Effect of Fangji Huangqitang on DBA/1 Mice Collagen Induced Arthritis and Synovial Angiogenesis / 中国实验方剂学杂志

Objective:To observe the effect of Fangji Huangqitang （FJHQT） on collagen induced arthritis （CIA） and synovial angiogenesis in DBA/1 mice. Method:DBA/1 mice were randomly divided into normal group， CIA group and FJHQT group. DBA/1 mice in CIA group and FJHQT group were immunized with bovine type Ⅱ collagen and complete Freund's adjuvant on the first day， and DBA/1 mice were immunized with bovine type Ⅱ collagen and incomplete Freund's adjuvant on the 21^st day to establish CIA model. On the day of the second immunization， the drug was given by gavage once a day for 28 days. On the 22^nd day， the arthritis score and other symptoms of CIA mice were observed. On the 49^th day， Hematoxylin eosin （HE） staining was carried out to observe the angiogenesis in the synovium of CIA mice， the expression of vascular endothelial cell marker platelet endothelial cell adhesion molecule-1 （CD31） and vascular endothelial growth factor （VEGF） in the synovium of CIA mice were detected. Immunofluorescence double staining was used to detect the mature and immature vessels in the synovium of CIA mice. And the microvascular growth of the rat thoracic aortic ring was induced by VEGF （20 μg·L^-1）. The effects of FJHQT （0.25， 0.5， 1 g·L^-1） at different concentrations were observed under microscope. Result:Compared with the normal group， the inflammation， joints， red and swelling of the inflammatory joints of the CIA group were significantly increased （<italic>P</italic><0.01）. The scores of clinical arthritis， the incidence rate， synovial inflammation and angiogenesis were significantly increased （<italic>P</italic><0.01）. The density of blood vessels， the positive expression of CD31 and VEGF， the number of immature vessels in synovial membrane were significantly increased （<italic>P</italic><0.01）. And compared with the CIA group， the inflammation， joint swelling， and malformation of the FJHQT group were significantly improved， the clinical arthritis score， incidence rate， synovial inflammation and angiogenesis were significantly reduced （<italic>P</italic><0.01）. The vascular density， the positive expression of CD31 and VEGF， and the number of immature blood vessels in synovial membrane were significantly increased （<italic>P</italic><0.01）. Compared with blank group， VEGF could significantly induce the growth of microvasculature in rat thoracic aortic ring （<italic>P</italic><0.01）. Compared with VEGF group， FJHQT（0.25， 0.5， 1 g·L^-1） could significantly inhibit the formation of microvasculature in rat thoracic aortic ring （<italic>P</italic><0.01）. Conclusion:FJHQT can effectively alleviate the clinical symptoms and condition of CIA mice， reduce the clinical arthritis score and incidence rate，and inhibit the synovial angiogenesis of CIA mice joints and VEGF induced microvascular formation in rat thoracic aortic rings.

Molecular mechanism of Chuanxiong Rhizoma in treating coronary artery diseases / 中草药·英文版

Objective: Most of the studies on the herb Chuanxiong Rhizoma (CR) have focused on the L-arginine-nitric oxide (NO) pathway, but the nitrate-nitrite-NO (NO

Anti-proliferative and anti-angiogenic activities of ion-channel modulators: In-ovo, in-vitro and in-vivo study

Objective: Angiogenesis is the development of new blood vessels. The ion channels on endothelium play a vital action in cell proliferation and so in the related angiogenesis. We aimed to investigate the anti-angiogenic effects of Mefloquine (Cl?channel blocker) and 4-Aminopyridine (K+channel blocker). Methods: The anti-angiogenic activities of Mefloquine and 4-Aminopyridine (4-AP) were investigated by in-vivo (sponge implantation method), in-vitro (aortic ring assay) and in-ovo (CAM, Chick Chorioallantoic membrane) methods. The standard anti-angiogenic drug used was Bevacizumab. Results: In the CAM assay, both the ion channel blockers exhibited noticeable anti-angiogenic activity at the concentrations of 10?5 M and 10?4 M where they significantly exhibited ant proliferative activity by inhibiting the new blood vessel formation. For the further confirmation anti-angiogenic activity was evaluated in vitro and in vivo. In Rat aortic ring assay reduction in the area of sprouts were observed with 40μM of 4-AP and 7 μM of Mefloquine. A significant reduction in weight of sponges, number of blood vessels formed and hemoglobin content were observed at 4.2 mg/kg of 4-AP and 20 mg/kg and 30 mg/kg of Mefloquine. Conclusions: These scientific findings indicate the use of Mefloquine and 4-Aminopyridine in pathological situations involving excessive angiogenesis. Negative regulation of cell volume, cell migration and proliferation of blood vessels may be the underlying molecular mechanisms.

In vitro and in vivo evaluation of the antiangiogenic activities of Trigonella foenum-graecum extracts

Objective: To assess the antiangiogenic activity of fenugreek. Methods: Different fractions of fenugreek crude extracts were prepared and their anti-angiogenic properties were assessed using the ex vivo rat aortic ring assay and in vivo chicken embryo chorioallantoic membrane (CAM) assay. They were investigated for their direct cytotoxic activity in the MCF7 cells using the MTT assay. Results: The ethanol extract showed 100％ inhibition of blood vessel outgrowth from primary tissue explants in the rat aortic ring assay at a concentration of 100μg/mL while the other extracts did not show significant antiangiogenic activity. The ethanol extract was therefore investigated at varying concentrations and exhibited a significant dose dependent effect. The CAM assay coincided with the results of the aortic ring assay as ethanol extract showed a significant inhibition of formation of new blood vessels. The extracts only showed anti-proliferative activity at the highest concentration of 400μg/mL towards MCF7 breast cancer cell lines in the MTT assay. Conclusions: Findings of the both assays confirmed that the ethanol extract inhibited vascularization significantly. Further studies on the ethanol extract would be beneficial in isolating the active ingredient responsible for the inhibition.

Anti-proliferative and anti-angiogenic activities of ion-channel modulators: In-ovo, in-vitro and in-vivo study

Objective Angiogenesis is the development of new blood vessels. The ion channels on endothelium play a vital action in cell proliferation and so in the related angiogenesis. We aimed to investigate the anti-angiogenic effects of Mefloquine (Cl− channel blocker) and 4-Aminopyridine (K+ channel blocker). Methods The anti-angiogenic activities of Mefloquine and 4-Aminopyridine (4-AP) were investigated by in-vivo (sponge implantation method), in-vitro (aortic ring assay) and in-ovo (CAM, Chick Chorioallantoic membrane) methods. The standard antiangiogenic drug used was Bevacizumab. Results In the CAM assay, both the ion channel blockers exhibited noticeable antiangiogenic activity at the concentrations of 10

In vitro and in vivo evaluation of the antiangiogenic activities of Trigonella foenum-graecum extracts

Objective To assess the antiangiogenic activity of fenugreek. Methods Different fractions of fenugreek crude extracts were prepared and their antiangiogenic properties were assessed using the ex vivo rat aortic ring assay and in vivo chicken embryo chorioallantoic membrane (CAM) assay. They were investigated for their direct cytotoxic activity in the MCF7 cells using the MTT assay. Results The ethanol extract showed 100% inhibition of blood vessel outgrowth from primary tissue explants in the rat aortic ring assay at a concentration of 100 μg/mL while the other extracts did not show significant antiangiogenic activity. The ethanol extract was therefore investigated at varying concentrations and exhibited a significant dose dependent effect. The CAM assay coincided with the results of the aortic ring assay as ethanol extract showed a significant inhibition of formation of new blood vessels. The extracts only showed anti-proliferative activity at the highest concentration of 400 μg/mL towards MCF7 breast cancer cell lines in the MTT assay. Conclusions Findings of the both assays confirmed that the ethanol extract inhibited vascularization significantly. Further studies on the ethanol extract would be beneficial in isolating the active ingredient responsible for the inhibition.

Effect and Mechanism of Liraglutide on Vasodilatation of Thoracic Aortic Ring in Experimental Rats / 中国循环杂志

Objective: To investigate the effect and mechanism of liraglutide on vasodilatation of thoracic aortic ring in experimental rats. Methods: The thoracic aortic rings were isolated from 32 male SD rats and divided into 2 groups: Without endothelium group and With intact endothelium group, n=16 in each group. The contractile force of vascular ring was detected and the effect of liraglutide (1×10-5 mol/L) on vasodilatation of norepinephrine (NE, 1×10-6 mol/L) pre-contracted ring was observed. The aortic ring in With intact endothelium group was further divided into 2 sub-groups:①the aortic ring was pre-treated by the inhibitor of nitric oxide synthase (NOS) (L-NAME at 10-4 mol/L),② the aortic ring was pre-treated by non-specific ATP-sensitive-potassium (KATP) channel (Glibenclamide at 10-5 mol/L), n=8 in each group. The impacts of liraglutide on those 2 sub-groups were studied. Results: Liraglutide had no effect on isolated aortic ring at basic condition. Liraglutide at (10-5 mol/L) had vasodilatation effect in both Without endothelium and With intact endothelium groups, the effect was stronger in With intact endothelium group and the maximum vasodilatation reached 17%, P reached 14%, P>0.05. Conclusion: Liraglutide had obvious effect of vasodilatation on NE pre-contracted thoracic aortic ring in experimental rats, the mechanism might be related to NOS, while KATP channel could not block the vasodilatation effect of liraglutide.

Ethyl-p-methoxycinnamate isolated from kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-α, and angiogenesis by blocking endothelial functions

OBJECTIVE: The present study aimed to investigate the mechanisms underlying the anti-inflammatory and anti-angiogenic effects of ethyl-p-methoxycinnamate isolated from Kaempferia galanga. METHODS: The anti-inflammatory effects of ethyl-p-methoxycinnamate were assessed using the cotton pellet granuloma assay in rats, whereby the levels of interleukin-1 and tumor necrosis factor-α were measured in the animals' blood. In addition, the levels of interleukin, tumor necrosis factor, and nitric oxide were measured in vitro using the human macrophage cell line (U937). The analgesic effects of ethyl-p-methoxycinnamate were assessed by the tail flick assay in rats. The anti-angiogenic effects were evaluated first by the rat aortic ring assay and, subsequently, by assessing the inhibitory effects of ethyl-p-methoxycinnamate on vascular endothelial growth factor, proliferation, migration, and tube formation in human umbilical vein endothelial cells. RESULTS: Ethyl-p-methoxycinnamate strongly inhibited granuloma tissue formation in rats. It prolonged the tail flick time in rats by more than two-fold compared with the control animals. The inhibition of interleukin and tumor necrosis factor by ethyl-p-methoxycinnamate was significant in both in vivo and in vitro models; however, only a moderate inhibition of nitric oxide was observed in macrophages. Furthermore, ethyl-p-methoxycinnamate considerably inhibited microvessel sprouting from the rat aorta. These mechanistic studies showed that ethyl-p-methoxycinnamate strongly inhibited the differentiation and migration of endothelial cells, which was further confirmed by the reduced level of vascular endothelial growth factor. CONCLUSION: Ethyl-p-methoxycinnamate exhibits significant anti-inflammatory potential by inhibiting pro-inflammatory cytokines and angiogenesis, thus inhibiting the main functions of endothelial cells. Thus, ethyl-p-methoxycinnamate could be a promising therapeutic agent ...

Vasorelaxant effect of Laelia speciosa and Laelia anceps: Two orchids as potential sources for the isolation of bioactive molecules.

The aim of the current study was to investigate the vasorelaxant effect of several extracts from Laelia speciosa and Laelia anceps, on an ex vivo method using aorta rat rings with and without endothelium pre-contracted with norepinephrine (0.1 μM), in order to establish them as a real source for the isolation of bioactive compounds with potential use as antihypertensive agent. All extracts caused concentration-dependent relaxation in -precontracted aortic rings with and without endothelium; the most active extracts were the hexanic and dichlorometanic extracts from roots of L. anceps and L. speciosa (HERLanc, DERLanc, HERLspec and DERLspec, respectively), and were less potent than positive controls used (carbachol and sodium nitroprusside). These results suggest that secondary metabolites, responsible for the vasorelaxant activity, belong to a group of compounds of medium and low polarity, and the roots were the main tissues of the plant where the vasorelaxant compounds are stored. In conclusion, both orchids represent an ideal source for obtaining lead compounds for designing new therapeutic agents, with potential vasorelaxant and antihypertensive effects.

Vasorelaxant activity of extracts obtained from Apium graveolens:Possible source for vasorelaxant molecules isolation with potential antihypertensive effect

Objective:To investigate the vasorelaxant effect of organic extracts from Apium graveolens (A. graveolens) which is a part of a group of plants subjected to pharmacological and phytochemical study with the purpose of offering it as an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects. Methods:An ex vivo method was employed to assess the vasorelaxant activity. This consisted of using rat aortic rings with and without endothelium precontracted with norepinephrine. Results:All extracts caused concentration-dependent relaxation in precontracted aortic rings with and without endothelium;the most active extracts were Dichloromethane and Ethyl Acetate extracts from A. graveolens. These results suggested that secondary metabolites responsible for the vasorelaxant activity belong to a group of compounds of medium polarity. Also, our evidence showed that effect induced by dichloromethane and ethyl acetate extracts from A. graveolens is mediated probably by calcium antagonism. Conclusions: A. graveolens represents an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects.

Endothelium-dependent and independent vasorelaxant effects of aqueous extract of Tridax procumbens Lin. leaf in rat aortic rings.

Tridax procumbens leaf extract induced aortic relaxation in a concentration-dependent manner, for both phenylephrine (PE) and KCl- induced contractions in isolated rat aortic rings. The relaxation effect of the extract on PE-induced contraction was 57% greater than that on KCl- induced contraction. The extract caused dose-dependent relaxations in precontracted isolated rat aorta with phenylephrine; the relaxation was attenuated by the removal of endothelium. However, the relaxation responses to sodium nitroprusside were not significantly abolished by the removal of endothelium. The vasorelaxatory effect of the extract was completely abolished in presence of L-NAME. The results indicate that the vasorelaxant effect of T. procumbens extract is probably mediated by both endothelium-dependent and-independent mechanisms.

Cardiovascular activity of the n-butanol fraction of the methanol extract of Loranthus ferrugineus Roxb

We investigated the vascular responses and the blood pressure reducing effects of different fractions obtained from the methanol extract of Loranthus ferrugineus Roxb. (F. Loranthaceae). By means of solvent-solvent extraction, L. ferrugineus methanol extract (LFME) was successively fractionated with chloroform, ethyl acetate and n-butanol. The ability of these LFME fractions to relax vascular smooth muscle against phenylephrine (PE)- and KCl-induced contractions in isolated rat aortic rings was determined. In another set of experiments, LFME fractions were tested for blood pressure lowering activity in anesthetized adult male Sprague-Dawley rats (250-300 g, 14-18 weeks). The n-butanol fraction of LFME (NBF-LFME) produced a significant concentration-dependent inhibition of PE- and KCl-induced aortic ring contractions compared to other fractions. Moreover, NBF-LFME had a significantly higher relaxant effect against PE- than against high K+-induced contractions. In anesthetized Sprague-Dawley rats, NBF-LFME significantly lowered blood pressure in a dose-dependent manner and with a relatively longer duration of action compared to the other fractions. HPLC, UV and IR spectra suggested the presence of terpenoid constituents in both LFME and NBF-LFME. Accordingly, we conclude that NBF-LFME is the most potent fraction producing a concentration-dependent relaxation in vascular smooth muscle in vitro and a dose-dependent blood pressure lowering activity in vivo. The cardiovascular effects of NBF-LFME are most likely attributable to its terpenoid content.

Effects of Netrin-1 on angiogenesis in vitro and in vivo / 中国综合临床

Objective To investigate the effects of Netrin-1 on angiogenesis in vitro and in vivo. Methods We performed in vitro rat aortic ring assay and in vivo Matrigel plug assay to determine the effect of Netrin-1 on angiogenesis. Results 10 μg/L, 50 μg/L and 100 μg/L Netrin-1 stimulated microvessel sprouting from the adventitia of aortic rings and the effect reached maximum at 50 μg/L The in vivo Matrigel plug assay showed orange color change if Nestrin-1 was positive; and CD34 immunofluorescent staining showed vascular structures in the Matrigel plug with hemachrome ( 53.4 ± 7. 3 ), which was significantly higher than control ( 5. 8 ± 0. 9 )Conclusions Netrin-1 can induce angiogenesis in vitro and in vivo.

Effect of astragaloside Ⅳ on contraction and relaxation in isolated rat aortic rings / 中国药理学通报

Aim To study the effect and investigate the underlying mechanism of astragaloside Ⅳ on contraction and relaxation in isolated rat aortic rings.Methods The relaxation effect of astragaloside Ⅳ(1～100 mg?L~(-1))on phenylephrine-preconstricted aorta ring was recorded.The effect of astragaloside Ⅳ on the contraction induced by cumulative phenylephrine,KCl or CaCl_2,was recorded respectively.Results Astragaloside Ⅳ dilated aortic vessels in a dose-dependent manner,which was partly inhibited by preincubation with non-selective nitric oxide synthase inhibitor,guanylyl cyclase inhibitor and cyclooxygenases inhibitor indomethacin.Astragaloside IV could also antagonize phenylephrine-,KCl-and CaCl_2-induced vessel contraction.Conclusion Astragaloside IV dilated aortic vessels partially though endothelium-dependent NO pathway and inhibited vessel contraction via interfering Ca~(2+) influx.

Effects of D-Polymannuronic sulfate on potential-dependent and/or receptor-operated calcium channel in rat aortic rings / 中国海洋药物

The effects of D-polymannuronic sulfate (DPS) on the norepinephrine (NA) or potassium chloride (KCL)-induced contraction of rat aortic rings were studied in this paper. The results showed that DPS at the final concentration of Img ? L-1 inhibited the contraction of aortic rings e-voked by NA or KCL and shift doseresponse curves for NA or KCL to the right in a non-parallel fa-sion and depressed their maximal response, implicating that DPS afforded the noncompetitive antagonism on contraction of rat aortic rings induced by NA or KCL. This finding suggested that DPS exerted an inhibitory action of potential-dependent calcium channel and that of receptor-operated calcium channel in vascular smooth muscle.

Study on Vasodilating Mechanism of the Acetone Extract from Cortex Mori / 中药新药与临床药理

Objective To study the vasodilating effect of the acetone- extract (AE) from Cortex Mori (CM) and its vasodilating mechanism. Methods Guinea pig models with contraction of mesentery blood capillary induced by noradrenalin were used to study the in- vivo vasodilating effects of AE from CM. In- vitro effect of AE from CM on rat thoracic aortic ring was observed. The contents of nitric oxide (NO), nitric oxide synthase (NOS), constitutive NOS(cNOS) and inducible (iNOS) in plasma and aortic tissue were determined by method of nitroreductase chromatometry. Results AE from CM had vasodilating effect on the contracti on of mesentery blood capillary in guinea pigs and the contraction of rat thoracic aortic ring induced by 10? mol/L phenylephrine, even under the condition of pre- treating with glibenclamide (1 ? mol/L) or propranolol (3 ? mol/L). When the endothelium of the rat thoracic aortic ring was removed, AE from CM had not vasodilating effect but constrictive effect. AE from CM could also increase the contents of NO, NOS and cNOS in the aortic tissue and had no obvious effect on the NO content in plasma and iNOS in aortic tissue of rats. Conclusion The vasodilating mechanism of AE from CM may be related to promoting the release of NO from endothelium of blood vessel and synthesis of NOS and cNOS in aortic tissue.

Estudo anatômico do posicionamento do anel aórtico em relaçäo ao anel mitral / Anatomic study between aortic and mitral rings

Objetivo Avaliar as relações entre os anéis aórtico e mitral. Métodos Cem corações humanos normais, em 61% de indivíduos brancos, em 84%, de homens e em 85%, na faixa de 11 a 40 anos. O ponto de referência no anel aórtico foi a comissura entre os seios não coronariano e coronariano esquerdo; no anel mitral foi o meio caminho entre os trígonos anterior e posterior. A coincidência dos pontos de referência caracterizou a posição média, a referência aórtica mais próxima do trígono posterior, a posição posterior e a mais próxima do trígono anterior, a anterior ou muito anterior. Resultados Observamos 47% de posição média, 27% de muito anterior, 22% de anterior e 4% de posterior. Estes percentuais não foram influenciados por sexo e idade. Os corações de indivíduos negros evidenciaram maior freqüência de posição posterior do que os demais. Conclusão Corações considerados normais apresentam variações na interrelação dos anéis mitral e aórtico.

Purpose Evaluate the relations between aortic and mitral rings. Methods One hundred hearts were studied, in 84% men, 61% white and 85% were between 11 and 40 years old. The commissure between non coronary/left coronary sinus in the aortic ring and the middle point between anterior (AT) and posterior trigone (PT) in the mitral ring were used as references. When these points werencoincidents the position was middle; when the aortic point (AP) was closer the PT the position was posterior and when the AP was closer the AT the position was anterior or much anterior. Results Forty seven (47%) showed middle position, twenty seven (27%) much anterior, twenty two (22%) anterior and only four (4%) posterior. These arent related to sex and age. The hearts of black people showed more posterior position than the others. Conclusion Variations in aortic/mitral rings relations may be observed in normal hearts

An a-Adrenoceptor Blocking Action of Dihydrolycorine / 昆明医科大学学报

Dihydrolycorine(DL)HCI was produced semisynthetically from lycorine which is an alkaloid isolated from lycoris radiata Herb.The dose-response curves for phenylephrine iv to increase mean arterial pressure were shifted rightward by DL 40 mg/kg iv in anesthetized cats.The dose- response curves for phenylephrine iv to increase diastolic pressure were shift- ed rightward by DL iv in pithed rats:but DL didn't shift the dose-response curves of BHT_(920).In rat anococcygeal muscle,DL 3,10,30,100uM/L shifted cumulative dose-response curves of methoxamine rightward parallelly with pa2 value 6.35.In the isolated rabbit aortic ring,DL 10,30,100uM/L also shifted cumulative dose-response curves of methoxamine rightward parallelly with pA2 value 5.93.These results suggest that DL can block a-adrenoceptors.

A comparing study of aortic function between renal hyper-tension rat and renal hypertensive-hyperlipidemia rat / 中国药理学通报

Aim To investigate the difference of aortic function between renal hypertension rat(2K1C) and renal hypertensive-hyperlipidemia rat(RHHR).Methods Animals were divided into 3 groups: the sham-operated group,RHHR and 2K1C model groups.The vascular function test was performed in vitro.The response of aortic ring to phenylephrine(PE),acetylcholine(ACh) and sodium nitroprusside(SNP) was measured.Then aortic ring was incubated with nitricoxide synthase inhibitor N-nitro-L-arginine-methyl-ester(L-NAME) and its response to Ach was observed.Results The contraction in response to PE was augmented in the two model groups.ACh-induced vasorelaxation was reduced in both model groups,and such relaxation was more depressed in RHHR than that in 2K1C.The ability of relaxation evoked by NO was impaired in two model groups.SNP elicited complete relaxation in three groups,but the sensitivity to SNP was more decreased in RHHR than those in sham-operated and 2K1C groups.Conclusion These findings suggest that the vasodilation function of aorta is more impaired in RHHR than that in 2K1C group.The decrease in utilization of vascular smooth muscle to NO induced by hyperlipidemia may contribute to the main cause.

Comparison of effects of dofetilide derivative V03(CPU228) and dofetilide on coronary occlusion and reperfusion arrhythmia, vascular contractions and proarrhythmic potential of torsade de pointes / 中国药理学通报

AIM To investigate the cardiovascular activity of new compound V03(CPU228) derived from dofetilide. METHODS Arrhythmias was induced by the occlusion and reperfusion of left anterior descending coronary artery. The effects of CPU228 and dofetilide on QT interval and inducing Tdp were compared in anesthetized rabbits during stimulation with methoxamine. The contractions of thoracic aortic rings induced by KCl (rat) and Phe (guinea pig) in Ca 2+-free and calcium recovered K-H solution was studied to determinate the activity of CPU228 on intracellular calcium mobilization and calcium entry. RESULTS ① CPU228 suppressed the maximal arrhythmia scores, decreased the AUC of arrhythmia score( reduced the duration of VF and VT significantly). PU228 is more potent than dofetilide.②The potency of CPU228 of inducing Tdp is significantly weaker than that of dofetilide.③There were significantly inhibitions of CPU228 on the contractions of aortic rings induced by KCl and Phe in Ca 2+-free solution and dofetilide only had a inhibition on the former. CPU228 inhibited contractions of aortic ring by adding calcium which influx via L-type calcium channel while dofetilide had no effects on these. CONCLUSION CPU228 has stronger inhibition on coronary occlusion and reperfusion arrhythmia and lower potency of inducing Tdp than dofetilide. All the results suggest that CPU228 is a nonselective I Kr-blocker combined with a blockade on the L-type Ca 2+ channel and?adrenergic receptor.