Study on the Diastolic Effect and Mechanism of Hui Medicine Hexin Oil Solution on Isolated Thoracic Aor-tic Vascular Rings of Rats / 中国药房

OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.

Study on the Diastolic Effect and Mechanism of Hui Medicine Hexin Oil Solution on Isolated Thoracic Aor-tic Vascular Rings of Rats / 中国药房

OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.

A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase.

QSAR study was performed on a series of 1,2-dihydro-4-quinazolinamines, 4,5-dialkylsubstituted-2-imino-1,3-thiazolidine derivatives and 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives studied by Tinker et al. [J Med Chem (2003), 46, 913-916], Ueda et al. [Bioorg Med Chem (2004) 12, 4101-4116] and Ueda et al. [Bioorg Med Chem Lett (2004) 14, 313-316], respectively, as potent, highly selective inhibitors of inducible nitric oxide synthase (iNOS). The iNOS inhibition activity of the whole series of compounds was analyzed in relation to the physicochemical and molecular properties of the compounds. The QSAR analysis revealed that the inhibition potency of the compounds was controlled by a topological parameter 1v (Kier’s first order valence molecular connectivity index), density (D), surface tension (St) and length (steric parameter) of a substituent. This suggested that the drug-receptor interaction predominantly involved the dispersion interaction, but the bulky molecule would face steric problem because of which the molecule may not completely fit in active sites of the receptor and thus may not have the optimum interaction.

A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors.

A quantitative structure-activity relationship (QSAR) and molecular modeling study were performed on a series of 3,4-dihyro-1-isoquinolinamines and thienopyridines reported by Beaton et al. [Beaton et al. (2001) Bioorg Med Chem Lett 11, 1023-1026, 1027-1030] as potent, highly selective inhibitors of two isoforms of nitric oxide synthase (NOS) — neuronal NOS (nNOS) and endothelial NOS (eNOS), in order to find the physicochemical properties that governed their activity and the mode of interaction with the receptors, so that still more potent compounds in the series could be suggested. A multiple regression analysis revealed that nNOS and eNOS inhibition potency of these compounds could be controlled by their hydrophobic property and molar refractivity, respectively. Thus, nNOS and eNOS inhibition was indicated to involve the hydrophobic interaction and steric effects, respectively, suggesting some structural differences of the two isoforms of NOS. Based on the correlations obtained, some new, more potent compounds belonging to the series were predicted. These compounds were then docked into the receptors to see their interactions and find out the docking scores. The docked structures of two representative compounds, whose interaction energies with nNOS and eNOS, respectively were found to be the lowest, were given as an example to exhibit the possible orientation of the compounds to interact with the receptors.

Nitric oxide synthase inhibitors and cerebral ischemia / 中国临床药理学与治疗学

As the effects of the nitric oxide and nitric oxide synthase have been investigated a lot,the nitric oxide synthase inhibitors were widely explored and become one of the highlights in the cerebral ischemia research.This paper reviewed the effects of nitric oxide synthase inhibitors especially the nNOS inhibitors and iNOS inhibitors on the cerebral ischemia damage.

Effects of L-NAME, Aminoguanidine and Hydroxocobalamin on Aortic Contractile Responses in Endotoxemic Rats during Halothane Administration / 대한마취과학회지

BACKGROUND: Recent studies demonstrated that volatile anesthetics suppress the NO-cGMP system in the vascular system. It has been known that the hemodynamic changes produced by volatile anesthetics in septic patients are mediated by upregulation of iNOS leading to excessive release of NO. The mechanisms underlying suppression of the NO-cGMP system by anesthetics are still controversial. It has been elucidated that nitric oxide synthase (NOS) plays a major role in the regulatory function in the L-arginine-NO system. So we examined the effects of NOS inhibitor (L-NAME, aminoguanidine) and NO scavenger (hydroxocobalamin) on vascular smooth muscle contractile function in lipopolysaccharide (LPS)-treated rat aorta during halothane administration. METHODS: Aortic ring preparations were obtained from LPS-treated (1.5 mg/kg, ip, for 18 h) rats. We evaluated the effects of hydroxocobalamin, L-NAME and aminoguanidine on contractile responses to phenylephrine during halothane (1 & 2 MAC) administration respectively. Statistical significances (P<0.05) were analyzed according to data characterictics by repeated measures ANOVA test and student's t-test. RESULTS: The contractile responses to phenylephrine in LPS-treated rats aorta were significantly (P<0.05) increased in the presence of hydroxocobalamin and L-NAME. During the halothane (1 and 2 MAC) administration, the contractile responses to phenylephrine in LPS-treated rats aorta were increased significantly (P<0.05) in the presence of hydroxocobalamin and L-NAME. CONCLUSIONS: From these results, it is suggested that hydroxocobalamin and L-NAME may be useful in the therapy of septic shock.

Effects of Inhalational Anesthetics on Contractile Responses and Nitric Oxide Synthase Activity in Endotoxemic Rats / 대한마취과학회지

BACKGROUND: Recent studies revealed that inhalational anesthetics (IA) attenuate NO production. But the hemodynamic changes produced by IA in septic syndrome patient are still sufficient to threaten patient, surgeon and anesthesiologist. So we examined which IA is proper to maintain vascular contractile force and evaluated the effects of NOS inhibitors on contractile force of septic rat aorta under IA. METHODS: Aortic ring preparation was obtained from LPS-treated (1.5 mg/kg, i.p. for 18h) rats. The development of sepsis was confirmed by iNOS activity and iNOS expression using RT-PCR. Contractile responses of aorta to phenylephrine admministation in the presence or absence of halothane, enflurane and isoflurane were evaluated. We also evaluated the effects of NOS inhibitors, one is NG-nitro-L-arginine methyl ester (L-NAME) and the other is aminoguanidine. Statistical significances (p<0.05) were analyzed according to data characteristics by unpaired t-test and paired t-test. RESULTS: The contractile responses to phenylephrine admministration were attenuated in LPS-treated rings. Isoflurane, even at the dose of 2 MAC, didn't affect the contractile response while both halothane and enflurane decreased the contractile response even at the dose of 1 MAC. The potentiation of contractile responses by NOS inhibitors were not affected during administeration of IA. CONCLUSIONS: From these results, it is suggested that isoflurane is the safest inhalational anesthetic and NOS inhibitors, especially L-NAME, may be very useful in the therapy of septic shock patients during general anesthesia.

Effects of nitric oxide synthase inhibitors on osteoclast-like cell formation / 대한치과교정학회지

Orthodontic tooth movement in response to orthodontic force results from actions of osteoclasts and osteoblasts in the cell level. Convincing evidence has now been provided to support the view that osteoclasts are derived from mononuclear cells that originate in the bone marrow or other hematopoietic organs and they migrate to the bones via vascular routes. Nitric oxide(NO), which accounts for the biological properties of endothelium-derived relaxmg factor(EDRF), is the endogenous stimulator of soluble guanylate cylase. The discovery of the formation of nitric oxide(NO) from L-arginine in mammalian tissues and its biologioal roles has, in the last 7 years, thrown new light onto many areas of research. Data from experiments in vitro showed that N-metyl-L-arginine(L-NMA) and L-nitro-L-arginine(L-NAME) are competitive inhibitors of nitric oxide synthase. This study suggest that the multinucleated cells in our culture have characteristics of osteoclasts and that the potential bone cell activity of nitric oxide in vitro may be mediated in part by stimulation of marrow mononuclear cells to form osteoclast-like cells. Bone marrow cells were obtained from tibia of 19-days old chick embryo. After sacrifice, tibia was quickly dissected and the bone were then split to expose the medullary bone. The cells were attached for 4 hours and the nonadherent cells were collected. Marrow cells were cultured in 96-well plate in medium 199. To examine the number of TRAP-positive multinucleated cells(MNCs), 10(-8) M Vit-D3 and various concentration of L-NMA and L-NAME were added at the beginning of cultures and with each medium change. After 7 days of culture, tartrate-resistant acid phosphatase(TRAP) staining was performed for microscopic evaluation. Cells having more than three nuclei per cell were counted as MNCs. The observed results were as follows; 1. 1,25-dihydroxyvitamine D3 stimulated the osteoclast-like multinucleated cells in cultures of chick embryo bone marrow. 2. Nitric oxide synthase inhibitors(NOSI ; N-NMA, N-NAME) stimulated the osteoclast-like cells in cultures of chick embry bone marrow. 3. 1,25-dihydroxyvltamine D3 and nitric oxide synthase inhibitors did not appear to have additive effect on the generation of TRAP-positive MNCs. These results suggest that nitric oxide synthase inhibitors may stimulate the osteoclast-like multinucleated cell formation and fusion in cultures of chick bone marrow.