bluuebunny/crossref_metadata_2025 huggingface dataset:
ANTI‐ISCHAEMIC AND VASOSPASMOLYTIC EFFECTS OF A NOVEL Ca2+ CHANNEL BLOCKER, SD‐3211, IN VITRO
Authors: Miyawaki Nobuaki , Furuta Tatsuji , Shigei Tatsuro , Yamazaki Fumiko , Yamauchi Hideyasu
Published: June 2007

1. The present study was undertaken to determine the vasospasmolytic activity of a novel non‐dihydropyridine type of Ca2+ channel blocker, SD‐3211, in isolated canine coronary arteries and its ability to reduce myocardial ischaemic damage in isolated perfused rabbit hearts.

2. The vasospasmolytic effect of SD‐3211 was investigated using 3,4‐diaminopyridine‐induced rhythmic contraction, in comparison with its enantiomer (SD‐3212), nicardipine and diltiazem. SD‐3211 was shown to reduce the peak tension and increase the contraction frequency. The order of potency for the relaxation of the peak tension was as follows: nicardipine > SD‐3211 > diltiazem > SD‐3212 and being compatible with that for the relaxant effects of these compounds on KCl‐induced contraction in the same specimen.

3. Furthermore, the effect of SD‐3211 on myocardial damage due to global ischaemia for 60 min followed by 60 min of reperfusion was examined. SD‐3211 at a concentration of 2 × 10−8 mol/L was given for 40 min before and again for 60 min after the ischaemia. SD‐3211 attenuated the increase in leakage of creatine phosphokinase from the hearts and the decrease in pH of perfusate during reperfusion, while concomitantly providing a significant improvement in the post‐ischaemic recovery of developed tension.

4. These results suggest that SD‐3211 has properties to reduce coronary vasospasm and to provide protection against ischaemic damage, both of which may have beneficial actions in the treatment of ischaemic heart disease.
FACTORS ASSOCIATED WITH SILENT MULTIPLE LACUNAR LESIONS ON MAGNETIC RESONANCE IMAGING IN ASYMPTOMATIC ELDERLY HYPERTENSIVE PATIENTS
Authors: Kawamoto Akiko , Shimada Kazuyuki , Matsubayashi Kozo , Nishinaga Masanori , Kimura Shigeaki , Ozawa Toshio
Published: June 2007

1. Factors associated with advanced cerebrovascular damage incidentally seen on brain magnetic resonance imaging (MRI) were investigated in a population of 34 normotensive and 54 hypertensive asymptomatic elderly individuals (69±5 years).

2. Four or more ‘lacunar’ lesions per subject were considered to be advanced changes, based on the distribution in normotensive subjects and were found in 11 (20%) out of 54 hypertensive subjects.

3. Compared with the remaining 43 hypertensive patients with fewer or no lacunae, the proportion of subjects over 70 years of age who had electrocardiographic (ECG) evidence of left ventricular hypertrophy (LVH) was significantly higher in this group of hypertensive patients. Patients with multi‐lacunar lesions also showed significantly higher ‘office’ and average ambulatory, in particular, blood pressure during sleep and less nocturnal blood pressure fall, than those with fewer or no lacunae. Furthermore, they showed a higher predicted whole blood viscosity and a lower high density lipoprotein (HDL)‐cholesterol. The predictive values of LVH on ECG for the presence of multi‐lacunar lesions in hypertensive patients were substantially high (70–90%).

4. The data suggest that silent advanced cerebrovascular damages on MRI are not rare among asymptomatic elderly hypertensive patients and are associated with various cerebrovascular risk factors. A useful marker for their identification appears to be ECG‐LVH.
PATHOGENETIC ROLE OF VASCULAR ANGIOTENSIN‐CONVERTING ENZYME IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Okunishi H. , Kawamoto T. , Kurobe Y. , Oka Y. , Ishii K. , Tanaka T. , Miyazaki M.
Published: June 2007

1. This study was undertaken to examine the possibility that the level of angiotensin‐converting enzyme (ACE) increases in vascular tissue, and that this may participate in the pathogenesis of hypertension in spontaneously hypertensive rat (SHR).

2. In SHR, at the established hypertensive stage, the prolonged antihypertensive effect induced by a single oral dose of spirapril was closely correlated to the long‐lasting inhibition of ACE in aortae and mesenteric arteries. In contrast, ACE in plasma, lung, heart and kidney recovered from inhibition faster than in vessels.

3. Prolonged daily oral treatment of SHR with spirapril, initiated at the age of 8 weeks and continued for 8 weeks, prevented the development of hypertension with concomitant decrease in aortic ACE activity. Blood pressure continued to be suppressed after the drug was withdrawn, as did the aortic ACE activity.

4. Spontaneously hypertensive rats developed hypertension with age as well as with the increase in aortic ACE activity which became higher with age than that of Wistar‐Kyoto (WKY) normotensive control rats. On the contrary, ACE activity in plasma and lung of SHR was substantially lower than that of WKY at any age from 4 to 20 weeks old. Brain ACE activity of SHR did not differ from that of WKY at any age. Aged SHR showed the lower enzyme activity in the kidney compared with that of age‐matched WKY.

5. Our results support the hypothesis that increased vascular ACE may play an essential role in the development and maintenance of hypertension in SHR.
BUPRENORPHINE AND GASTROINTESTINAL TRANSIT IN RATS: EFFECT OF NALOXONE ON THE BIPHASIC DOSE‐RESPONSE CURVE
Authors: Cowan Alan
Published: June 2007

1. Buprenorphine (0.01–10 mg/kg, subcutaneous [s.c.]) slowed the passage of a charcoal meal along the gastrointestinal tract in rats. The dose‐response relationship was U‐shaped.

2. When rats were pretreated with naloxone (0.30 mg/kg, s.c), both the descending and ascending components of the buprenorphine dose‐response curve were displaced to the right.

3. Buprenorphine‐induced delay of transit was maximal at a dose of 0.10 mg/kg. In rats pretreated with naloxone, a 30‐fold higher dose of buprenorphine was required for a comparable peak effect.

4. Moderate‐high doses of buprenorphine may be acting on a functionally related binding site which non‐competitively inhibits the usual buprenorphine‐μ opioid receptor interaction.
AMRAD: THE FIRST 4 YEARS
Authors: Grace John P.
Published: June 2007

1. AMRAD (Australian Medical Research and Development) Corporation is a Melbourne biomedical research and development based pharmaceutical company that has successfully completed the first 4 years of its activities.

2. The success of the company is a result of a number of factors including the association with world class medical research institutes, adequate seed capital and sound management skills.
INHIBITION OF NO SYNTHESIS HAS AN ADDITIVE EFFECT ON HYPERTENSION INDUCED BY ACTH IN CONSCIOUS RATS
Authors: Li Ming , Dusting G. J. , Whitworth Judith A.
Published: June 2007

1. The haemodynamic and metabolic effects of oral intake of ∼30 mg/kg per day N‐nitro‐l‐arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague‐Dawley rats (n= 33).

2. NOLA administration produced an increase in systolic blood pressure of 24±6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH.

3. Compared with sham injection, ACTH‐treated rats demonstrated an increase in systolic blood pressure (water + sham, 3±1 mmHg; water + ACTH, 16±3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume.

4. The magnitude of the blood pressure rise in ACTH‐treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16±3 mmHg; NOLA + ACTH, 37±3 mmHg; P < 0.05). Metabolic changes were similar.

5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH‐induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.
ANGIOTENSIN‐CONVERTING ENZYME INHIBITION CAUSES DETERIORATION IN RENAL FUNCTION IN ONE‐KIDNEY GOLDBLATT HYPERTENSIVE RATS WITH AND WITHOUT RENAL ARTERIAL STENOSIS
Authors: Huang Wann‐Chu , Wu Jian‐Nan , Jin Jong‐Shiaw
Published: June 2007

1. The renal and hypotensive effects of a new angiotensin‐converting enzyme (ACE) inhibitor, cilazapril, were evaluated in 18 one‐kidney, one‐clip Goldblatt hypertensive rats (1K1C), 10 one‐kidney normotensive rats (1K) and eight 1K1C rats with acute unclipping (1KU). Cilazapril was infused intravenously (25 μg/kg per min) into anaesthetized rats, and the arterial blood pressure (BP) and renal clearance of rats were measured.

2. In 1K rats, cilazapril reduced BP from 123 ± 4 to 117 ± 4 mmHg (P < 0.05), and produced diuresis, natriuresis and kaliuresis without significantly changing glomerular filtration rate (GFR).

3. In 1K1C rats, cilazapril significantly reduced BP (from 157 ± 5 to 143 ± 6 mmHg; P < 0.05), GFR (14.4 ± 6.7%), urine flow (27.1 ± 8.5%) and sodium excretion (39.4 ± 7.4%). Mechanically graded reductions of renal arterial pressure alone also produced parallel decreases in GFR and renal excretory function.

4. In 1KU rats, removal of the renal arterial clip significantly decreased BP and increased renal function. Subsequent infusion of cilazapril further reduced BP and urinary excretions of sodium and water but did not significantly change GFR.

5. These results suggest that the renal function of the 1K1C hypertensive model is pressure‐dependent, and that ACE inhibitor exerts a mild antihypertensive effect but causes a pressure associated reduction in renal function. Furthermore, the detrimental effect of ACE inhibitor on the residual kidney persists after acute surgical correction of the stenosis.
RESPONSE OF PLASMA RENIN‐ANGIOTENSIN SYSTEM TO A SINGLE CAPTOPRIL ADMINISTRATION IN PATIENTS RECEIVING LONG‐TERM TREATMENT WITH CAPTOPRIL
Authors: Iwata Takeru , Dazai Yasunobu , Kitami Yutaka , Muneta Shinjiro , Imamura Yoichi , Murakami Eiki , Hiwada Kunio
Published: June 2007

1. The responses of angiotensin II (AII), AIII, aldosterone and plasma renin activity (PRA) to a single dose of captopril were investigated in hypertensive patients receiving long‐term (more than I year) captopril therapy (CT patients) and compared with those of non‐treated hypertensive patients (NT patients).

2. Baseline levels of AII and aldosterone were significantly lower in CT patients than in NT patients. AM tended to be lower and PRA was slightly higher in CT than in NT patients, but these differences were not significant.

3. A single administration of captopril (50 mg orally) significantly decreased plasma levels of AII, AIII and aldosterone as well as blood pressure in both CT and NT patients.

4. These results demonstrate that chronically repeated administration of captopril to hypertensive patients effectively reduces the daily blood pressure and concomitantly the plasma AII level to acceptable levels in patients with no experience of ACE inhibition.
IN VIVO AND IN VITRO EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON RENIN RELEASE
Authors: Ishimitsu Toshihiko , Hirata Yasunobu , Matsuoka Hiroaki , Ishii Masao , Sugimoto Tsuneaki , Kangawa Kenji , Matsuo Hisayuki
Published: June 2007

1. This study investigated the effect of atrial natriuretic peptide on renin release from the kidney. The in vitro direct effect was examined in the animal experiment using renal cortical slices of rat, and the in vivo effect was observed in the human infusion study.

2. In the in vitro experiments, α‐human atrial natriuretic peptide (α‐hANP) ranging 10−9 to 10−6 mol/L did not change the basal renin release rate from the renal cortical slices (∼9% at 10−6 mol/L, NS). Isoproterenol (10−6 mol/L) increased renin release by 40% (P < 0.001), whereas angiotensin II (10−6 mol/L) suppressed it by 48% (P < 0.001). However, α‐hANP did not affect the stimulative effect of isoproterenol or the inhibitory effect of angiotensin II.

3. Also in the human study, infusion of 25 ng/kg per min α ‐hANP failed to change the plasma renin activity in normotensive subjects (–4%) or patients with essential hypertension (+5%), or even in patients with raised renin levels such as renovascular hypertension (+ 10%) or congestive heart failure (‐13%).

4. These results put forth negative views on the direct involvement of atrial natriuretic peptide in renin release from the juxtaglomerular apparatus.
DIFFERENT BIVENTRICULAR REMODELLING OF MYOSIN AND COLLAGEN IN PULMONARY HYPERTENSION
Authors: Ishikawa Shigenori , Honda Masaaki , Yamada Sachiko , Goto Yasutoshi , Morioka Shigefumi , Ishinaga Yuji , Murakami You , Masumura Sumio , Moriyama Katsutoshi
Published: June 2007

1. To clarify the metabolism of contractile and non‐contractile proteins of the ventricles during the development of right ventricular hypertrophy (RVH) and accompanying congestive heart failure (CHF) in response to a pressure overload, monocrotaline was injected subcutaneously into Sprague‐Dawley (SD) rats. Myosin isoenzymes (MIE) were analysed by pyrophosphate gel electrophoresis under non‐dissociating conditions. Acid‐soluble collagens were analysed by an improved, non‐interrupted sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS‐PAGE). Tissue collagen content was also measured after the estimation of hydroxyproline concentration in tissues.

2. Monocrotaline induced RVH, but not left ventricular hypertrophy, at 2 weeks after the injection of monocrotaline, with severe RVH with CHF present at 4 weeks. In the right ventricles (RV) treated with monocrotaline, MIE shifted significantly from V1 to V3 at 2 weeks. The shift of MIE was more pronounced at 4 weeks. The proportion of type III collagen increased significantly compared with controls at 2 weeks. At 4 weeks, the proportion of types III and V collagens increased significantly compared with controls.

3. In left ventricles (LV) treated with monocrotaline, a similar but less remarkable shift of MIE was observed without remodelling of collagen types at 2 and 4 weeks. The concentration of collagen in either the RV or LV treated with monocrotaline showed no significant changes at 2 and 4 weeks compared with controls.

4. These results demonstrate a remodelling of the contractile and non‐contractile proteins during the development of RVH and accompanying CHF, and provide evidence for changes in protein metabolism of the counterpart of RV (i.e. the LV). These results may provide important insights into the pathophysiology of adaptive or non‐adaptive cardiac hypertrophy in response to a pressure overload.
AFFERENT CONTROL OF VASOPRESSIN AND RENIN RELEASE DURING HAEMORRHAGE IN NORMAL AND AUTONOMICALLY BLOCKED RABBITS
Authors: Courneya Carol‐Ann , Korner Paul I. , Oliver Judith R. , Woods Robyn L.
Published: June 2007

1. The role of the arterial and cardiac baroreceptors on the arginine vasopressin (AVP) and plasma renin activity (PRA) responses to haemorrhage was studied in conscious rabbits. They were bled at a rate of approximately 3% of their blood volume (BV)/min, both when the autonomic nervous system (ANS) was intact and during ANS blockade, which markedly enhances the AVP response due to the much greater haemodynamic disturbance. Under each condition of ANS function 2×2 factorial analysis was performed, each with four groups of rabbits, including animals with both sets of baroreceptors working, one or other set working and neither set working.

2. With intact ANS, haemorrhage had to be terminated at different times in the four groups. This presents problems for factorial analysis due to differences in the relationship between plasma AVP (or PRA) and release rate. A method for overcoming this was developed by extrapolating the BV‐log AVP curves to a common time from the start of bleeding.

3. Under both conditions of ANS function the arterial and cardiac baroreceptors together accounted for 90‐95% of the rise in AVP during haemorrhage. With normal ANS function, the rise in AVP was about 70% through cardiac (probably ventricular) baroreceptors (P= 0.01) and about 30% through arterial baroreceptors (P= 0.08). This compares with an earlier study at a rate of bleeding of 1.8% BV/min, where the entire drive came from the cardiac receptors. During ANS blockade, plasma AVP was enhanced approximately five‐fold, which was mostly mediated through the arterial baroreceptors, but the cardiac baroreceptor component was also greater; arterial/cardiac baroreceptor drive was 2/1.

4. Baroreflexes played no role in renin release during haemorrhage, but the experiments with ANS blockade suggest that a hormonal factor, which was related to the cardiac innervation, may limit the rise in PRA in the latter part of haemorrhage.
CARDIAC β‐ADRENOCEPTOR CHANGES IN EXPERIMENTAL HYPERTHYROIDISM IN DOGS
Authors: Hoey Andrew , Brown Lindsay , Marchant Catherine , Atwell Rick , Sernia Conrad
Published: June 2007

1. Triiodothyronine (T3; 1.0 mg/kg per day subcutaneously) was administered to 10 dogs for 14 days; 10 saline‐treated dogs served as controls. T3‐treated dogs showed the expected physiological responses of hyperthyroidism; further, chronotropic responses to isoprenaline in vivo were significantly increased in T3‐treated dogs.

2. β‐Adrenoceptor subtype density was measured in membrane preparations by displacement of l25I‐iodocyanopindolol binding by the selective β2‐adrenoceptor antagonist, ICI 118, 551. T3 treatment led to a 93% increase in right atrial β1‐adrenoceptor density and a 141% increase in left ventricular β1‐adrenoceptor density; β2‐adrenoceptor densities in right atrial, left ventricular and lung membranes were unchanged.

3. T3‐treatment did not change basal or maximally stimulated adenylate cyclase activities in left ventricular membranes.

4. Thus, the cardiovascular changes in experimental hyperthyroidism in dogs were accompanied by an increased chronotropic response in vivo to isoprenaline and an increased β1‐adrenoceptor density in atrial and ventricular membranes. However, there was no corresponding change in basal or maximal responsiveness of adenylate cyclase in ventricular membranes.
EPITHELIAL DISRUPTION BY PROTEASES AUGMENTS THE RESPONSIVENESS OF PORCINE BRONCHIAL SEGMENTS
Authors: Taher I , Sparrow Malcolm P.
Published: June 2007

1. The effect of disruption to the epithelium of intact porcine bronchi was examined by comparing the responsiveness to agonists applied to the adventitial and luminal surfaces. The development of smooth muscle tone was measured as an increase in pressure in an isovolumic bronchial segment of approximately 2 mm i.d. The reactivity and sensitivity to acetylcholine (ACh) introduced intraluminally was greatly attenuated when compared with adventitial addition.

2. Luminal exposure to K+ and vanadate (VO3) had little effect compared with strong responses obtained by adventitial application.

3. Intraluminal exposure to trypsin, chymotrypsin and elastase (1 mg/mL) selectively augmented both the sensitivity and the reactivity to the luminal addition of ACh, K+ and carbachol.

4. Mechanical removal of the epithelium produced a 716‐fold increase in sensitivity to ACh introduced luminally but had no effect on ACh applied adventitially.

5. The inhibitory effects of luminally introduced isoprenaline on electrical field stimulation responses were also significantly potentiated in segments stripped of epithelium.

6. The evidence presented here indicates that the responsiveness of in vitro airways segments is highly influenced by the epithelial layer, which acts most prominently as a barrier inhibiting the penetration of luminally introduced agonists.
INFLUENCE OF CIMETIDINE ON GALLAMINE‐INDUCED NEUROMUSCULAR PARALYSIS IN RATS
Authors: Mishra Yogendra , Ramzan Iqbal
Published: June 2007

1. The effect of cimetidine on gallamine‐induced neuromuscular paralysis was evaluated in urethane‐anaesthetized and mechanically ventilated rats.

2. Intravenous cimetidine (between 3.2 and 100 mg/kg) produced an immediate and sustained potentiation of gallamine‐induced neuromuscular paralysis.

3. Intravenous calcium (0.35 mmol/kg) completely reversed the cimetidine‐induced potentiation of gallamine's effect.

4. Cimetidine alone did not produce neuromuscular paralysis.

5. Cimetidine did not alter either the serum concentration or the total serum clearance of gallamine.

6. Cimetidine thus potentiates the action of gallamine via a pharmacodynamic and not a pharmacokinetic mechanism.
DIRECT RENAL EFFECTS OF ENDOTHELIN IN CHRONIC HYPOXIC SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Chen C. F. , Chien C. T. , Wu M. S.
Published: June 2007

1. The direct renal effects of endothelin (ET) were studied in eight chronic hypoxic rats (HA) and eight sea level (SL) spontaneously hypertensive rats (SHR).

2. After 4 weeks of exposure to simulated 5486 m (18000 ft) hypoxia, all HA rats were in apparently good health, and baseline renal function, except effective renal blood flow, was not significantly different from SL rats.

3. Intrarenal arterial administration of ET (600 ng/ kg per h) reduced ipsilateral renal excretion of water, sodium and potassium, glomerular filtration rate and effective renal plasma flow in both SL and HA rats to almost the same extent.

4. Administration of ET antiserum, however, increased the renal excretion of water in HA rats.

5. It is concluded that ET may play a role in the renal regulation of chronic hypoxic SHR.
EFFECTS OF NOISE ON BLOOD PRESSURE AND VASCULAR REACTIVITIES
Authors: Wu Chin‐Chen , Chen Shiu‐Jen , Yen Mao‐Hsiung
Published: June 2007

1. The present study investigated the effects of noise stress (100 dB, 1 kHz, 4 h/day, 6 days/ week) on both systolic blood pressure and vascular reactivities in rats exposed to noise for 2 and 4 weeks. The systolic blood pressure was significantly increased after rats were exposed to noise for 4 weeks but not 2 weeks.

2. In isolated thoracic aortic rings, the responses to serotonin were enhanced in noise‐treated rats while there were no changes in response to phenylephrine and high K4between noise‐treated and control rats.

3. The relaxant responses to endothelium‐dependent vasodilators (A23187 and acetylcholine) in noise‐treated rats were less than those in control rats. The vasodilator responses to acetylcholine were completely abolished by methylene blue or Nω‐nitro‐L‐arginine.

4. Responses to the endothelium‐independent vasodilator, nitroglycerin, were not significantly changed after rats were exposed to noise.

5. The enhanced response to vasoconstrictors and the attenuation to endothelium‐dependent vasodilators may account for elevations in blood pressure during noise stress. This indicates that the elevation in blood pressure by noise stress may be partly due to the deterioration of endothelial function.
THE EFFECTS OF THYROXINE TREATMENT ON SLOW‐ AND FAST‐CONTRACTING SKELETAL MUSCLE CONTRACTIONS OF THE CAT AND THEIR CYCLIC AMP LEVEL
Authors: Merican Zainuddin , Sukumaran S. , Raj Vijaya Lechimi , Rajikin Mohd Hamim , Khalid B. A. K.
Published: June 2007

1. The effects of thyroxine treatment on soleus and extensor digitorum longus (EDL) muscle contractions and their cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels were examined in anaesthetized cats.

2. Thyroxine treatment decreased the tension of incomplete tetanic contractions of the soleus as well as the EDL muscles. The effect on tension of these muscles was not associated with an increase in the cyclic AMP level of the muscle as is the case with a β2‐adrenoceptor agonist effect.

3. The results do not support the involvement of cyclic AMP in the tension depressant effect of thyroxine on contractions of skeletal muscle.

4. It is suggested that the muscle weakness and tremor observed in thyrotoxicosis and during administration of β‐adrenoceptor agonists are mediated by different mechanisms.
INCREASED Na+/H+ EXCHANGE ACTIVITY IN VASCULAR SMOOTH MUSCLE CELLS OF SPONTANEOUSLY HYPERTENSIVE RATS AND POSSIBLE INVOLVEMENT OF PROTEIN KINASE C
Authors: Inariba Hiromi , Kanayama Yoshiharu , Takaori Kazuo , Negoro Nobuo , Inoue Takatoshi , Takeda Tadanao
Published: June 2007

1. Na+ influx into cultured vascular smooth muscle cells (VSMC) obtained from spontaneously hypertensive rats (SHR) and from Wistar‐Kyoto rats (WKY) was measured. Na+ influx via the Na+/H+ exchange system was measured as the rate of 22Na+ influx into cultured VSMC sensitive to ethylisopropylamiloride (EIPA), a specific inhibitor of the exchange system.

2. The total 22Na+ influx rate in SHR was significantly higher than in WKY (6.08 ±0.16 vs 4.13±0.09 nmol/min per mg protein; P < 0.001; n= 14). The EIPA (1 × 104 mol/L)‐sensitive 22Na+ influx rate in SHR was significantly higher than that in WKY (4.32 ± 0.27 vs 2.17 ± 0.14 nmol/min per mg protein; P < 0.001; n= 14). There was no difference in EIPA‐insensitive 22Na+influx between SHR and WKY. The EIPA‐sensitive 22Na+ influx rate into VSMC was significantly decreased in SHR but not in WKY by the addition of 1 × 10 ‐4 mol/L 1‐(5‐isoquinoline‐sulfonyl)‐methylpiperazine (H‐7), an inhibitor of protein kinase C (PK‐C).

3. These results suggest that the increase in Na+ influx in SHR may be due to elevation of the Na+/H+ exchange activity, and possible involvement of PK‐C in the increased Na+/H+ exchange activity in VSMC from SHR.
CARDIOVASCULAR HABITUATION TO EMOTIONAL STRESS IN LYON HYPERTENSIVE RATS
Authors: Julien Claude , Sacquet Joëlle , Kandza Patrice , Su Ding‐Feng , Vincent Madeleine , Barrés Christian
Published: June 2007

1. Intra‐aortic blood pressure was recorded continuously in freely moving genetically hypertensive (LH), normotensive (LN) and low blood pressure (LL) rats of the Lyon strain during two 11 h periods (08:00‐19:00 h). During the first period (control), the animals were left undisturbed and during the second period (stress), a jet of air was applied for 20 min every hour. Urine was collected simultaneously and analysed for its content in norepinephrine and epinephrine.

2. The first exposure to the stressor induced larger increases in blood pressure and heart rate in LH than in LN and LL rats. However blood pressure and heart rate responses to the 10 following stressors decreased in LH rats while they remained stable in LN and LL animals.

3. Repeated stress exposure induced significant increases in epinephrine excretion in both LN and LL but not in LH rats.

4. It is concluded that LH rats exhibit marked cardiovascular habituation to repeated stress. Taken together with the lack of stress‐induced sympathoadrenal activation, this suggests a reduced level of emotional responsiveness in Lyon hypertensive rats.
INCREASED SENSITIVITY TO ENDOTHELIN‐1 IN ISOLATED KREBS‐PERFUSED KIDNEYS OF STREPTOZOTOCIN‐DIABETIC RATS
Authors: Tammesild Paul J. , Hodgson Wayne C. , King Roger G.
Published: June 2007

1. Vascular responses to endothelin‐1 (ET‐1) and noradrenaline (NA) were measured in isolated Krebs'‐perfused kidneys of 2 week old streptozotocin‐diabetic and non‐diabetic rats.

2. Bolus injections of either ET‐1 or NA caused dose‐dependent increases in perfusion pressure. Responses to ET‐1 (10–60 ng/g kidney), but not to NA (0.001–10 μg/g kidney), were significantly potentiated in kidneys of diabetic rats compared with non‐diabetics.

3. Indomethacin significantly attenuated responses to NA (0.3–10 μg/g kidney) in kidneys of both diabetic and non‐diabetic rats.

4. Neither indomethacin (1 μmol/L) nor the cyclo‐oxygenase/lipoxygenase inhibitor BW755C (1 μmol/L) had any significant effect on the log dose‐response curve to ET‐1 in either group of kidneys.

5. Perfusion with N‐nitro‐L‐arginine (NOLA; 10 μmol/L) had no effect on basal perfusion pressures, but potentiated responses to ET‐1 in both groups of kidneys. However, the difference in responses to ET‐1 between kidneys from diabetic and non‐diabetic rats remained significant in the presence of NOLA.

6. ET‐1 responses were inhibited in Ca2+‐free Krebs’ solution (plus 1 mmol/L EGTA).

7. The results of the present study indicate an increased sensitivity to ET‐1 in isolated Krebs'‐perfused kidneys of diabetic rats. Responses to ET‐1 were unaffected by cyclo‐oxygenase and/ or lipoxygenase inhibitors, but were potentiated by an endothelium‐derived relaxing factor (EDRF) synthesis inhibitor.
ENALAPRIL DECREASES PLASMA NORADRENALINE LEVELS DURING THE COLD PRESSOR TEST IN HUMAN HYPERTENSIVES
Authors: Minatoguchi Shinya , Ito Hiroyasu , Koshiji Masatoshi , Masao Kakami , Hirakawa Senri , Majewski Henryk
Published: June 2007

1. The effects of the angiotensin‐converting enzyme (ACE) inhibitor enalapril on the responses of blood pressure and plasma catecholamine levels to the cold pressor test in human hypertensives were examined.

2. Systolic and diastolic blood pressure decreased significantly after treatment with enalapril (5 mg/ day for 4 weeks) as did the resting level of plasma noradrenaline.

3. The cold pressor test induced a rise in blood pressure and plasma noradrenaline levels. After 2 and 4 weeks enalapril treatment, the rises in the plasma noradrenaline level and systolic and diastolic pressure due to cold pressor test were reduced significantly.

4. These results suggest that ACE inhibition has a sympatho‐inhibitory effect. One possible explanation is that enalapril reduces angiotensin II formation thus decreasing the activation of release‐enhancing angiotensin II receptors on postganglionic sympathetic nerve endings.
INAPPROPRIATELY ELEVATED LEVELS OF ATRIAL NATRIURETIC PEPTIDE MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF ORTHOSTATIC HYPOTENSION
Authors: Tunny Terry J. , Gordon Richard D. , Klemm Shelley A. , Bachmann Anthony W. , Finn Wendy L.
Published: June 2007

1. Overnight recumbent and upright plasma atrial natriuretic peptide (ANP) levels were markedly elevated (P < 0.001) in patients with orthostatic hypotension (OH).

2. Overnight urinary clearance of ANP was significantly lower (P < 0.01) in patients with OH, and was inversely correlated with plasma ANP levels (r=–0.94, P < 0.01). The same negative correlation (r=–0.87, P < 0.01) was seen in normal subjects.

3. Reduced urinary clearance of ANP may be associated with reduced filtered load and increased binding of ANP to the neutral endopeptidase 24.11 receptor binding sites in the proximal renal tubule.

4. ANP may be involved in the pathophysiology of orthostatic hypotension.
EFFECTS OF REPEATED DOSES OF PSEUDOEPHEDRINE ON BLOOD PRESSURE AND PLASMA CATECHOLAMINES IN NORMAL SUBJECTS AND IN PATIENTS WITH PHAEOCHROMOCYTOMA
Authors: Gordon Richard D. , Ballantine Donna M. , Bachmann Anthony W.
Published: June 2007

1. Increases in blood pressure (BP) and in plasma noradrenaline concentration (NA) were observed after two doses of a non‐prescription decongestant containing pseudoephedrine (PE) in two of three patients with phaeochromocytoma, before but not after removal of the tumour. The pressor response was terminated by oral phenoxybenzamine, and modified by prior exposure to this drug.

2. In eight normal subjects administration of the same two doses prevented falls in BP and in NA usually seen with prolonged recumbency, but neither BP nor NA increased. However, a pressor response was observed in a normal subject with a strong family history of hypertension.

3. Exposure to PE in non‐prescription decongestants is not without risk in hypertension.
SUBPRESSOR CALCIUM INFUSION INCREASES ISOVOLUMIC LEFT VENTRICULAR RELAXATION TIME AND ATRIAL NATRIURETIC PEPTIDE IN HUMANS
Authors: Finn Wendy L. , Gordon Richard D. , Seneviratne Basil I. , Tunny Terry J. , Klemm Shelley A.
Published: June 2007

1. Subpressor calcium infusion for 1 h, which raised calcium levels to the upper limit of normal in normal subjects, increased plasma and urinary levels of atrial natriuretic peptide (ANP).

2. Heart rate fell, presumably due to carotid baroreflex stimulation (supported by the fall in noradrenaline) and the resultant fall in cardiac output prevented the expected rise in blood pressure due to the rise in total peripheral resistance (TPR). Thus the increase in ANP was not explained by an increase in blood pressure or noradrenaline.

3. There was no evidence for increased atrial stretch (no increase in atrial area or early velocity of left ventricular filling) as a mechanism for increased ANP.

4. Isovolumic left ventricular relaxation time increased, early velocity of ventricular filling decreased and TPR increased, consistent with increased tone in left ventricular and arteriolar muscle.

5. This suggests a direct effect of calcium on the atrial myocyte, stimulating ANP either through contractile or secretory mechanisms.
POLYMORPHISMS OF CANDIDATE GENES IN ESSENTIAL HYPERTENSION
Authors: West M. J. , Summers K. M. , Huggard P. R.
Published: June 2007

1. Family and population studies have reported that blood pressure has a heritability of 30–50%, but simple genetic models do not readily explain the patterns of inheritance of hypertension.

2. Restriction fragment length polymorphisms were used to study allele frequencies of a selection of candidate genes that may be important in determining the genetic component of hypertension. These included the genes for renin, haptoglobin, neuropeptide Y and cardiac myosin β heavy chain.

3. There was no significant association between alleles at any of these loci and the presence of hypertension in this population, suggesting that the contribution of variation at these loci to the genetic component of the variance in hypertension may be quite small.
AXONAL PROJECTIONS FROM RESPIRATORY CENTRES TOWARDS THE ROSTRAL VENTROLATERAL MEDULLA IN THE RAT
Authors: Pilowsky Paul , Wakefield Bruce , Minson Jane , Llewellyn‐Smith Ida , Chalmers John
Published: June 2007

1. Efferent pathways from brainstem respiratory centres towards bulbospinal tyrosine hydroxylase immunoreactive neurons were identified in the rat using a combination of electrophysiology, retrograde and anterograde tract‐tracing, and immunohistoehemistry.

2. Varicose axons originating from respiratory centres were found in close apposition to bulbospinal tyrosine hydroxylase immunoreactive neurons in the ventrolateral medulla.

3. These findings support the idea that respiratory rhythms in sympathetic nerves may be due to a synaptic connection between brainstem respiratory neurons and bulbospinal tyrosine hydroxylase immunoreactive neurons of the CI cell group.
MESENTERIC VASCULAR ANGIOTENSIN‐CONVERTING ENZYME IS INCREASED IN EXPERIMENTAL DIABETES MELLITUS
Authors: Jandeleit Karin , Rumble Jon , Jackson Bruce , Cooper Mark E.
Published: June 2007

1. Diabetes mellitus was induced by streptozotocin in male Wistar rats, and angiotensin‐converting enzyme measured in plasma and mesenteric vessels 3 weeks later.

2. Diabetes was associated with increased mesenteric wet weight/ bodyweight ratio (control 0.2 s.e.m. 0.02 mg/g, n= 21, vs diabetes 1.0 s.e.m. 0.3 mg/g, n= 27, P < 0.01, ANOVA).

3. Plasma angiotensin‐converting enzyme activity was increased in diabetic rats (98 s.e.m. 3 nmol HL/mL per min) compared with controls (64 s.e.m. 6 nmol HL/mL per min, P < 0.01, ANOVA).

4. Mesenteric vessel angiotensin‐converting enzyme was increased in diabetes mellitus estimated by radioligand binding site density (fmol/mg protein; 1407 s.e.m. 166 fmol/mg protein) compared with controls (890 s.e.m. 56 fmol/mg protein, P < 0.05, ANOVA) and by enzyme kinetic assay (diabetes, 15.5 s.e.m. 1.5 nmol HL/mg protein per min, controls, 8.3 s.e.m. 0.7 nmol HL/mg protein per min, P < 0.01, ANOVA). The equilibrium dissociation constant of ligand‐angiotensin‐converting enzyme interaction was unchanged.

5. Increased vascular angiotensin‐converting enzyme concentration may contribute to vascular hypertrophy and diabetic vasculopathy by increased local synthesis of angiotensin II.
MESENTERIC RESISTANCE AND BRAIN MICROVASCULAR ANGIOTENSIN‐CONVERTING ENZYME IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Jandeleit Karin , Perich Rose , Jackson Bruce , Johnston Colin I.
Published: June 2007

1. Angiotensin‐converting enzyme (ACE) concentration was measured in mesenteric and brain microvessels from spontaneously hypertensive rats (SHR) and compared with normotensive controls using a specific radioligand binding assay.

2. Plasma angiotensin‐converting enzyme activity was similar in SHR (n= 15) and normotensive controls (n= 21; 58 ± 1 nmol HL/mL per min, vs 64 ± 6 nmol HL/mL per min).

3. There was no significant difference between the mesenteric vascular angiotensin‐converting enzyme radioligand binding site density (Bmax, fmol/ mg protein) of SHR and normotensive controls (954 ±77 vs 890 ±56, P= 0.5, unpaired Student's t‐test), despite significant differences in systolic blood pressure (220 ± 8 mmHg vs 120 ± 6 mmHg respectively, P < 0.01) and increased mesenteric wet weight to body weight ratio in the hypertensive rats (0.28 ± 0.02 mg/g, n= 5 vs 0.16 ± 0.02 mg/g, n= 7, P < 0.01).

4. Brain vascular angiotensin‐converting enzyme radioligand binding site density (Bmax, fmol/ mg protein) was also similar in SHR and normotensive controls (467 ±62, n= 5 vs 497 ± 64, n= 5, P= 0.7, unpaired Student's t‐test).

5. These results demonstrate that vascular angiotensin‐converting enzyme concentration is not altered in the SHR and that vascular ACE is not increased in this form of vascular hypertrophy or regulated by the blood pressure level.
VARIATION IN ANGIOTENSIN‐CONVERTING ENZYME (ACE) INHIBITOR AFFINITY AT TWO BINDING SITES ON RAT PULMONARY ACE: INFLUENCE ON BRADYKININ HYDROLYSIS
Authors: Perich Rose B. , Jackson Bruce , Johnston Colin I.
Published: June 2007

1. ACE from rat lung and testis was characterized by radioligand binding studies using [125I]‐Ro 31‐8472, the radioiodinated hydroxy derivative of the potent ACE inhibitor cilazaprilat.

2. Analysis of the displacement of [125I]‐Ro 31‐8472 from ACE by ACE inhibitors of different structure by the ligand program was best fitted by a two binding site model for lung ACE and a one binding site model for testis ACE.

3. There was marked variation in ACE inhibitor binding affinity at the two binding sites of lung ACE across the panel of ACE inhibitors studied (equilibrium dissociation constant; Kd; pmol/ L) for site one vs site two: cilazaprilat 40 ± 3 vs 430 ± 92*; lisinopril 25±1 vs 848 ± 107**; and quinaprilat 4 ± 1 vs 1869 ± 720; **P < 0.05; **P < 0.005, t‐test, n= 3). Reduction in binding affinity at site two of lung ACE was related to an increase in ACE inhibitor side chain length or complexity of carboxyl terminal moiety. ACE inhibitor binding affinity at the testis ACE binding site resembled site one of lung ACE.

4. Inhibition of bradykinin hydrolysis by lung ACE in the presence of increasing concentrations of cilazaprilat or quinaprilat was similar (F= 0.64; P>0.05), suggesting that bradykinin cleavage predominates at ACE active site one.

5. The differences in ACE inhibitor affinity at the two ACE active sites has implications in physiological substrate selectivity, and may influence the pharmacodynamic effects of different ACE inhibitors.
DEVELOPMENT AND VALIDATION OF ECHOCARDIOGRAPHY METHODS FOR ESTIMATING LEFT VENTRICULAR MASS IN RATS
Authors: Jones Elizabeth F. , Harrap Stephen B. , Calafiore Paul , Tonkin Andrew M.
Published: June 2007

1. The aim of this study was to develop non‐invasive echocardiography methods of measuring left ventricular mass (LVM) in rats, and to determine their usefulness in detecting left ventricular hypertrophy.

2. After initial studies to identify the optimum transducer and to ascertain the resolution limits of echocardiography, the repeatability of LVM estimates was studied. The average difference between two independent estimates in 86 male rats (average LVM = 674.7 mg) was 5.4 mg, and the standard deviation of the difference was 107.6 mg.

3. To determine agreement between direct and indirect methods, LVM was measured in 38 male rats by echocardiography and compared with direct measurement of the left ventricular weight at sacrifice. The mean difference between the two methods was 9.14 ± 56.6 mg. The limits of agreement were from ‐ 122.4 to +104.1 mg.

4. Echocardiography was then used to measure LVM in eight male spontaneously hypertensive rats and eight male normotensive Donryu rats at 9 weeks of age. The mean LVM of SHR was 768.2 mg ± 152.6, which was significantly (2P < 0.001) greater than the LVM of DRY (435.4 mg ± 32.2).

5. We conclude that echocardiography provides a non‐invasive, repeatable and relatively accurate estimate of LVM in rats. The method is a potentially useful tool for studying the development or regression of cardiac hypertrophy in longitudinal experiments.
EFFECT OF NEUTRAL ENDOPEPTIDASE INHIBITOR IN RATS WITH CONGESTIVE HEART FAILURE
Authors: Murohara Yoshiharu , Johnston Colin I.
Published: June 2007

1. The acute hormonal, renal and haemodynamic effects of SCH 39370, a new neutral endopeptidase (NEP) inhibitor, were evaluated in rats with congestive heart failure (CHF) produced by coronary ligation.

2. Left ventricular systolic pressure and left ventricular end diastolic pressure were significantly decreased by SCH 39370 treatment.

3. SCH 39370 improved cardiac function by increasing cardiac index and decreasing total peripheral resistance.

4. SCH 39370 induced a transient but significant diuresis and natriuresis.

5. These effects were associated with significant increases in urinary atrial natriuretic peptide (ANP) and cyclic GMP excretion, but not with an increase in plasma ANP levels.

6. The results suggest that NEP inhibition may be a new therapeutic method for treating CHF possibly by potentiating the biological activities of endogenous ANP.
INTERACTION BETWEEN VASOPRESSIN AND ENDOTHELIN IN RENAL PAPILLARY TUBULES: UNCOUPLING FOLLOWING CELL ISOLATION AND CULTURE
Authors: Woodcock Elizabeth A. , Land Sarah
Published: June 2007

1. In freshly prepared rat renal papillary tubules, endothelin‐related peptides inhibited the vasopressin‐stimulated accumulation of cAMP. No inhibition was observed when tubules were cultured overnight ex vivo.

2. Endothelin‐1, endothelin‐3 and sarafatoxin S6b had similar potencies as inhibitors of cAMP accumulation, indicating an endothelin (ETb) receptor.

3. These results demonstrate an interaction between ETb receptors and vasopressin receptors at the level of their signal transduction pathways, and show that this relationship is lost following cell culture.
ENDOTHELIUM‐DEPENDENT AND‐INDEPENDENT RELAXATION BY DOPAMINE IN THE RABBIT PULMONARY ARTERY
Authors: Yamauchi Masanobu , Kobayashi Yuta , Shimoura Keiko , Hattori Keisuke , Nakase Akira
Published: June 2007

1. The relaxing response of dopamine (DA) was studied in the rabbit pulmonary artery. DA caused concentration‐related relaxation in helically cut strips of the artery contracted with prostaglandin F2α in the presence of prazosin.

2. The DA‐induced relaxation in endothelium‐denuded strips was reduced to about 40% compared with that in endothelium‐intact strips.

3. Methylene blue and haemoglobin, inhibitors of endothelium‐dependent relaxation, reduced the DA‐induced relaxations in endothelium‐intact strips to the level of endothelium‐denuded strips. These results indicate that the DA‐induced relaxation is partially mediated or modified by the release of endothelium‐derived relaxing factor (EDRF).

4. Apomorphine, as a DA agonist, caused concentration‐dependent relaxation in endothelium‐intact strips. Bromocriptine, a DA2 agonist, produced only a little relaxation at higher concentration.

5. In endothelium‐intact strips, haloperidol, a DA antagonist, and the DA1 antagonists, fluphenazine and SCH 23390 inhibited DA‐induced relaxations. On the other hand spiperone and domperidone, DA2 antagonists, were inactive.

6. In endothelium‐denuded strips, fluphenazine and SCH 23390 inhibited DA‐induced relaxations, but domperidone was inactive.

7. These results indicate that the DA‐induced relaxation is mediated by DA receptors, and that DA1 receptors are involved in both endothelium‐dependent and‐independent relaxation in the rabbit pulmonary artery.
RANITIDINE INHIBITS ADRENERGIC TRANSMISSION IN THE RAT ISOLATED ANOCOCCYGEUS MUSCLE
Authors: Gwee M. C. E. , Cheah L. S.
Published: June 2007

1. The effects of ranitidine on adrenergic transmission in the rat isolated anococcygeus muscle were investigated.

2. Cumulative doses (2–8 mmol/ L) of ranitidine produced a concentration‐dependent inhibition of motor responses of the rat isolated anococcygeus muscle evoked by field stimulation (20–25 V, 10 Hz for 10 s, 1 ms pulse width) every 2 min, but also potentiated the contractile response to exogenous noradrenaline (5 μmol/L). The inhibited motor responses recovered rapidly and completely after washing out ranitidine.

3. 4‐Aminopyridine (100 μmol/L) effectively reversed the partially inhibited (55% or greater) motor responses.

4. The results strongly suggest that ranitidine can inhibit adrenergic transmission in the anococcygeus muscle by a prejunctional mechanism with, presumably, consequent development of supersensitivity of the effector cells to noradrenaline.
CARDIAC EFFECTS OF LOCAL ANGIOTENSIN‐CONVERTING ENZYME INHIBITION IN HYPERTENSIVE PATIENTS
Authors: Nakashima Yoshiyuki , Nii Takanobu , Tashiro Eiichiro , Ikeda Masaharu , Arakawa Kikuo
Published: June 2007

1. The direct cardiac effects of angiotensin‐converting enzyme (ACE) inhibitor in 22 hypertensive patients were investigated. Radionuclide ventriculography and echocardiography were performed to measure left ventricular function before and 60 min after administration of a subdepressor dose of captopril.

2. Since the response to ACE inhibitor is not uniform, patients were classified into 12 patients without significant blood pressure change following captopril (group I) and 10 patients with reduction of blood pressure (group II).

3. Clinical and baseline haemodynamic characteristics were similar for the two groups.

4. Ejection fraction (EF) increased without changes of heart rate and end‐diastolic dimension after ACE inhibitor in group I as well as group II. The change of EF was not different for the two groups. No correlation was found between changes in EF and blood pressure in group I patients.

5. This study indicates that ACE inhibitor might directly influence left ventricular function independent of systemic haemodynamic changes.
MODELLING OF FREQUENCY‐DEPENDENT EFFECTS OF LIGNOCAINE HOMOLOGUES ON THE MAXIMUM UPSTROKE VELOCITY OF ACTION POTENTIALS IN GUINEA‐PIG PAPILLARY MUSCLES
Authors: Hamamoto Takuyuki , Ichiyama Masashi , Takahashi Yoshihiro , Ban Takashi
Published: June 2007

1. The effects of 14 lignocaine homologues on the maximum upstroke velocity (Vmax) of the action potentials (AP) were studied in guinea‐pig papillary muscles. These drugs possess one, two or three methyl groups in different positions: an ortho‐chloro,‐carbomethoxy or‐ethyl group instead of an ortho‐methyl group; or an N‐butyl group instead of an N‐diethyl group in lignocaine molecules.

2. At 50–100 μol/L, six drugs possessing two ortho substituents (but not the other eight) reduced Vmax more prominently at 2‐4 Hz than at 1 Hz, and slowed the time courses of recovery of the premature responses. None of the drugs affected resting potential.

3. Besides the two‐state piecewise exponential model (models I and II) frequently used, a time‐dependent and time‐independent, two‐state model (model III) was formulated and applied to these experimental data. The above two groups were effectively distinguished by the difference of the estimated association and dissociation rate constants (model II) and equilibrium constants for phasic state (model III) and for resting (model II) or tonic (model III) states.

4. The equilibrium constants for resting or tonic state correlated well with log P (where P = the n‐octanol: water partition coefficients), but correlated better with an indicator variable that denotes the existence of two ortho substituents, suggesting the importance of the contribution of steric factors to the activity.