
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• 2006

The present study was designed to investigate the protein expression of nitric oxide synthase (NOS) and guanylyl cyclase (GC) activity in ischemia/perfusion (I/R) renal injury in rats. Renal I/R injury was experimentally induced by clamping the both renal pedicle for 40 min in Sprague-Dawley male rats. The renal expression of NOS isoforms was determined by Western blot analysis, and the activity of guanylyl cyclase was determined by the amount of guanosine 3', 5'-cyclic monophosphate (cGMP) formed in response to sodium nitroprusside (SNP), NO donor. I/R injury resulted in renal failure associated with decreased urine osmolality. The expression of inducible NOS (iNOS) was increased in I/R injury rats compared with controls, while endothelial NOS (eNOS) and neuronal NOS (nNOS) expression was decreased. The urinary excretion of NO metabolites was decreased in I/R injury rats. The cGMP production provoked by SNP was decreased in the papilla, but not in glomerulus. These results indicate an altered regulation of NOS expression and guanylyl cyclase activity in I/R-induced nephropathy.

• Archives of Pharmacal Research
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• v.26 no.8
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• pp.612-619
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• 2003

In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.

• Korean Journal of Veterinary Research
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• v.40 no.4
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• pp.691-699
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• 2000

We investigated the effects of nitric oxide (NO) donors, S-nitroso-L-cysteine (Cys-NO) and 3-morpholinosydnonimine hydrochloride (SIN-1), on the contractile and electrical activity of the circular muscle of guinea pig gastric antrum by using intracellular microelectrode technique. The gastric antral circular muscle showed spontaneous phasic contraction and slow wave of membrane potential. Cys-NO ($0.001{\sim}10{\mu}M$) and SIN-1 ($0.001{\sim}100{\mu}M$) reduced not only the tonic and phasic contraction but also the amplitude of slow wave in a concentration dependent manner. NO donors were more potent to inhibit phasic contraction than to do slow wave. These inhibitory effects of NO donors were mimicked by the membrane permeable guanosine-3',5'-cyclic monophosphate (cGMP) analogue, 8-bromo-cyclic GMP (8-br-cGMP, $10{\sim}300{\mu}M$). The inhibitory effects of SIN-1 and Cys-NO were antagonized by the guanylate cyclase inhibitor, 1H[ [1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, $10{\mu}M$). These results suggest that the inhibitory effects of NO donors on the mechanical and electrical activity is mainly mediated by cGMP pathway.

• Journal of Ginseng Research
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• v.39 no.2
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• pp.169-177
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• 2015

Background: Ginsenoside Rd (GSRd), one of the most abundant ingredients of Panax ginseng, protects the heart via multiple mechanisms including the inhibition of $Ca^{2+}$ influx.We intended to explore the effects of GSRd on L-type $Ca^{2+}$ current ($I_{Ca,L}$) and define the mechanism of the suppression of $I_{Ca,L}$ by GSRd. Methods: Perforated-patch recording and whole-cell voltage clamp techniques were applied in isolated rat ventricular myocytes. Results: (1) GSRd reduced $I_{Ca,L}$ peak amplitude in a concentration-dependent manner [half-maximal inhibitory concentration $(IC_{50})=32.4{\pm}7.1{\mu}mol/L$] and up-shifted the current-voltage (I-V) curve. (2) GSRd ($30{\mu}mol/L$) significantly changed the steady-state activation curve of $I_{Ca,L}$ ($V_{0.5}:-19.12{\pm}0.68$ vs. $-6.26{\pm}0.38mV$; n = 5, p < 0.05) and slowed down the recovery of $I_{Ca,L}$ from inactivation [the time content (${\zeta}$) from 91 ms to 136 ms, n = 5, p < 0.01]. (3) A more significant inhibitive effect of GSRd ($100{\mu}mol/L$) was identified in perforated-patch recording when compared with whole-cell recording [$65.7{\pm}3.2%$ (n = 10) vs. $31.4{\pm}5.2%$ (n = 5), p < 0.01]. (4) Pertussis toxin ($G_i$ protein inhibitor) completely abolished the $I_{Ca,L}$ inhibition induced by GSRd. There was a significant difference in inhibition potency between the two cyclic adenosine monophosphate elevating agents (isoprenaline and forskolin) prestimulation [$55{\pm}7.8%$ (n = 5) vs. $17.2{\pm}3.5%$ (n = 5), p < 0.01]. (5) 1H-[1,2,4]Oxadiazolo[4,3-a]-quinoxalin-1-one (a guanylate cyclase inhibitor) and N-acetyl-$\small{L}$-cysteine (a nitric oxide scavenger) partly recovered the $I_{Ca,L}$ inhibition induced by GSRd. (6) Phorbol-12-myristate-13-acetate (a protein kinase C activator) and GF109203X (a protein kinase C inhibitor) did not contribute to the inhibition of GSRd. Conclusion: These findings suggest that GSRd could inhibit $I_{Ca,L}$ through pertussis toxin-sensitive G protein ($G_i$) and a nitric oxide-cyclic guanosine monophosphate-dependent mechanism.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.99-106
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• 2005

Background: Cyclic guanosine monophosphate (cGMP) and opioid receptors are involved in the modulation of nociception. Although the opioid receptors agonists are active in pain, the effect of an phospodiesterase inhibitor (zaprinast) for increasing the level of cGMP has not been thoroughly investigated at the spinal level. This study examined the effects of intrathecal zaprinast and morphine in a nociceptive test and we also examined the nature of the pharmacological interaction after the coadministration of zaprinast with morphine. The role of the nitric oxide (NO)-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution was applied to the hindpaw. Isobolographic analysis was used for the evaluation of the drug interaction between zaprinast and morphine. Furthermore, NO synthase inhibitor ($_L-NMMA$), guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide) were intrathecally administered to verify the involvement of the NO-cGMP- potassium channel pathway on the antinociception effect of zaprinast. Results: Both zaprinast and morphine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after the intrathecal administration of the zaprinast-morphine mixture in both phases. Intrathecal $_L-NMMA$, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase. Conclusions: These results suggest that zaprinast, morphine and the mixture of the two drugs are effective against acute pain and they facilitated pain state at the spinal level. Thus, the spinal combination of zaprinast with morphine may be useful for the management of pain. However, the NO-sensitive cGMP-potassium channel pathway did not contribute to the antinocieptive mechanism of zaprinast in the spinal cord.

• Journal of Microbiology and Biotechnology
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• v.17 no.7
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• pp.1134-1138
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• 2007

Cordycepin (3'-deoxyadenosine) is an adenosine analog, isolated from Cordyceps militaris, and it has been used as an anticancer and anti-inflammation ingredient in traditional Chinese medicine. We investigated the effects of cordycepin (3'-deoxyadenosine) on human platelet aggregation, which was induced by thapsigargin, a tumor promoter, and determined the cytosolic free $Ca^{2+}$ levels ($[Ca^{2+}]_i$) (an aggregation-stimulating molecule) and cyclic-guanosine monophosphate (cGMP) (an aggregation-inhibiting molecule). Cordycepin inhibited thapsigargin-induced platelet aggregation in a dose-dependent manner, and it clearly reduced the levels of $[Ca^{2+}]_i$, which was increased by thapsigargin ($1\;{\mu}M$) or U46619 ($3\;{\mu}M$). Cordycepin also increased the thapsigargin-reduced cGMP levels. Accordingly, our data demonstrated that cordycepin may have a beneficial effect on platelet aggregation-mediated thrombotic diseases through the $[Ca^{2+}]_i$-regulating system such as cGMP.

• YAKHAK HOEJI
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• v.41 no.3
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• pp.370-380
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• 1997

The role of nitric oxide (NO) on the non-adrenergic non-cholinergic (NANC) relaxations induced by the short and prolonged electrical field stimulation (EFS) has been studied in the rabbit corpus cavernosum. In the presence of atropine and guanethidine the prolonged EFS (2-16 Hz) of corpus cavernosal strips precontracted with phenylephrine produced frequency-dependent relaxations, which were abolished by tetrodotoxin as shown in the relaxations induced gy the short EFS, indicating that their orgin is NANC nerve stimulation. $N^G$-nitro-L-arginine (L-NNA), inhibitor of nitirc oxide synthase, caused a concentration-dependent inhibition to the NANC relaxation, and at 100 M L-NNA the relaxation were virtually abolished. The inhibitory effect of L-NNA was reversed by L-arginine. Hemoglobin abolished the relaxations to NO and also caused a concentration-dependent inhibition of the NANC relaxation. The hemoglobin-resistant relaxation induced by EFS was eliminated by L-NNA. Methylene blue significantly reduced the NANC relaxation in a conentration-dependent manner. The NANC relaxation was not affected by a VIP-inactivating pepridase, alpha0chymotrypsin, whereas VIP-induced relaxation was completely abolished. NO- and VIP-induced relaxation were not affected by L-NNA. These results indicate that the NANC relaxation induced by prolonged EFS of the rabbit corpus cavernosum is mediated by NO-guanosine 3',5'-cyclic monophosphate pathway as shown in the relaxation induced by the short EFS, and that VIP release is not essential for the NANC relaxation of the rabbit corpus cavernosum and VIP is not involved the generation fo NO.

• Proceedings of the Ginseng society Conference
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• 1993.09a
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• pp.40-48
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• 1993

Intravenous administration of saponin extracted from the root of Panax ginseng lowered the blood pressure dose-dependently (10-200 mg/kg, B.W) in anesthetized rats. Therefore, experiments were designed to study the hypothesis that the lowering of blood pressure is associated with the release of endothelium-derived relaxing factor and the accumulation of guanosine 3, 5-cyclic monophosphate (cGMP). Rings of thoracic aorta with and without endothelium were suspended for the measurement of isometric tension in organ chamber and the tissue content of cGMP was measured by radioimmunoassay. All experiments were performed in the presence of $indomethacin(10^{-5}M).$ Ginseng saponin $(10^{-5}-3{\times}10^{-6}g/ml)$ relaxed contractions induced by phenylephrine $10^{-6}M)$ in the aorta with endothelium but not in that without endothelium. Treatment of aortic rings with $N^G$ monomethyl-L-arginine (L-NMMA, $10^{-4}M$ for 30 min), a competitive inhibitor of nitric oxide synthase, and methylene blue $(MB,\;3{\times}10^{-7}M$ for 30 min). an inhibitor of soluble guanylate cyclase, diminished the relaxation induced by Ginseng saponin. Ginseng saponin $10^{-4}g/ml$ for 2 min) increased the accumulation of cGMP in rings with endothelium. L-NMMA and MB inhibited the accumulation of cGMP induced by Ginseng saponin. These data suggest that vascular relaxations induced by Ginseng saponin are mediated by release of endothelium-derived relaxing factor and the accumulation of cGMP. The effect of Ginseng saponin on endothelial function in hypercholesterolemic rabbits was examined. In hypercholesterolemic rabbits fed with $2\%$ cholesterol for 8 weeks, relaxation of aortic rings to acetylcholine was impaired. The impaired relaxations of aortic rings in hypercholesterolemic rabbits were improved by dietary supplementation of Ginseng saponin, probably because of an improved release of endothelium - derived relaxing factor.

• Korean Journal of Veterinary Research
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• v.45 no.4
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• pp.507-515
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• 2005

Melatonin, the principal hormone of the vertebral pineal gland, participates in the regulation of cardiovascular system in vitro and in vivo. However, the effects of melatonin on vascular tissues are still vague. The aim of this study was to assess the relationship between phospholipase C (PLC) and nitric oxide synthase (NOS)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling cascade in the relaxatory action of melatonin in isolated rat aorta. Melatonin induced a concentration-dependent relaxation in phenylephrine (PE)- and KCl-precontracted endothelium intact (+E) aortic rings. In KCl-precontracted +E aortic rings, the melatonin-induced vasorelaxation was not inhibited by endothelium removal or by pretreatment with NOS inhibitors, L-$N^G$-nitor-arginine (L-NNA) and L-$N^G$-nitor-arginine methyl ester (L-NAME), guanylate cyclase (GC) inhibitors, methylene blue (MB) and 1H-[1,2,4] oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ). In PE-precontracted +E aortic rings, the melatonin-induced vasorelaxation was inhibited by endothelium removal or by pretreatment with L-NNA, L-NAME, MB, ODQ and 2-nitro-4-carboxyphenyl-n,n-diphenylcarbamate (NCDC). Moreover, in without endothelium (-E) aortic rings and in the presence of L-NNA, L-NAME, MB and ODQ in +E aortic rings, the melatonin-induced residual relaxations and residual contractile responses to PE were not affected by NCDC, a PLC inhibitor. It is concluded that melatonin can evoke vasorelaxation due to inhibition of PLC pathway through the protein kinase G activation of endothelial NOS/cGMP signaling cascade.