A thorny path: the developmental course of problem-based learning for health sciences education in Asia.

Problem-based learning (PBL), has been in existence for half a century as of 2019 and still remains the most innovative medical education innovation due to its revolutionary pedagogical approach characterized by student-centered learning (SCL) and self-directed learning (SDL) using simulated real-life scenarios as the learning platform. Here, learning becomes more self-driven, meaningful and relevant, pertaining to the social accountability principle of higher education. Being popular worldwide and driven by a strong demand for medical education reform during the past two decades, PBL has rapidly swept across the medical education communities in Asian countries. Many medical schools in Asia were drawn in by the innovative pedagogical methodology that PBL embraces, but tended to neglect with time, often unintentionally, the philosophy that PBL embodies. As a result, PBL in Asia, for various local academic, cultural, economic and administrative reasons started drifting away from its intended educational purposes. Consequently, the acceptance and practice of PBL in Asia has taken compromised forms as PBL-hybrids embedded within long existing and incorrigibly traditional curricula, or other less effective forms for easier implementation and management, at the expense of SCL and SDL. PBL in health sciences education, which has had a 50-year flourishment in the West, remains a continuous struggle in Asia. PBL for health science education in Asia is certainly no panacea, and is probably heading for a thorny path, despite the ultimate hope for a promising future.

Examining the effects of interprofessional problem-based clinical ethics: Findings from a mixed methods study.

Understanding how interprofessional education (IPE) works in learning clinical ethics via problem-based learning (PBL) and how different professions' perspectives influence each other in this setting may inform future IPE. Eighty-nine students participated in a clinical ethics PBL and were assigned into three study groups, i.e., medical, nursing, and interprofessional groups. This study applied an explanatory sequential mixed methods design. The quantitative phase involved observation of the learning process in PBL tutorial with checklists to code students' performance of learning behaviour, ethics discussion skills, learning content explored, and analysis through comparison of accumulative percentage of the coded performance between groups. Content analysis of post-PBL homework self-reflections from interprofessional group was conducted as the following explanatory qualitative phase. Quantitative results indicated that nursing students performed favourably on course engagement, caring, and communication while medical students performed positively on issue identification and the life science aspect. Interprofessional group showed the strength of the both professions and performed best through the learning process. Content analysis revealed that students in the interprofessional group achieved interprofessional learning from recognizing the differences between to appreciating learning from each other and to sense the need of future collaboration. With early exposure to IPE, undergraduate students may learn to balance their socialized viewpoints by seeing ethical dilemmas from each other's standpoint.

Pharmacological evidence that potentiation of plasmalemmal Ca(2+)-extrusion is functionally coupled to inhibition of SR Ca(2+)-ATPases in vascular smooth muscle cells.

Cyclopiazonic acid (CPA), a specific inhibitor of sarcoplasmic reticulum (SR) Ca(2+)-ATPases, causes slowly developing and subsequently diminishing characteristic contractions in vascular smooth muscle, and the second application of CPA has incompletely repeatable effects, depending on the vessel type. The objective of the present study was to examine the mechanisms underlying the significant decrease of CPA-induced contractions upon the second application. A pharmacological intervention of Ca(2+) extrusion process as a strategy was performed to modulate vasoconstrictor effects of CPA in rat aortic ring preparations. CPA-induced contractions, expressed as percentages of the contractions induced by KCl (80 mM), were significantly decreased from 44.1 ± 5.7 to 7.6 ± 1.8 % (P < 0.001) upon the second application. The contractions, however, were completely repeatable in the presence of vanadate, an inhibitor of ATPases, but not of ouabain, an inhibitor of Na(+)-pumps. Strikingly, CPA-induced contractions were sustained and completely repeatable in Na(+)-free and low Na(+) medium. Furthermore, we found that the contractions were completely repeatable in the presence of 2',4'-dichlorobenzamil, an inhibitor of the forward mode of Na(+)/Ca(2+) exchangers, but not of KBR7943, an inhibitor of the reverse mode of Na(+)/Ca(2+) exchangers. Our findings indicate that CPA by inducing a transient rise in cytosolic Ca(2+) level causes a long-lasting upregulation of plasma membrane (PM) Ca(2+) extruders and thus leads to a diminished contraction upon its second application in blood vessels. This suggests that there is a functional coupling between PM Ca(2+) extruders and SR Ca(2+)-ATPases in rat aortic smooth muscle cells.

Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway.

Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE), also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma "antihypertensive tea" is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs). Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase), wortmannin (30 nM) and LY294002 (20 µM; PI3 (phosphatidylinositol3)-Kinase inhibitor), N(G)-nitro-L-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS)) and ODQ (1 µM; soluble guanylyl cyclase inhibitor). Total nitrite and nitrate (NOx) level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.

Dental and medical students' perspectives on early exposure to PBL in Taiwan.

A hybrid problem-based learning (PBL) curriculum adopted in 2002 for medical students at China Medical University, Taiwan, was extended to dental students in 2007. Before that, PBL workshops were conducted for all students. Two PBL cases on basic biomedical issues were used for second-year medical students and second-year dental students to explore the feasibility of adopting PBL as part of the dental curriculum. This study compared the medical and dental students' attitudes toward the PBL tutorials and PBL curricula. Upon completion of the PBL component, an eighteen-item questionnaire asked students to assess (on a ten-point scale with 10 as the most positive response) their perceptions of the learning process in the PBL tutorials. Forty-six dental students from a cohort of fifty (92 percent) and 107 medical students from a cohort of 119 (90 percent) completed the questionnaires (fifty-three females and 100 males). The importance of all items was rated above 6.00. The medical students' mean score (7.29) was higher than the dental students' mean score (7.10). Of the eighteen attributes of the PBL process, the students indicated being generally comfortable with fourteen. No statistical significance was found between the dental and medical students' scores, but there was a significant difference (p=0.006) in their perception of PBL curricula. Overall, the medical students expressed a more positive outlook toward the PBL learning process than the dental students and were more willing to accept PBL as a pedagogy.

Apocynum venetum leaf aqueous extract inhibits voltage-gated sodium channels of mouse neuroblastoma N2A cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Apocynum venetum Linn. (Apocynaceae family), also called Luobuma, is a shrub which grows widely in the Xinjiang Autonomous Region of China. Its leaves are used in herbal tea for the treatment of hypertension, anxiety and depression. Animal studies have also shown that Apocynum venetum leaf extract (AVLE) also exerts anti-depressant and anti-anxiety activities. The effects of AVLE on neuronal tissues in vitro are not fully understood. MATERIALS AND METHODS: Using the whole-cell voltage-clamp method, we studied the effects of AVLE on ion channels in cultured mouse neuroblastoma N2A cells. RESULTS: AVLE inhibited voltage-gated inward Na(+) current in a reversible and concentration-dependent manner (half-inhibitory concentration was 18 µg/ml and maximum inhibition at 100 µg/ml). AVLE specifically promoted steady-state inactivation of Na(+) channels but did not affect voltage-dependence of activation. The inhibitory effect was not use-dependent and was not affected by 300µM L-NAME, suggesting that NO was not involved in the action of AVLE in neuronal cells. AVLE also had a mild inhibitory effect on voltage-gated K(+) channels, but did not affect ATP-sensitive K(+) channels. CONCLUSIONS: Since voltage-gated Na(+) and K(+) channels are associated with neuronal excitability and therefore affect neurotransmission, the modulation of neuronal ion channels by AVLE may exert neuropharmacological effects. In particular, the inhibition of voltage-gated Na(+) currents by AVLE may in part account for the psychopharmacological effects of this herbal remedy.

Obesity, metabolic syndrome, adipocytes and vascular function: A holistic viewpoint.

1. Obesity is a metabolic disease of pandemic proportions largely arising from positive energy balance, a consequence of sedentary lifestyle, conditioned by environmental and genetic factors. Several central and peripheral neurohumoral factors (the major ones being the anorectic adipokines leptin and adiponecin and the orexigenic gut hormone ghrelin) acting on the anorectic (pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript) and orexigenic (neuropeptide Y and agouti gene-related protein) neurons regulate energy balance. These neurons, mainly in the arcuate nucleus of the hypothalamus, project to parts of the brain modulating functions such as wakefulness, autonomic function and learning. A tilt in the anorectic-orexigenic balance, perhaps determined genetically, leads to obesity. 2. Excess fat deposition requires space, created by adipocyte (hypertrophy and hyperplasia) and extracellular matrix (ECM) remodelling. This process is regulated by several factors, including several adipocyte-derived Matrix metalloproteinases and the adipokine cathepsin, which degrades fibronectin, a key ECM protein. Excess fat, also deposited in visceral organs, generates chronic low-grade inflammation that eventually triggers insulin resistance and the associated comorbidities of metabolic syndrome (hypertension, atherosclerosis, dyslipidaemia and diabetes mellitus). 3. The perivascular adipose tissue (PVAT) has conventionally been considered non-physiological structural tissue, but has recently been shown to serve a paracrine function, including the release of adipose-derived relaxant and contractile factors, akin to the role of the vascular endothelium. Thus, PVAT regulates vascular function in vivo and in vitro, contributing to the cardiovascular pathophysiology of the metabolic syndrome. Defining the mechanism of PVAT regulation of vascular reactivity requires more and better controlled investigations than currently seen in the literature.

New perspectives on vascular wall signaling: role of perivascular adipocytes and fibroblasts.

This communication represents personal perspectives of recent development in the newly evolved areas in vascular signaling mechanisms at the anatomical level of vascular walls from outside in, that is, from perivascular adventitial side to effectuate the control of vascular reactivity. Since half a century ago, the focus of interest in vascular biology has been confined primarily to the study of the excitation-contraction coupling of vascular smooth muscle (VSM) as well as neuroeffector mechanisms. During the past 3 decades, considerable advancement in the understanding of vascular signaling has been made via the discovery of endothelium-derived relaxation factors (EDRF), endothelium-derived hyperpolarizing factors (EDHF) and endothelium-derived contracting factors (EDCF). The discovery of nitric oxide (NO) as a major cellular messenger has also helped open up another huge area of research in oxidative stress and vascular diseases. In the past decade, concepts on vascular wall signaling have been extended from vascular endothelial cells and then translated to the other seemingly inert cellular components, such as perivascular adipocytes and adventitial fibroblasts. Growing body of evidences show that these cellularities contribute to both functional as well as structural integrity in vasculature with significant pathophysiological implications.

Rhynchophylline from Uncaria rhynchophylla functionally turns delayed rectifiers into A-Type K+ channels.

Rhynchophylline (1), a neuroprotective agent isolated from the traditional Chinese medicinal herb Uncaria rhynchophylla, was shown to affect voltage-gated K(+) (Kv) channel slow inactivation in mouse neuroblastoma N2A cells. Extracellular 1 (30 microM) accelerated the slow decay of Kv currents and shifted the steady-state inactivation curve to the left. Intracellular dialysis of 1 did not accelerate the slow current decay, suggesting that this compound acts extracellularly. In addition, the percent blockage of Kv currents by this substance was independent of the degree of depolarization and the intracellular K(+) concentration. Therefore, 1 did not appear to directly block the outer channel pore, with the results obtained suggesting that it drastically accelerated Kv channel slow inactivation. Interestingly, 1 also shifted the activation curve to the left. This alkaloid also strongly accelerated slow inactivation and caused a left shift of the activation curve of Kv1.2 channels heterologously expressed in HEK293 cells. Thus, this compound functionally turned delayed rectifiers into A-type K(+) channels.

Unrepeatable extracellular Ca2+-dependent contractile effects of cyclopiazonic acid in rat vascular smooth muscle.

Cyclopiazonic acid (CPA), a specific reversible inhibitor of Ca(2+)-pumps in sarcoplasmic reticulum, causes a slowly developing and subsequently diminishing characteristic contraction in endothelium-denuded rat vascular smooth muscle. We recently found that CPA-induced contractions were not completely repeatable in endothelium-denuded rat aorta and superior mesenteric artery. 10 microM CPA-induced contractions expressed as a percentage of 80 mM KCl-induced contraction were significantly decreased from 51.4+/-5.7% to 11.8+/-2.6% (P<0.0001) upon the second application in endothelium-denuded rat aorta, and this was not due to any irreversible cytotoxic effects of CPA. The decrease of CPA-induced contractile responses upon the second application was dependent on both types of blood vessels and doses of CPA upon the first application. CPA upon the second application in Ca(2+)-containing solutions did induce its characteristic contractions in the rings pretreated with Ca(2+)-free solutions or Ca(2+) entry blockers before and during its first application, suggesting that capacitative mode of Ca(2+) influx during the application of CPA might be responsible for the diminishment of contractions upon the second application. These data suggest that CPA by inducing a transient rise in cytosolic Ca(2+) level might cause a long-lasting upregulation of Ca(2+) extrusion across the plasma membrane in vascular smooth muscle cells and thus accelerate Ca(2+) efflux over a prolonged period, leading to unrepeatable contractile effects of CPA. Such long-lasting upregulation of Ca(2+) extrusion may contribute to the regulation of excitability of vascular smooth muscle cells and protect the cells against excitotoxic injury.

Dual vascular effects of leptin via endothelium: hypothesis and perspective.

Secreted by adipocytes, leptin is a hormone which regulates appetite and metabolism. Leptin secretion is proportional to the fat mass, and thus leptin concentration is raised in most obese subjects. In recent years, more and more biological effects have been attributed to leptin; one of the most well-known effects is the effect of leptin on the vascular tone. Obesity is very often associated with hypertension, and it has been known that leptin affects the blood pressure by activating the sympathetic nervous system and causing endothelial cell (EC) dysfunction. However, there has been strong evidence that leptin is able to dilate blood vessels. Such vasodilation has been shown to be EC-dependent and EC-independent. Further, both nitric oxide-dependent and nitric oxide-independent mechanisms have been reported. In this mini-review, we summarize the heterogeneous mechanisms by which leptin causes relaxation of vascular smooth muscle. We also argue that while leptin may act as a direct dilator on the vasculature in healthy subjects, hyperleptinemia in obese subjects gradually dysregulates blood pressure control by deteriorating EC functions. How these dual effects of leptin on EC might be related to EC ionic channels is also discussed.

Dental education in Wuhan, China: challenges and changes.

The aim of this article is to describe the innovations in the School of Stomatology at Wuhan University (WHUSS) that are likely to shape the future of dental education in the People's Republic of China. There are forty dental schools in China; the five most well known are located in Beijing, Chengdu, Shanghai, Xi'an, and Wuhan. Although patient-centered, comprehensive care has been recommended as the future of dental education, traditional dental education in China still faces many challenges to accomplish this goal. WHUSS, one of the more progressive dental schools in China, has implemented several educational innovations to traditional dental education by restructuring the curriculum through the introduction of problem-based learning (PBL) and other strategies in clinical training. Although implementation of educational innovations is still at an early stage throughout China, it is reasonable to speculate that many schools will develop similar strategies as those developed at Wuhan to improve dental education during the next several years. However, additional research is necessary to evaluate the efficacy of such educational strategies and to determine the appropriate implementation of a contemporary dental curriculum and pedagogic methodology. The curriculum modifications that have been achieved to date as well as the existing challenges are discussed to provide the reader with an understanding of contemporary dental education in China.

Ca2+-mediated ascorbate release from coronary artery endothelial cells.

1.--The addition of Ca(2+) ionophore A23187 or ATP to freshly isolated or cultured pig coronary artery endothelial cells (PCEC) potentiated the release of ascorbate (Asc). Cultured PCEC were used to characterize the Ca(2+)-mediated release. An increase in Ca(2+)-mediated Asc release was observed from PCEC preincubated with Asc, Asc-2-phosphate or dehydroascorbic acid (DHAA). 2.--The effects of various ATP analogs and inhibition by suramin were consistent with the ATP-induced release being mediated by P2Y2-like receptors. 3.--ATP-stimulated Asc release was Ca(2+)-mediated because (a) ATP analogs that increased Asc release also elevated cytosolic [Ca(2+)], (b) Ca(2+) ionophore A23187 and cyclopiazonic acid stimulated the Asc release, (c) removing extracellular Ca(2+) and chelating intracellular Ca(2+)inhibited the ATP-induced release, and (d) inositol-selective phospholipase C inhibitor U73122 also inhibited this release. 4.--Accumulation of Asc by PCEC was examined at Asc concentrations of 10 microM (Na(+)-Asc symporter not saturated) and 5 mM (Na(+)-Asc symporter saturated). At 10 microM Asc, A23187 and ATP caused an inhibition of Asc accumulation but at 5 mM Asc, both the agents caused a stimulation. Substituting gluconate for chloride did not affect the basal Asc uptake but it abolished the effects of A23187. 5.--PCEC but not pig coronary artery smooth muscle cells show a Ca(2+)- mediated Asc release pathway that may be activated by agents such as ATP.

The control of vascular smooth muscle function: my life-long learning and continuous discovery with Professor E.E. Daniel.

This communication is neither a comprehensive review of my research, nor a description about my recent new original scientific findings in smooth muscle or in cell Ca2+. For that intention, I will choose to publish via a regular channel, certainly not in this special edition. My intention is to take this opportunity to recapitulate Dr. Daniel's thoughts and spirits through the progress of my research, teaching, and personal development at McMaster University, stemming largely from Dr. Daniel's life-long interest in the regulation of Ca2+ in the control of smooth muscle function, specifically the vascular smooth muscle. Being a culturally adsorbent person, I am sure that my thoughts and behavior must have been substantially influenced by Dr. Daniel over 27 years of our collaboration. His influence may have molded me into whom and what I am today, both socially and scientifically. Equally, I may also have influenced him in some particular or peculiar way. Dr. Daniel's academic contribution is globally well known for, but not limited to, his insightful and productive research in smooth muscle, but also for his effective application of problem-based learning to education in pharmacology and his influence on students and colleagues.

Exploratory thoughts concerning educational reform with problem-based learning in China.

The author, a novice problem-based learning (PBL) advocate in China and a young faculty member of the School of Stomatology at Wuhan University, joined a PBL tutorial group as an observer during his two-month visit at McMaster University. He describes his observations and thoughts as they relate to the current reform of health sciences education in China.

A novel in vitro endothelium-dependent vascular relaxant effect of Apocynum venetum leaf extract.

1. In the present study, a novel in vitro vascular relaxant effect of Apocynum venetum leaf extract (AVLE; also called 'Luobuma'), obtained from a traditional Chinese medicinal herb with known antihypertensive effects, is reported in isometric contraction studies of rat aorta and superior mesenteric artery. At low concentrations (0.3-10 microg/mL), AVLE had no effect on the resting tension of either blood vessel and caused relaxation in agonist-precontracted vessels with functionally intact endothelium. 2. We demonstrated pharmacologically that the AVLE-induced vasorelaxation was mediated selectively by the endothelial cells in both blood vessels. Using NG-nitro-L-arginine methyl ester (L-NAME) and a low concentration of KCl (15 mmol/L), we also demonstrated that AVLE acted by releasing endothelium-derived relaxation factors; nitric oxide (NO) in the rat aorta and NO plus endothelium-derived hyperpolarizing factor in the rat mesenteric artery. 3. The vascular relaxation following brief exposure to AVLE appeared to persist even after subsequent prolonged washout; this was manifested as an attenuated contraction to subsequent application of phenylephrine (PE) compared with the PE-induced contraction after exposure to carbachol (CCh) and subsequent similar washout. The addition of L-NAME at this point in the absence of AVLE totally restored the contraction to PE, suggesting that enzymatic generation of endothelial NO persisted even after brief exposure to AVLE. 4. Unlike the endothelium-dependent NO-mediated relaxation induced by CCh, which is mediated by endothelial muscarinic receptors (and inhibited by atropine), the relaxation induced by AVLE was not inhibited by atropine and, thus, was not mediated by muscarinic receptors. However, similar to CCh-induced relaxation, AVLE-induced relaxation was associated with the activation of K+ channels. 5. These results provide a strong scientific basis for the folk use of AVLE decoction for antihypertensive therapy in traditional Chinese medicine.

Learning of medical pharmacology via innovation: a personal experience at McMaster and in Asia.

Pharmacology, a discrete preclinical discipline of the traditional medical curriculum, identifies itself distinctly different from the other preclinical or clinical subjects in knowledge base as well as learning/teaching instructions. It exists in series with other pre-clinical courses (e.g., anatomy, biochemistry and physiology), and in parallel with other paraclinical courses such as pathology, microbiology and community medicine. Such arrangement makes learning of pharmacology rather difficult and deficient with regard to its therapeutic relevance and clinical application. In recent years, medical curricula based on clinical cases have emerged as a platform in which pharmacology is one integrated component in a holistic approach to medical education. In this problem-based learning (PBL) model, students learn, with teachers' facilitation, in a student-centered environment, based on self-directed, clinically relevant and case-oriented approach, usually in a small-group tutorial format. In PBL, pharmacology is learned in concert with other subject issues relevant to the case-problem in question, such as anatomy, physiology, pathology, microbiology, population health, behavior science, etc. Students learn via problem-evoked curiosity and motivation, in an environment which encourages free inquiries and intensive discussions in a cooperative rather than competitive atmosphere. Teachers facilitate students' learning objectives rather than deliver pre-packed knowledge and dictate what they think students should learn. A change towards PBL curriculum appears to be beneficial in better preparing the medical students as life-long learners capable of coping with changes in knowledge and skills associated with the progressive and dynamic social/economic transformation in the Asia-Pacific regions. Evidence is presented that this is indeed happening.

Peroxynitrite resistance of sarco/endoplasmic reticulum Ca2+ pump in pig coronary artery endothelium and smooth muscle.

We examined the effects of peroxynitrite pre-treatment on sarco/endoplasmic reticulum Ca(2+) (SERCA) pump in pig coronary artery smooth muscle and endothelium. In saponin-permeabilized cells, smooth muscle showed much greater rates of the SERCA Ca(2+) pump-dependent (45)Ca(2+) uptake/mg protein than did the endothelial cells. Peroxynitrite treatment of cells inhibited the SERCA pump more severely in smooth muscle cells than in endothelial cells. To determine implications of this observation, we next examined the effect of the SERCA pump inhibitor cyclopiazonic acid (CPA) on intracellular Ca(2+) concentration of intact cultured cells. CPA produced cytosolic Ca(2+) transients in cultured endothelial and smooth muscle cells. Pre-treatment with peroxynitrite (200 microM) inhibited the Ca(2+) transients in the smooth muscle but not in the endothelial cells. CPA contracts de-endothelialized artery rings and relaxes precontracted arteries with intact endothelium. Peroxynitrite (250 microM) pre-treatment inhibited contraction in the de-endothelialized artery rings, but not the endothelium-dependent relaxation. Thus, endothelial cells appear to be more resistant than smooth muscle to the effects of peroxynitrite at the levels of SERCA pump activity, CPA-induced Ca(2+) transients in cultured cells, and the effects of CPA on contractility. The greater resistance of endothelium to peroxynitrite may play a protective role in pathological conditions such as ischemia-reperfusion when excess free radicals are produced.

Vascular effects of Siberian ginseng (Eleutherococcus senticosus): endothelium-dependent NO- and EDHF-mediated relaxation depending on vessel size.

Siberian ginseng (SG) has been widely and historically consumed as a health food product for the improvement of self well-being, but whether vascular relaxation may contribute to such a therapeutic health effect has not been studied. We therefore investigated the vasorelaxant effect of the aqueous extract of the roots of SG (Eleutherococcus senticosus Maxim) using several in vitro vascular rings prepared from dog carotid artery, rat aorta and rat mesenteric artery. SG extract (0.04-0.8 mg/ml) caused concentration-dependent relaxation in dog carotid arterial rings pre-contracted with 100 microM phenylephrine (PE), and the relaxation was primarily endothelium-dependent. Treatment with 100 microM L-NOARG (a nitric oxide synthase inhibitor) either prevented or totally reverted SG-induced relaxation, suggesting that the endothelium-dependent relaxation was mediated by NO. Similar endothelium-dependent vascular relaxant responses were also obtained with rat aortic and mesenteric arterial rings, except that it occurred over a relatively higher concentration range of SG (0.5-2.0 mg/ml). When tested in the presence of 300 microM L-NAME, the vasorelaxant effect of SG was inhibited totally in rat aorta but only partially in rat mesenteric artery. The relaxation to SG that was insensitive to L-NAME in rat mesenteric arterial rings was eliminated when the rings (both proximal and distal ends) were pre-treated with a combination of 300 microM L-NAME and 15 mM KCl indicating the involvement of endothelium-derived hyperpolarizing factor (EDHF). This vasorelaxant response of the SG extract was inhibited partially by atropine (1 microM), completely by TEA (5 mM), but not by indomethacin (1 microM) or propranolol (10 microM). SG up to 2 mg/ml had no effect on KCl-induced contraction in any of the vascular rings studied. When compared with carbachol-induced (CCh) relaxation, SG resembles CCh in that the sensitivity to L-NAME inhibition is dependent on vascular size, i.e. aorta >proximal end of mesenteric artery >distal end of mesenteric artery. However, SG exhibited different potencies to relaxation while CCh showed similar potency (EC(50) of about 0.2 microM) in all three vascular segments. In conclusion, we have demonstrated that the vascular effect of SG is endothelium-dependent and mediated by NO and/or EDHF depending on the vessel size. Other vasorelaxation pathways, such as inhibition of K(+)-channels and activation of muscarinic receptors, may also be involved.