bluuebunny/crossref_metadata_2025 huggingface dataset:
ETA AND ETB RECEPTORS ON VASCULAR SMOOTH MUSCLE CELLS FROM MESENTERIC VESSELS OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Schiffrin Ernesto L. , Larivière Richard , Touyz Rhian M.
Published: June 2007

1. To investigate the contribution of ETA and ETB receptors, calcium responses to the ETB agonist, IRL‐1620, to endothelin‐1 (ET‐1) and to the ETA antagonist, BQ‐123, were examined in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric vessels of 3, 9 and 17 week old spontaneously hypertensive rats (SHR), Wistar and Wistar‐Kyoto (WKY) rats using Fura‐2 methodology.

2. IRL‐1620 (10‐7mol/L) and ET‐1 (10‐9mol/L) increased [Ca2+]i in all strains and ages. Responses to ET‐1 and IRL‐1620 were blunted in 17 week SHR. BQ‐123 significantly reduced ET‐1‐stimulated [Ca2+]i. In endothelium‐denuded mesenteric vessels, ET‐1 and IRL‐1620 induced significant [Ca2+]i responses.

3. Binding of ET‐1 was significantly lower in mesenteric artery membranes from 17 week SHR compared to controls.

4. Thus, ETA and ETB receptors are present in rat mesenteric VSMC. In adult SHR, a reduced density of ET receptors results in decreased responses to IRL‐1620 and to ET‐1.
ENDOTHELIN‐INDUCED ACTIVATION OF MITOGEN‐ACTIVATED PROTEIN KINASES IN GLOMERULAR MESANGIAL CELLS FROM NORMOTENSIVE AND STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kishimoto I. , Yoshimasa T. , Arai H. , Takaya K. , Miyamoto Y. , Yamashita J. , Suga S. , Komatsu Y. , Nakagawa O. , Tanaka I. , Itoh H. , Nakao K.
Published: June 2007

1. Kinase assay in myelin basic protein (MBP) containing polyacrylamide gels revealed that endothelin‐1 (ET‐1) and ET‐3 increased MBP kinase activities in glomerular mesangial cells (MC) from Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rat (SHRSP). ET‐1 stimulated MBP kinase activities more potently than ET‐3.

2. Immunoprecipitation with anti‐41‐kDa MAPK antiserum showed that the MBP kinases activated by ET‐1 correspond to 43‐ and 41‐kDa MAPK.

3. Since Phorbol 12‐myristate 13‐acetate, a direct activator of protein kinase C, also activated MAPK, protein kinase C was suggested to mediate ET‐induced activation of MAPK.

4. These results suggest that MAPK may mediate the ET actions in glomerular mesangial cells from normotensive rats as well as spontaneously hypertensive rats. Since ET is produced by vascular endothelial cells of the kidney and glomerular mesangial cells, the ET signalling pathway may have some physiological and pathophysiological significance in wivo glomerulus.
DEVELOPMENT OF HYPERTENSION IN SPONTANEOUSLY HYPERTENSIVE RATS: ROLE OF MILK ELECTROLYTES
Authors: MeCarty Richard , Tong Hongyun
Published: June 2007

1. Milk samples were collected from lactating spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) normotensive females at 8, 14 or 18 days postpartum.

2. Milk samples were later analysed for content of calcium (Ca++), sodium (Na+), potassium (K+), chloride (CI‐) and total protein.

3. Milk samples from SHR females had significantly higher concentrations of Na+ (at 8 and 14 days) and CI‐ and significantly lower concentrations of Ca++, K+ (at 8 and 14 days) and total protein compared to milk samples from WKY females.

4. Preweanling dietary content of several electrolytes implicated in the development of hypertension differred dramatically between SHR and WKY strains. This altered diet early in life may serve as an environmental trigger for progressive age‐related increases in arterial pressure in SHR.
INCREASED CA2+ INFLUX IN THE RESTING STATE MAINTAIN THE MYOGENIC TONE AND ACTIVATES CHARYBDOTOXIN‐SENSITIVE K+ CHANNELS IN FEMORAL ARTERIES FROM YOUNG SHR
Authors: Asano M. , Nomura Y. , Hayakawa M. , Ito K. M. , Ito K. , Uyama Y. , Imaizumi Y. , Watanabe M.
Published: June 2007

1. To determine the possible role of voltage‐dependent Ca2+ channels (VDCC) and Ca2+‐activated K+ (KCa) channels in the regulation of resting tone of arteries from young spontaneously hypertensive rats (SHR), mechanical responses to the agents which interact with these channels were examined in endothelium‐denuded strips of femoral arteries from 4 week old SHR and age‐matched normotensive Wistar‐Kyoto (WKY) rats. Systolic blood pressures at this age were not significantly different between SHR and WKY.

2. The strips from SHR, but not from WKY, maintained a myogenic tone; that is, the resting tone decreased when nifedipine was added.

3. Studies using 1 or 5 min pulse labelling of the strips with 45Ca showed that the basal Ca2+ influx was increased in SHR when compared with WKY, and this increase in SHR was abolished by nifedipine. Similar results were obtained when the cytoplasmic Ca2+ concentration ([Ca2+]i) in the resting state of the strips was measured by fura‐PE3.

4. The addition of charybdotoxin (ChTX, a blocker of large conductance Kca channels) to the resting state caused a concentration‐dependent contraction, which was much greater in SHR than in WKY. The ChTX‐induced contraction in SHR was abolished by nifedipine.

5. In strips preloaded with 86Rb, the basal 86Rb efflux rate constant was significantly greater in SHR than in WKY. The increase in 86Rb efflux in SHR was abolished by nifedipine.

6. The results suggest that the Ca2+ influx via L‐type VDCC was increased in the resting state of the femoral artery from 4 week old SHR, and therefore the myogenic tone was maintained and ChTX‐sensitive K+ channels were highly activated.
WHAT IS THE DIFFERENCE OF BONE GROWTH IN SHR AND SD RATS?
Authors: Inoue Tsutomu , Moriya Atsuko , Goto Kosei , Tanaka Toshimitsu , Inazu Mizuho
Published: June 2007

1. Both sexes of spontaneously hypertensive rats (SHR) and Sprague‐Dawley (SD) rats were used in this study.

2. At 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 weeks old, tibia length (L), volume (V), dry weight (DW), bone mineral density (BMD) in tibia and serum biochemical parameters (Ca2+, Ca, iP, ALP, TRAP) were measured.

3. At the 18 and 48 weeks old, bone morphometry was performed (mineral apposition rate, trabecular bone volume and trabecular thickness). Serum PTH and osteocalcin level were determined in 18 week old rats.

4. The time course change of DW, L and V were almost the same as the trends of bodyweight in each group, namely, male SD had the highest value, female SD and male SHR showed the same value and the lowest figures were obtained in female SHR.

5. BMD of the middle area showed almost the same trends with the time course change of bodyweight. On the other hand, both sexes of SHR had lower BMD than that of SD in the proximal area.

6. Serum biochemical parameters showed the same trends in both sexes of SD and SHR except for ALP (a marker of bone formation) which was higher in male than in female rats.

7. Mineral apposition rate, trabecular bone volume and trabecular thickness were not different between the same sex of SD and SHR.

8. These findings suggest that trabecular bone in SHR had a lower mineral status than that of SD rats not only in the adult but also in the young. This alteration may due to the abnormal mineralization mechanisms.
STROKE‐PRONE SHR AND ARTERIOLIPIDOSIS‐PRONE SHR AS MODELS FOR ATHEROSCLEROSIS: THEIR MECHANISMS AND APPLICATION FOR NUTRITIONAL AND PHARMACOLOGICAL STUDIES
Authors: Yamori Yukio , Murakami Shigeru , Nara Yasuo , Ikeda Katsumi
Published: June 2007

1. Peritoneal macrophages (Mø) were harvested from non‐stimulated 2 month old SHRSP and WKY, and incubated with acetyl LDL or [14C]‐oleate‐albumin complex to check total, free and esterified cholesterol (Cho) accumulation as well as acy coenzyme A‐cholesterol acyltransferase (ACAT) activity and its activation by hyperlipidaemic serum.

2. Total and esterified Cho accumulation as well as ACAT activity were enhanced in Mø from SHRSP compared with those from WKY.

3. To observe the dietary or pharmacological influence on atherogenesis, arteriolipidosis‐prone SHR (ALR) were given a high fat cholesterol diet with 3% taurine or a Ca blocker (Nilvadipine, N; 30 mg/kg), both of which significantly decreased serum Cho level and clearly attenuated arterial fat deposition.
DECREASED EXPRESSION OF THE VERY LOW DENSITY LIPOPROTEIN RECEPTOR mRNA IN THE CARDIAC VENTRICLE OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Jingami H. , Masuzaki H. , Matsuoka N. , Nakagawa O. , Ogawa Y. , Mizuno M. , Yamamoto T. , Nakao K.
Published: June 2007

1. To elucidate the functional implication of very low density lipoprotein (VLDL) receptor, we studied the gene expression of VLDL receptor in rats. The VLDL receptor mRNA was highly expressed in the cardiac ventricle and skeletal muscle. Intermediate amounts of VLDL receptor mRNA were detected in adipose tissue, adrenal gland, brain and lung. Thus the tissue distribution of VLDL receptor mRNA in rats was similar to that reported previously in rabbits.

2. We studied the gene expression of the VLDL receptor in the heart of stroke‐prone spontaneously hypertensive rats (SHRSP), an animal model for hypertension‐induced cardiac hypertrophy. RNase protection assay showed that the level of ventricular VLDL receptor mRNA was already decreased to one half when hypertension was not fully developed, and further diminished to one fifth when cardiac hypertrophy was established.

3. It is reported that energy utilization in SHRSP hypertrophied myocardium is impaired. Our results suggest that inactive fatty acid metabolism in the ventricle of SHRSP is related to the lowered expression of the VLDL receptor which is postulated as a gate for triglyceride‐rich lipoprotein particle.
ACCELERATION OF RENAL DISEASE IN OBESE SHR BY EXACERBATION OF HYPERTENSION
Authors: Koletsky Richard J. , Boccia Joseph , Ernsberger Paul
Published: June 2007

1. Obese SHR have lower blood pressures than lean litter‐mates on ad libitum diets of standard rat chow and develop spontaneous progressive kidney disease with marked proteinuria, whereas lean SHR have only mild proteinuria.

2. On a high‐salt diet, obese SHR show dramatic elevations in blood pressure accompanied by accelerated renal disease and mortality. Lean SHR are also salt sensitive but to a lesser degree.

3. Weight cycling elevates blood pressure in obese SHR to levels comparable to lean SHR littermates. This elevation in blood pressure is accompanied by an exacerbation of kidney disease relative to age‐matched controls.

4. Ganglionic blockade reversed the elevation in blood pressure in obese SHR elicited by either high‐salt diet or weight cycling. Therefore, excess sympathetic nervous activity contributes to the impact of these hypertensive stimuli,

5. Exacerbation of hypertension accelerates renal disease in obese SHR.
ALTERED PRODUCTION OF NERVE GROWTH FACTOR IN CULTURED VASCULAR SMOOTH MUSCLE CELLS FROM GENETICALLY HYPERTENSIVE RATS
Authors: Ueyama Takashi , Hamada Masanori , Hano Takuzo , Nishio Ichiro , Furukawa Shoei
Published: June 2007

1. Nerve growth factor (NGF) is a neurotrophic peptide for peripheral sympathetic nerves. Hypotrophy of sympathetic nerve ganglia and reduced content of neuropeptide Y were reported in genetically hypertensive (GH) rats. These facts led us to consider that production of NGF might be altered in GH rat cells.

2. Vascular smooth muscle cells (VSMC) were prepared from the aortic media of 12 week old GH rats and age‐matched normotensive (NT) rats by enzyme digestion method. Growth rates and the maximum cell densities were fairly equivalent between GH cells and NT cells.

3. The NGF content in the medium was measured using an enzyme immunoassay against mouse beta NGF. The amount of NGF secreted from VSMC of GH were 1.2pg/104 cells per 48 h in the progressive phase and 0.7 pgj 104 cells per 48 h in the quiescent phase, while those of NT were 8 pg/104 cells per 48 h and 1pg/104 cells per 48 h, respectively. The levels of NGF secretion per cells were greater in NT cells. In summary, NGF secretion from VSMC were reduced in GH.

4. These results suggested that a reduced production of NGF from VSMC might be involved in the reported hypotrophy of sympathetic nerve cells in GH.
FIBRINOLYTIC ACTIVITY IN LIVER TISSUES OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Okada Kiyotaka , Yuasa Haruyuki , Hagiya Yasuhiro , Takaishi Tomoaki , Fukao Hideharu , Ueshima Shigeru , Matsuo Osamu
Published: June 2007

1. Plasminogen activator activity was detected in the extract solution of the liver tissues of both stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats by the synthetic substrate assay.

2. The total PA activity in the liver extract of WKY (26.8 ± 8.3 i.u.) was about 1.5‐fold higher than that of SHRSP (18.5 ± 4.1 i.u., n = 8, P < 0.005).

3. The enzymography of the liver extract revealed three lytic bands with a molecular weight of 67 kDa, 44 kDa and 38 kDa.

4. The inhibitor activity of the liver extract was detected by the reverse fibrin autography method with one lytic resistance hand at 70 kDa.

5. Thus, fibrinolytic components exist in the liver tissue of both strains of rats, but their contribution to the stroke requires further study.
GLIAL ENDOTHELIN/NITRIC OXIDE SYSTEM PARTICIPATES IN HIPPOCAMPUS CA1 NEURONAL DEATH OF SHRSP FOLLOWING TRANSIENT FOREBRAIN ISCHAEMIA
Authors: Yamashita Kimihiro , Kataoka Yasufumi , Yamashita Yasuko S. , Himeno Akihiko , Tsutsumi Keisuke , Niwa Masami , Taniyama Kohtaro
Published: June 2007

1. When delayed neuronal death occurred in the hippocampus CA1 pyramidal cell layer of stroke‐prone spontaneously hypertensive rats (SHRSP) at 4 and 7 days after a 10 min bilateral carotid occlusion and reperfusion, intense endothelin‐1 (ET‐1)‐ and ET‐3‐like immunoreactivities became evident in astrocytes in the damaged hippocampus CA1 subfields.

2. We also observed that microglia equipped with an ETb receptor aggregated within the CA1 pyramidal cell layer with neuronal death.

3. There was a dramatic increase in nitric oxide synthase (NOS) activity in astrocytes and microglia in the damaged hippocampus CA1 subfields.

4. Thus, the possibility that microglia with the ETb receptor are activated to produce NO, a neurotoxic factor, by astrocytic ET‐1 and ET‐3 produced in response to transient forebrain ischaemia would have to be considered.
TEMPORAL AND SPATIAL PROPERTIES OF SLOW WAVES IN THE ELECTROENCEPHALOGRAM OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Chichibu Shiko , Ohta Yoshio , Chikugo Taka‐aki , Suzuki Tsuneyuki
Published: June 2007

1. Electroencephalogram (EEG) of stroke‐prone spontaneously hypertensive rats (SHRSP) and M(malignant)‐SHRSP were analysed for excitability changes in the cerebral neuronal circuit using power spectral comparisons.

2. EEG in hypertensive SHRSP and M‐SHRSP showed the emergence of slow wave bursts parallel to the development of hypertension.

3. These bursts were composed of spikes and sharp waves, and became dominant in the later stages of hypertension.

4. Bursts were interposed by a silent period indicating a strongly depressed state of neuronal activities. The ratio of the periods of the depressed to the burst increased with the progress of the hypertension.

5. A shift of the major component toward a lower frequency band also indicated decreased cerebral activity.
VASCULAR EFFECTS OF SELECTED ANTIHYPERTENSIVE DRUGS DERIVED FROM TRADITIONAL MEDICINAL HERBS
Authors: Kwan Chiu‐Yin
Published: June 2007

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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 (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

1. 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

1. 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

1. 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

1. 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

1. 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.
MECHANISMS FOR REGULATION OF ARTERIAL TONE BY Ca2+‐ DEPENDENT K+ CHANNELS IN HYPERTENSION
Authors: Rusch Nancy J. , Liu Yanping , Pleyte Kay A.
Published: June 2007

1. The membrane potential and reactivity of arterial smooth muscle cells is regulated by a variety of K+ channels, which are highly expressed in vascular smooth muscle meuscle membrances.

2. Of these K+ channel types, the high‐conductance, Ca2+‐ependent K+ channel appears to be up‐regulated in arterial smooth muscle membrances from hypertensive animals.

3. Patch‐clamp studies show that whole‐cell membrances and membrane patches of arterial smooth muscle obtained from rats with genetic or renal hypertension show an increased macroscopic and single‐channel Ca2+‐activated K+ current. Pharmacological block of this K+ current profoundly constricts aortic, renal, mesenteric and femoral arteries obtained from the same hypertensive animals, suggesting that Ca2+‐dependent K+ current is a critical determinant of resting membrane potential in arterial muscle exposed to elevated blood pressure.

4. Thus, K+ efflux through Ca2+‐dependent K+ channels appears to constitute an important homeostatic mechanism for buffering increases in arterial reactivity in hypertension.
POTASSIUM CHANNELS AND THE CORONARY CIRCULATION
Authors: Dellsperger Kevin C.
Published: June 2007

1. Mechanisms responsible for the regulation of coronary blood flow during physiologically important situations, such as reactive hyperamia, hypoxia, ischeaemia, coronary artery occlusion and increased metabolic demand, have eluded the scientific community.

2. As knowledge regarding potassium channel physiology and biophysics has expanded, the potential role of these channels in regulating coronary blood flow has been studied.

3. Recent data have demonstrated that ATP‐sensitive potassium channels (K+[ATP]) play an important role in maintaining basal coronary blood flow, contribute to the regulation of coronary blood flow during hypoxia, acidosis, ischaemia, reactive hyperaemia and ischaemic preconditioning. The role of potassium channels in the regulation of coronary blood flow during increases in metabolic stimulation is controversial.

4. Thus, potassium channels, particularly K+[ATP], appear to play an important role in regulating coronary blood flow during physiologically important stimuli.
ELECTRICAL STIMULATION OF THE AUDITORY NERVE: THE CODING OF FREQUENCY, THE PERCEPTION OF PITCH AND THE DEVELOPMENT OF COCHLEAR IMPLANT SPEECH PROCESSING STRATEGIES FOR PROFOUNDLY DEAF PEOPLE
Authors: Clark Graeme M.
Published: June 2007

1. The development of speech processing strategies for multiple‐channel cochlear implants has depended on encoding sound frequencies and intensities as temporal and spatial patterns of electrical stimulation of the auditory nerve fibres so that speech information of most importance for intelligibility could be transmitted.

2. Initial physiological studies showed that rate encoding of electrical stimulation above 200 pulses/s could not reproduce the normal response patterns in auditory neurons for acoustic stimulation in the speech frequency range above 200 Hz and suggested that place coding was appropriate for the higher frequencies.

3. Rate difference limens in the experimental animal were only similar to those for sound up to 200 Hz.

4. Rate difference limens in implant patients were similar to those obtained in the experimental animal.

5. Satisfactory rate discrimination could be made for durations of 50 and 100 ms, but not 25 ms. This made rate suitable for encoding longer duration suprasegmental speech information, but not segmental information, such as consonants. The rate of stimulation could also be perceived as pitch, discriminated at different electrode sites along the cochlea and discriminated for stimuli across electrodes.

6. Place pitch could be scaled according to the site of stimulation in the cochlea so that a frequency scale was preserved and it also had a different quality from rate pitch and was described as tonality. Place pitch could also be discriminated for the shorter durations (25 ms) required for identifying consonants.

7. The inaugural speech processing strategy encoded the second formant frequencies (concentrations of frequency energy in the mid frequency range of most importance for speech intelligibility) as place of stimulation, the voicing frequency as rate of stimulation and the intensity as current level. Our further speech processing strategies have extracted additional frequency information and coded this as place of stimulation. The most recent development, however, presents temporal frequency information as amplitude variations at a constant rate of stimulation.

8. As additional speech frequencies have been encoded as place of stimulation, the mean speech perception scores have continued to increase and are now better than the average scores that severely‐profoundly deaf adults and children with some residual hearing obtain with a hearing aid.
ELEVATED EPIDERMAL GROWTH FACTOR RECEPTOR LEVELS IN HYPERTENSIVE LYON RAT KIDNEY AND AORTA
Authors: Swaminathan Narayan , Vincent Madeleine , Sassard Jean , Sambhi Mohinder P.
Published: June 2007

1. The adult spontaneously hypertensive Lyon rats (LH strain) exhibited increased maximal epidermal growth factor (EGF) binding in freshly prepared kidney and aortic tissue membranes compared with age‐matched normotensive (LN) or hypotensive (LL) strains. However, the binding affinity of the receptors to EGF was the same in all the three strains studied. These findings indicate an increased number of EGF receptors (EGFR) in the hypertensive LH strain.

2. Protein tyrosine kinase activity associated with the EGFR was also elevated in the LH strain compared with LN or LL strains, indicating that these receptors are functionally active.

3. There was a correlation between maximal EGF binding by aortic membranes and blood pressure in individual animals (r = 0.55; P < 0.001).

4. Taken together with previously reported similar findings in other models of genetic hypertension, the present results suggest a possible role for increased levels of EGFR in the development and maintenance of genetic hypertension.
REPRODUCIBILITY OF CONVENTIONAL AND POWER SPECTRAL MEASUREMENTS OF CARDIOVASCULAR SYMPATHETIC ACTIVATION IN NORMAL SUBJECTS
Authors: Taverner D. , Nunan TA , Tonkin AL
Published: June 2007

1. Normal subjects (n = 5; age 20‐42 years; mean resting blood pressure (± 1 s.d.) 116±21/61±11 mmHg) underwent cardiovascular reflex testing five times each. On every occasion systolic blood pressure (SBP) responses to sustained handgrip (GRIP) and cold pressure (COLD) tests were measured and continuous non‐invasive SBP and heart period (RRINT) data were analysed in the frequency domain using fast Fourier transforms. Power spectral (PS) density estimates of high frequency/total power (HF%; a measure of vagal activity), low frequency/HF ratio (LF/HF; a measure mainly of cardiovascular sympathetic activity for heart period) and low frequency/total power (LF%; a proposed measure of sympathetic activity for SBP) at rest, during and 2min after the end of stimuli were calculated.

2. The data from the rest and recovery periods did not differ and showed that cardiovascular recovery to baseline measures following sympathetic stimulation occurred within 2 min.

3. There was a significant rise in SBP with GRIP and COLD. The LF/HF(RRINT) rose significantly with GRIP, but not with COLD. The LF%(SBP) did not change significantly with GRIP or COLD.

4. The SBP and PS analyses showed low intra‐individual reproducibility of responses to reflex tests, with coefficients of variation for PS measures at rest of 25‐41% and on sympathetic stimulation of up to 80%.

5. The high variability of these observations indicates that PS methods may not be suitable for the analysis of transient cardiovascular reflexes.
EFFECTS OF EXERCISE ON INTRAOCULAR PRESSURE IN PHYSICALLY FIT SUBJECTS
Authors: Qureshi Imran Ahmad
Published: June 2007

1. Several studies have shown that exercise reduces intraocular pressure (IOP) in sedentary subjects, but the effects of exercise in physically fit subjects are not fully known. Accordingly, the present study was planned to investigate the effects of exercise on intraocular pressure in physically fit subjects after elimination of those factors that can affect intraocular pressure and have been neglected by previous studies.

2. Thirty‐two sedentary males of the same age group were categorized equally into control and experimental groups. Intraocular pressures were measured during and after exercise with the Goldmann applanation tonometer. The experimental group took a supervised exercise programme of 3 months duration. Physical fitness was evaluated by the measurements of maximum oxygen uptake. Each subject was tested twice by the same exercise protocol at an interval of 3 months.

3. After 3 months, resting IOP values decreased by 0.31±0.11 (P < 0.05) and 1.37±0.15 mmHg (P<0.001) in control and experimental groups, respectively. The acute decreases following the first exercise test were 4.18±0.41 and 4.38±0.47 mmHg, while after 3 months these values were 4.12±0.45 and 2.69±0.28 mmHg in control and experimental groups, respectively. After exercise conditioning, the mean recovery time was reduced by 43.03%.

4. The results are relevant to planning trials in glaucoma. Physical fitness reduces IOP and causes significant attenuation in the IOP response to physical exercise. It would seem reasonable at present not to discourage patients who have glaucoma from light exercise; perhaps, on the contrary, it should be encouraged.