bluuebunny/crossref_metadata_2025_split huggingface dataset:
VASCULAR EFFECTS OF SELECTED ANTIHYPERTENSIVE DRUGS DERIVED FROM TRADITIONAL MEDICINAL HERBS
Authors: Kwan Chiu‐Yin 
Published: June 2007

Summary1. The pharmacological actions of the active ingredients extracted or purified from two selected traditional Chinese medicinal plants on vascular smooth muscles are briefly reviewed. The active ingredients of these herbal drugs include tetrandrine (TET) and total ginseng saponins (TGS). These natural products have been clinically used in China for the treatment of cardiovascular diseases due to their vasodilatory and antihypertensive actions.2. Studies from this laboratory have confirmed previously reported characteristics of these drugs as Ca2+ antagonists in vascular tissues. On the other hand, they also elicited inhibitory effects in response to a wide variety of receptor stimulations as indicated by contractility studies using isolated vascular tissues and radioligand binding studies using isolated subcellular membranes.3. TET has been demonstrated as an effective but not very selective Ca2+ antagonist. Other than the vasodilatory action on arteries and veins, TET also shows a vasoconstrictive effect in veins.4. TGS from panax notoginseng may be acting as a novel and selective Ca2+ antagonist that does not interact with the L‐type Ca2+ channel (e.g. in KCl‐induced contraction) but may interact with the putative receptor operated Ca2+ channel (e.g. in phenylephrine‐induced contraction). TGS from panax quin‐quefolium, on the other hand, enhanced the vasoconstrictor effect produced by phenylephrine, but not KCI.
ANTIHYPERTENSIVE EFFECT OF THERMOLYSIN DIGEST OF DRIED BONITO IN SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Fujita H. , Yokoyama K. , Yasumoto R. , Yoshikawa M. 
Published: June 2007

Summary1. The thermolysin digest of dried bonito, Katsuo‐bushi, showed inhibitory activity (IC50= 29 μg/mL) for angiotensin I‐converting enzyme (ACE) and an antihypertensive effect after a single oral administration in SHR at a dose of 500 μg/kg. In a long‐term feeding experiment, in which 3 week old SHR were fed a standard chow supplemented with the digest for 7 weeks, elevation of the systolic blood pressure was significantly suppressed by 15 μg/kg per day of the digest.2. A digest of dried bonito by gastrointestinal proteases (pepsin–‐trypsin–‐chymotrypsin) failed to lower the blood pressure after a single oral administration (1000 μg/kg) in spite of a fairly strong ACEI activity (IC50= 41 μg/mL).3. The ACEI activity of the thermolysin digest did not change after preincubation with gastrointestinal proteases or ACE. However, that of the pepsin–‐trypsin–‐chymotrypsin digest was reduced after the preincubation with ACE suggesting that the apparent inhibitory activity was due to ACE substrate peptides.4. Eight ACEI peptides were isolated from the thermolysin digest. Most of them were true inhibitors or precursors that are converted into true inhibitors by ACE or gastrointestinal proteases in vivo. The precursor type peptides required a longer time than true inhibitors to show maximal antihypertensive effect after a single oral administration in SHR. Thus, the thermolysin digest of dried bonito is a mixture of a true inhibitor and precursor peptides differing from each other in maximally effective times.
EFFECTS OF GAMMA‐LINOLENIC AND EICOSAPENTAENOIC ACIDS ON BLOOD PRESSURE IN SHR
Authors: Sasaki S. , Nakamura K. , Uchida A. , Fujita H. , Itoh H. , Nakata T. , Takeda K. , Nakagawa M. 
Published: June 2007

Summary1. The present study was performed to determine whether chronic treatments with gamma linolenic acid (n‐6, GLA) or eicosapentaenoic acid (n‐3, EPA) would alter serum and red blood cell (RBC) unsaturated fatty acid composition, and to determine whether these treatments would affect blood pressure (BP), serum lipid metabolism and the development of atherosclerosis in spontaneously hypertensive rats (SHR).2. To compare the effects on atherosclerosis, some SHR were denuded of aortic endothelium so that the development of atherosclerosis would be accelerated. Olive oil (control), GLA or EPA (low dose: 5 mg/day per rat, high dose: 50 mg/day per kg, respectively) was administered intraperitoneally for 6 weeks in SHR.3. GLA treatments increased GLA and its metabolite, dihomo‐GLA, levels in serum but not in RBC, while EPA treatments increased EPA level both in serum and in RBC.4. The BP of control SHR was further elevated. EPA significantly reduced this elevation of systolic, mean and diastolic pressure within the first week and thereafter, whereas GLA did not affect BP elevation. Neither heart rate or bodyweight gain was affected by these treatments.5. Serum total cholesterol (TC), triglyceride (TG), and glucose (G) levels and the development of atherosclerosis were unaffected by either GLA or EPA treatment.6. In summary, chronic EPA but not GLA treatment slightly reduced BP elevation in SHR. Although chronic GLA or EPA treatment increased the respective serum level, these treatments unaltered serum TC, TG and G levels, and could not prevent the development of aortic atherosclerosis in SHR.
ALTERED BASAL RELEASE AND DEPRESSOR EFFECT OF L‐DOPA IN THE NUCLEUS TRACTUS SOLITARII OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Misu Yoshimi , Yue Jin‐Liang , Okumura Yoko , Miyamae Takeaki , Ueda Hiroshi 
Published: June 2007

Summary1. L‐DOPA as a probable neurotransmitter of baroreceptor afferents functions as a tonic to mediate cardiodepressor control in the nucleus tractus solitarii (NTS). We attempted to clarify further whether a transmitter‐like L‐DOPA system is altered in NTS of adult spontaneously hypertensive rats (SHR).2. By microdialysis of left NTS area, the basal L‐DOPA release was lower in SHR than in Wistar‐Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 μmol/L) to a similar degree in both strains. TTX‐sensitive L‐DOPA release was lower in SHR than in WKY.3. L‐DOPA (10–300 ng) and L‐glutamate (3–100 ng) micro‐injected into left NTS produced dose‐dependent hypotension and bradycardia. No difference of responses to L‐glutamate was seen in either strain. However, depressor but not bradycardic responses to L‐DOPA at higher doses were slightly greater in SHR than in WKY.4. In caudal dorsomedial medulla including NTS, tyrosine hydroxylase activity was increased in SHR compared to WKY, while there was no difference in either strain of L‐aromatic amino acid decarboxylase activity.5. Impaired tonic neuronal activity to release L‐DOPA in NTS may be involved in the maintenance of hypertension in SHR. An increase in sensitivity of a recognition site for L‐DOPA seems to occur as a compensatory mechanism for impairment of the neuronal activity.
BRIEF TREATMENT OF SHR WITH AN ACE INHIBITOR FAILS TO CAUSE LONG‐TERM NORMOTENSION BUT MARKEDLY INCREASES MORTALITY
Authors: Lan L. , Di Nicolantonio R. , Bramich C. , Morgan T. O. 
Published: June 2007

Summary1. We examined the effect of three doses (0.03, 0.3 and 3 mg/kg per day) of the angiotensin converting enzyme (ACE) inhibitor, perindopril, on the long‐term blood pressure of spontaneously hypertensive rats (SHR) of the Okamoto strain after treatment during the developmental stage of hypertension development.2. While the 0.03 mg/kg per day dose, given between the ages of 4–10 weeks of age, failed to lower blood pressure, the two higher doses resulted in normotension over this treatment period as did the highest dose given between the ages of 4–20 weeks of age.3. Only the 0.3 mg/kg per day dose resulted in a moderate (17%) long‐term fall in blood pressure upon cessation of treatment when compared to untreated SHR controls. The highest dose, given over the 4–20 week period resulted in a significant rebound hypertension above the blood pressure level of untreated, control SHR.4. The 3 mg/kg per day dose, whether given over the 4–10 or 4–20 week treatment period, resulted in 100% mortality in these groups by 52 weeks of age. There were no deaths in the groups receiving the two lower doses.5. We conclude that treatment of SHR with perindopril during the developmental phase of hypertension development results in only a modest fall in long‐term blood pressure upon cessation of treatment and that the relationship between the dose of this ACE inhibitor and long‐term blood pressure is not linear. The 100% mortality in the two groups receiving the highest dose of perindopril may be due to either a toxic action of this drug or vascular rupture due to insufficient hypertrophy for the rapid rise in blood pressure upon cessation of treatment.
EFFECT OF CHRONIC TREATMENT WITH ME3221 ON BLOOD PRESSURE AND MORTALITY IN AGED STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nagura Jun , Hui Chen , Yamamoto Mikio , Yasuda Sumie , Abe Mitsuhiro , Hachisu Mitsugu , Konno Fukio 
Published: June 2007

Summary1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke‐prone spontaneously hypertensive rats (SHRSP) was studied following long‐term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril.2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the anti‐hypertensive effect of ME3221 was more potent.3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age.4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N‐acetyl‐β‐d‐glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion).5. These results indicate that ME3221 has a stable anti‐hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.
CARDIOVASCULAR EFFECTS OF INTRACEREBROVENTRICULARLY ADMINISTERED GROWTH HORMONE‐RELEASING FACTOR IN SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Watanabe M. , Kobayashi M. , Kaneda T. , Ohtahara A. , Mashiba H. 
Published: June 2007

Summary1. We investigated the cardiovascular effects of intracerebroventricularly administered (ICV) growth hormone‐releasing factor (GRF) in both spontaneously hypertensive rats (SHR) and Wistar rats (WR) with reference to the involvement of adrenergic mechanisms and plasma AVP concentration.2. The ICV GRF induced biphasic changes of mean arterial pressure (MAP) in SHR. In the first phase, maximum pressor response was observed 2–3 min after injection. In the second phase, maximum depressor response was observed 12–13 min after injection, and lasted up to 21–22 min. In WRY there were no significant changes in MAP.3. ICV phentolamine attenuated the GRF‐induced pressor response, but did not affect the depressor response. ICV bunazosine had no effect in both responses. ICV yohimbine attenuated the GRF‐induced pressor response, but did not affect the depressor response.4. In SHR, plasma AVP concentration was not affected by ICV GRF.5. These data suggest that central GRF plays an important role in the maintenance of hypertension in SHR, since ICV GRF caused a significant depressor effect in SHR but not in WR. ICV GRF induced biphasic changes of MAP in SHR. The pressor response was mediated through central α2‐adreno‐ceptors. The depressor response was not mediated through central α‐adrenoceptors. The depressor effect of ICV GRF was not mediated by the changes of plasma AVP concentration.
ROLE OF BAROREFLEX AND CENTRAL α2‐ADRENERGIC RECEPTOR SYSTEMS IN THE DIURNAL VARIATION OF BLOOD PRESSURE AND HEART RATE IN NORMOTENSIVE AND HYPERTENSIVE RATS
Authors: Yoneda Yusuke , Takeda Kazuo , Nakamura Kazue , Fujita Hiroshi , Uchida Atsushi , Yoshitomi Tatsuo , Takenaka Ken , Itoh Hiroshi , Nakata Tetsuo , Sasaki Susumu , Nakagawa Masao 
Published: June 2007

Summary1. To elucidate whether baroreflex could contribute to manifest the diurnal blood pressure variations (DBPV) in normotension and hypertension, DBPV were recorded continuously via a femoral artery in awake normotensive (NT) rats and spontaneously hypertensive rats (SHR) with and without sinoaortic denervation (SAD). To determine the role of central cuzadrenergic receptor system in DBPV in hypertension, guanabentz (0.5–1.0 μg/kg per min) was infused in SHR.2. There were no differences in mean arterial pressure (MAP) variability (SD) of MAP of 24 h (MAP—SD/MAP) and SD of 24 h heart rate (HR—SD/HR) between SHR and NT. SAD did not elevate MAP and HR in both SHR and NT.3. However, in SAD rats, MAP—SD/MAP was significantly greater than those in sham‐operated rats in both SHR and NT, while MAP—SD/MAP and HR—SD/HR did not show any difference between the two groups even after SAD. On the other hand, SAD did not augment HR—SD/HR in either strain.4. During guanabentz infusion, MAP was significantly lowered in sham‐operated and SAD–‐SHR. Moreover, MAP –‐SD/MAP was significantly reduced in sham‐operated, but it was not in SAD–‐SHR.5. These findings suggest that baroreflex could suppress tonically the diurnal change of blood pressure in NT and SHR. The regulation of diurnal blood pressure by baroreflex via a central a‐adrenergic receptor system may be altered in SHR.
ROLE OF NITRIC OXIDE IN THE REGULATION OF CEREBRAL BLOOD FLOW IN THE OVINE FOETUS
Authors: McGrabb GJ , Harding R. 
Published: June 2007

SUMMARY1. Our aim was to determine the role of nitric oxide (NO) in regulating ceebral blood flow (CBF) in foetal sheep under conditions of both hypoxaemia and normaxaemia.2. Aseptic surgery was performed on 11 pregnant sheep at 125 ± 1.1 days of gestational age (g.a.) when foetal vascular catheters were implanted for the measurement of CBF using coloured microspheres. Additionally, each ewe was prepared for one of two procedures for inducing foetal hypoxaemia; either an adjustable clamp was placed around the maternal common internal iliac artery to reduce uterine blood flow, or a catheter was implanted into the maternal trachea for insufflation of N2. At 131 ± 0.3 days g.a., in control foetuses (n = 5), CBF and cerebral vascular resistnace (CVR) were measued under basal (normoxaemic) conditions and after 3h of hyposaemia. In ohter foetuses (n = 6) CBF and CVR were measured under basal conditions and after 3h of hypoxsaemia; in these foetuses NO synthesis was inhibited with N‐nitro‐L‐arginine (NOLA) between 2‐3h of hypoxaemia.3. In the hypoxaemia experiments foetal Sao2 and Pao2 were reduced (P < 0.05) in both control and NOLA‐treated foetuses, from normoxaemic values of 69.5 ± 2.1% and 23.8 ± 1.0 mmHg, respectively, to 29.3 ± 1.0% and 14.6 ± 0.4 mmHg during the period of hypoxaemia. In control foetuses, CBF (mL/min) was increased by 82.7% during hpoxaemia; in NOLA‐treated foetuses CBF increased by 55.3, which was less (<i>P < 0.05) than in control foetuses. In control foetuses CVR (mmHg/mL/min) was reduced by 43.5% during hypoxaemia, whereas in NOLA‐treated foetuses there was no significant change.4. In five of the 11 foetuses, the role of NO in regulating CBF under basal (normoxaemic) conditions was determined at 132 ± 0.3 days g.a. Cerebral blood flow and CVR did not significantly change from basal values after NOLA treatment.5. We conclude that in foetal sheep NO plays an important role in regulating cerebral vascular tone and hence CBF during hypoxaemia, but its contribution during normoxaemia is less apparent.
NEUROTROPHIC FACTORS AND THE DEVELOPMENT OF DRUGS TO PROMOTE MOTONEURON SURVIVAL
Authors: Hughes RA , O'Leary PD 
Published: June 2007

SUMMARY1. During embryonic development, neuronal populations undergo a period of naturally occurring cell death. In the vertebrate, the survival of neurons during this period is dependent upon specific neurotrophic factors. Recent advvances in in vitro and in vivo assays have led to the identification of a number of neurotrophic factors for spinal motoneurons, including brain‐derived neurotrophic factor, ciliary neurotrophic factor, fibroblast growth factors, insulin‐like growth factors and glial‐derived neurotrophic factor.2. The presence of multiple trophic factors promoting motoneuron survival suggests either that there is significant functional redunancy between the factors or that they act in concert to produce their effects.3. In addition to their physiological role, neurotrophic factors show tremendous clinical potential for the treatment of human neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, because they are poorly absorbed across biological membranes and are unstable in plasma, the recombinant neurotrophic factors themselves are not optimally suited as drugs. One means to circumvent these problems is to use the known three‐dimensional structures of theses factors as templates to design low molecular weight compounds that retain neurotrophic activity but exhibit better pharmacokinetic properties.
INFLUENCE OF PHARMACOGENETICS ON DRUG DISPOSITION AND RESPONSE
Authors: Eichelbaum M. , Evert B. 
Published: June 2007

SUMMARY1. Pharmacogenetics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal drug action in affected persons. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms.2. Glucose‐6‐phosphate dehydrogenase deficiency (G6PD) is the most common inherited enzymopathy affecting approximately 400 million people. The main clinical complication associated with G6PD deficiency is haemolysis after ingestion of oxidant drugs (anti‐malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.3. The activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g. N‐acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation BS to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive (EM) and poor metabolizer (PM).The prevalence of PM is different among different populations. The gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6‐formed metabolite morphine. The other extreme are the so called ultra‐rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra‐rapid metabolism has been identified to be due to CYP2D6 gene amplification.
CLEARING ‘THE FOG ON THE TYNE’: CAN THE QUALITY OF THERAPEUTICS BE ASSESSED?
Authors: Bateman DN 
Published: June 2007

SUMMARY1. The rise in prescribing costs in developed countries is a concern for all physicains, but a particular challenge for clinical pharmacologists.2. There are wide variations in the amounts and types of drugs prescribed in developed countries.3. In order to address cost appropriately it is also necessary to address quality. Various aspects of the quality of therapeutics may be considered, including audit of process, patterns of prescribing of specific drugs and reporting of adverse drug reactions.4. A consensus process is described in which primary care physicians developed criteria of prescribing quality, using data readily available within the UK. Practitioners scores using these criteria did not correlate directly with prescribing costs, indicating that cost alone cannot be used as a criterion of quality.5. The measurement of quality in therapeutics remains an important challenge for the future.
HYPOTHESIS: GLUCAGON RECEPTOR GLYCINE TO SERINE MISSENSE MUTATION CONTRIBUTES TO ONE IN 20 CASES OF ESSENTIAL HYPERTENSION*
Authors: Morris Brain J. , Chambers Susan M. 
Published: June 2007

SUMMARY1. A missense mutation leading to reduced ligand affinity in the glucagon receptor (GCG‐R) has been found recently to be five‐fold more common in essential hypertensives than normotensives. The present paper provides additional information on patients that harbour this variant and proposes a possible mechanism by which this may lead to hypertension.2. The seven hypertensives with the mutation were all female, had a later age of onset of the disease and a slightly higher body mass index.3. Glucagon is involved in the regulation of fluid and electrolyte excretion. Mutant GCG‐R results in reduced ligand affinity and cAMP response which, in the kidney, would reduce the normal natriuretic effect of glucagon. This could lead to enhanced fluid reabsorption, expansion of extracellular fluid volume and hypertension via long‐term autoregulation of blood pressure.
GAP JUNCTION AND TISSUE INVASION: A COMPARISON OF TUMORIGENESIS AND PREGNANCY
Authors: Winterhager E. , Reuss B. , Hellmann P. , Spray DC , Gruemmer R. 
Published: June 2007

SUMMARY1. Trophoblast invasion during embryo implantation in some aspects resembles tumour cell invasion but, unlike tumour cells, trophoblast cells are able to differentiate and establish a placenta. Because direct cell‐cell communication is believed to be involved in growth control and differentiation, we have investigated connexin (cx) gene expression during trophoblast development.2. he‐implantation embryos expressed cx43 as well as ex31 proteins from the 8‐cell stage onwards. Following implantation, compartmentalization of both connexins occurred: cx31 expression was restricted to the invasive trophoblast cell population, whereas the embryo proper was characterized by cx43. Trophoblast differentiation was indicated by induction of cx26 in the labyrinth and cx43 in the spongiotrophoblast accompanied by a disappearance of cx31. Comparison with trophoblast cell lines revealed that rat trophoblast HRP‐1 cells express connexin43, while malignant choriocarcinoma cells express cx31. Treatment with retinoic acid led to a disappearance of cx31 in the choriocarcinoma. Both cell lines reduced their invasion properties after retinoic acid treatment, but growth retardation was only observed in the malignant trophoblast.3. It seems that the cx31 channel is needed for trophoblast cell populations to maintain the highly proliferative properties but does not alter their invasion properties.