bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Variability Among Disease‐Resistant Inbred Rat Strains And In Comparison With Wild Rats (Rattus Norvegicus)
Authors: Brandt Jens van den , Kovács Peter , Klöting Ingrid
Published: March 2003

1. Inbreeding and optimization of environmental conditions for laboratory rats may have led to the survival of mutants with metabolic aberrations but without evident disease phenotype. Therefore, in the present study, we compared metabolic traits between so‐called disease‐resistant inbred rat strains Dark Agouti (DA), Brown Norway (BN), Lewis (LEW), Wistar‐Kyoto (WKY), Fischer 344 (F344) and wild rats (Rattus norvegicus).

2. Twelve males of each strain at 12, 13 and 14 weeks of age were studied for bodyweight, body mass index (BMI), blood glucose, serum triglycerides, total cholesterol, insulin and leptin.

3. In comparison with wild rats, the cholesterol values were significantly increased in all inbred rats studied. Except for DA rats, all rats were also significantly heavier than wild rats.

4. There were also significant differences between the different disease‐resistant strains and WKY rats were the biggest animals with the highest bodyweight, BMI and cholesterol values.

5. The strains could be separated into groups with either very high (F344, LEW, WKY) or low values (DA, BN) of serum insulin and leptin levels.

6. Because all rats were studied under the same conditions, the findings suggest a substantial strain dependence in feeding behaviour and energy balance caused by the different genotypes.
The Microvasculature As A Dynamic Regulator Of Volume And Solute Exchange
Authors: Huxley Vh , Rumbaut Re
Published: March 2003

1. It has long been held that the microvessels are passive pipes through which the formed elements of blood and plasma course and from which exchange occurs. Physiological and structural data from vascular cells in culture to whole organs strongly support the notion that microvessels, whether in their arrangement as networks, in their microvascular phenotypic subtypes or with regard to their permeability properties, are anything but static.

2. Examples from different models, organs and species are presented to illustrate the spatial and dynamic nature of the microvasculature.

3. Given that the ultimate goal of this cardiovascular research is to apply what is learned from component parts of the microvasculature to understand integrated tissue function, examples of the danger of generalizing results from limited studies are presented.

4. Finally, accurate interpretation of most of the research in this area is predicated on the assumption that probe molecules, rendered visible by the binding of dyes, are biologically inert.

5. We present data demonstrating that some dyes used widely in microvascular studies can alter the barrier under study and/or alter the physicochemical characteristics of the molecule to which they were bound.
Vasopressin V1A Receptor Antagonism Does Not Reverse Adrenocorticotrophin‐Induced Hypertension In The Rat
Authors: Fraser Tafline B , Turner Steven W , Wen Cheng , Li Ming , Burrell Louise M , Whitworth Judith A
Published: March 2003

1. The role of arginine vasopressin (AVP) was examined in adrenocorticotrophin (ACTH)‐induced hypertension in Sprague‐Dawley rats using the non‐peptide AVP V1a receptor antagonist OPC 21268.

2. In an acute study, six rats were pretreated with ACTH for 11 days and direct arterial blood pressure (4 h), plasma osmolality and electrolyte concentrations were measured after OPC 21268 gavage. In a chronic study, 40 rats were randomly divided into four groups: (i) sham injection + sham gavage; (ii) ACTH + sham gavage; (iii) sham injection + OPC 21268; or (iv) ACTH + OPC‐21268 for 16 days. Systolic blood pressure (SBP), water intake, urine volume (UV), urine osmolality and electrolytes, food intake, bodyweight and plasma osmolality and electrolyte concentrations were measured.

3. In the acute study, direct mean arterial blood pressure did not change with OPC 21268 (122±2 and 120±3 mmHg at 0 and 240 min, respectively).

4. In the chronic study, OPC 21268 did not affect ACTH‐induced rises in blood pressure (from 125±2 (control) to 145±5 mmHg (group 4) compared with 122±3 (control) to 149±5 mmHg (group2)). Water intake and UV increased (from 29±2 to 83±6 mL/day; and from 5±1 to 36±5 mL/day, respectively) and the change in bodyweight decreased from 0±2 to –107±7 g.

5. These results suggest that AVP (at the V1a receptor) does not play a significant role in the maintenance of ACTH‐induced hypertension.
Decreased Left Ventricular Contractility Reserve In Patients With Never‐Treated Essential Hypertension
Authors: Tanaka Mamoru , Hashimoto Yuji , Numano Fujio
Published: March 2003

1. Left ventricular diastolic dysfunction is often present in patients with essential hypertension. To determine whether left ventricular systolic function is normal or subnormal, we evaluated the global left ventricular contractile reserve in patients with untreated essential hypertension.

2. Thirty‐one untreated men with essential hypertension and 12 normotensive healthy men were evaluated. Hypertensives were divided into two groups based on the presence (group Hc; n = 21) or absence (group Hn; n = 10) of concentric left ventricular geometric remodelling, which was defined as a relative wall thickness ≥ 0.45 on M‐mode echocardiography. We compared echocardiographic data of left ventricular function in hypertensive men with those in healthy men under β‐adrenoreceptor activation by up to 10 μg/kg per min dobutamine infusion.

3. At baseline, endocardial (eFS) and midwall fractional shortening of the left ventricle, the early peak filling velocity (E), the peak late filling velocity (A) and the ratio E/A were similar in the three groups. During dobutamine infusion, eFS was significantly lower in groups Hc and Hn (54.1±9.2 and 54.1±7.9%, respectively) than that observed in group N (61.7±7.4%). In addition, eFS was highly correlated with circumferential end‐systolic wall stress (ESS) during dobutamine infusion in the three groups. In 11 subjects in group Hc (52%), the eFS‐ESS relationship was lower than the 95% confidence limit of the normal regression. Comparing group Hc with groups N and Hn, it was found that E (0.52±0.12, 0.71±0.16 and 0.63±0.15 m/s, respectively) and E/A (0.74±0.23, 1.24±0.53 and 0.98±0.37, respectively) were significantly lower.

4. Our results suggest that, in addition to diastolic dysfunction, the reserve of systolic function decreased under β‐adrenoceptor activation in patients with essential hypertension.
Changes In Absorptive Function Of Rat Intestine Injured By Methotrexate
Authors: Naruhashi Kazumasa , Nadai Masayuki , Nakao Makoto , Suzuki Nagao , Nabeshima Toshitaka , Hasegawa Takaaki
Published: March 2003

1. Methotrexate (MTX), an anticancer drug, has been shown to induce acute injury in the small intestine. The present study was designed to investigate the in vivo absorptive function of the small intestine injured by MTX using an amino‐β‐lactam antibiotic cephalexin (CEX). Time‐dependent changes in diamine oxidase (DAO) and alkaline phosphatase (ALP) activity in the small intestine and histopathological findings were also measured in rats treated with MTX (20 mg/kg).

2. Most severe mucosal damage was observed 2 days after MTX treatment and the area under the plasma concentration–time curve of CEX (AUCCEX) following oral administration of 20 mg/kg tended to decrease. Thereafter, the AUCCEX increased significantly and the histopathological changes diminished within 5 days.

3. Both villus height and mucosal weight followed the same pattern, decreasing in the first 2 or 3 days following treatment, increasing on the 5th day and returning to control levels by the 10th day. Methotrexate‐induced changes in the mucosal wet weight/whole intestinal weight ratio were significantly correlated with those of AUCCEX, but did not correlate with mucosal DAO and ALP activity.

4. These findings provide evidence that the change in the total amount of CEX is an index of the active transport function, probably by intestinal peptide transporter (PEPT1), and is well reflected by histopathological changes in the intestinal mucosa induced by MTX. In addition, there is a possibility that this method could be applied in the clinical setting for diagnosis of intestinal status and absorptive function.
Polymorphisms Of The Renin Gene Promoter In Spontaneously Hypertensive And Wistar‐Kyoto Rats
Authors: Leckie Brenda J
Published: March 2003

1. In the present study, 1.39 kb of the renin gene 5′region in spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats was amplified by polymerase chain reaction from genomic DNA and sequenced. Consistent differences in the renin gene sequence of SHR and WKY rats were found at positions –725, –727, –979 and –1126/–1129 as numbered from the transcription start site (+1). No polymorphism was specific to hypertensive rats.

2. Gel‐shift assays were performed using labelled SHR renin promotor DNA and nuclear proteins extracted from rat kidneys. The regions between –1122 and –1139 and between –701 and –797 showed protein binding.
Experimental Biology 2000 Symposium on Differential Control of Sympathetic Outflow MULTIPLE OSCILLATORS, DYNAMIC SYNCHRONIZATION AND SYMPATHETIC CONTROL
Authors: Gilbey Michael P
Published: March 2003

1. Intermittent bursts of activity are a robust feature of the discharges of sympathetic nerves. There are at least two major mechanisms producing such discharges: (i) phasic inputs influencing sympathetic circuits; and (ii) oscillators embedded within sympathetic networks. The functional significance of patterned and synchronized activity underlying bursts of population activity may reside in their influence on information transfer between excitable cells. At the level of the single neuron, firing pattern appears to be an important determinant of synaptic/neuroeffector function (e.g. the probability of transmitter release, the types of transmitter released, the types of receptor activated and plasticity). Synchronization of inputs at a target favours summation and, therefore, may influence response (short term and long term).

2. In the present paper, I review the work from my laboratory that has focused on furthering understanding of the potential functional importance of pattern and synchrony coding in sympathetic nervous control of cardiovascular function. Because the rat tail artery has been used extensively as a model for studying neuroeffector transmission, in our investigations we have recorded from its sympathetic innervation.

3. In the anaesthetized preparation, under steady state conditions, we have established that the discharges of these sympathetic neurons have a distinct rhythm (frequency approximately 0.8 Hz). This can be detected both at single neuron and population levels.

4. A family of oscillators appears to control their discharge such that under some conditions all neurons do not have the same frequency of rhythmical activity. However, these weakly coupled or uncoupled oscillators can be synchronized dynamically by various inputs, such as central respiratory drive, lung inflation cycle‐related inputs and inputs arising from visceral and somatic afferents.

5. The potential functional significance of dynamic synchronization of sympathetic oscillators in relation to sympathetic pattern generation and neuroeffector transmission is discussed.
Protective Effect Of Resveratrol On Oxidative Damage In Male And Female Stroke‐Prone Spontaneously Hypertensive Rats
Authors: Mizutani Kenichi , Ikeda Katsumi , Kawai Yasuhiro , Yamori Yukio
Published: March 2003

1. In the present study, we examined the effect of resveratrol (3,4′,5‐trihydroxystilbene), a phytoestrogen found in the skins of most grapes, on oxidative DNA damage in male and female stroke‐prone spontaneously hypertensive rats (SHRSP).

2. Five‐week‐old male and female SHRSP were divided into control and resveratrol groups. The resveratrol group was given 1 mg/kg per day, orally, resveratrol by gastric intubation once a day.

3. Following an 8 week feeding period, the levels of 8‐hydroxydeoxyguanosine (8‐OHdG), produced from deoxyguanosine under conditions of oxidative stress, in the urine of male and female resveratrol‐treated SHRSP were significantly lower than that in control SHRSP.

4. The urine of resveratrol‐treated male and female SHRSP had lower levels of hydroperoxide compared with control SHRSP, but the difference was not significant.

5. Treatment with resveratrol resulted in a 25 and 30% reduction in plasma glycated albumin in male and female SHRSP, respectively, compared with controls.

6. Gender differences for SHRSP with regard to 8‐OHdG, hydroperoxide and glycated albumin levels were not confirmed, resveratrol having similar protective effects on male and female SHRSP.

7. These results indicate that dietary resveratrol: (i) plays a role in suppressing oxidative DNA damage and glycoxidative stress in vivo; and (ii) has similar protective effects in both male and female SHRSP, suggesting that the direct effects of this phytoestrogen on oxidative stress in vivo are not sexually dimorphic.
Comparison Of Digoxin Versus Low‐Dose Amiodarone For Ventricular Rate Control In Patients With Chronic Atrial Fibrillation
Authors: Tse Hung‐Fat , Lam Yui‐Ming , Lau Chu‐Pak , Cheung Bernard My , Kumana Cyrus R
Published: March 2003

1. Rapid ventricular rate (VR) and rhythm irregularity during atrial fibrillation (AF) impair cardiac performance. Although digoxin has been widely used in patients with AF, its efficacy for the control of VR and rhythm irregularity is unsatisfactory. Whether low‐dose amiodarone is more effective remains unclear.

2. We randomized 16 patients (13 male, three female; mean (±SD) age 63 ± 9 years) with chronic AF to receive either digoxin or amiodarone for 24 weeks. At baseline and at 12 and 24 weeks follow up, Holter monitor recording and cardiopulmonary exercise test were performed to assess VR and rhythm irregularity control and exercise capacity.

3. Seven and nine patients received digoxin and amiodarone, respectively. After 12 and 24 weeks treatment, both digoxin and amiodarone significantly decreased the mean ambulatory VR and the VR during peak exercise compared with baseline (all P < 0.05). At 24 weeks, there were no significant differences between digoxin and amiodarone in the percentage reduction in VR during ambulatory (27 ± 13 vs 25 ± 12%, respectively; P = 0.8) and peak exercise (13 ± 12 vs 12 ± 10%%, respectively; P = 0.6).

4. The rhythm irregularity, as measured by SD of RR intervals and the root mean square of the SD of RR intervals, and the exercise capacity, as measured by exercise workload, maximal oxygen consumption (VO2), minute ventilation, ventilatory equivalent and oxygen pulse, were not significantly changed after treatment with digoxin or amiodarone (all P > 0.05).

5. Quality of life, determined by SF‐36 questionnaire, and AF symptomatology, as measured by the AF Symptom Checklist, were also not significantly changed after treatment with digoxin or amiodarone (all P > 0.05).

6. In conclusion, digoxin and low‐dose amiodarone had similar efficacy in the control of VR during ambulatory activity and exercise. However, both were less efficacious during exercise and did not significantly affect rhythm irregularity, exercise capacity, quality of life and AF symptomatology in patients with chronic AF.
Effects Of Digoxin, Furosemide, Enalaprilat And Metoprolol On Endothelial Function In Young Normotensive Subjects
Authors: Mühlen B von zur , Millgård J , Lind L
Published: March 2003

1. Endothelial dysfunction is seen in patients with essential hypertension or congestive heart failure (CHF). The present study aimed to evaluate the direct effect on endothelium‐ dependent vasodilation (EDV) of different pharmacological drugs commonly used in the treatment of these conditions.

2. Forearm blood flow (FBF) was measured in 37 young healthy normotensive subjects with venous occlusion plethysmography during local intra‐arterial infusions of methacholine (MCh; 2–4 μg/min), evaluating EDV, and sodium nitroprusside (SNP; 5–10 μg/min), evaluating endothelium‐independent vasodilation (EIDV). The measurements of EDV and EIDV were undertaken under baseline conditions and were repeated after 1 h intra‐arterial infusion of digoxin (0.1 mg/h), furosemide (5.0 mg/h), enalaprilat (2,4 mg/h), metoprolol (1.2 mg/h) or saline (controls).

3. Enalaprilat and digoxin improved the FBF response to MCh at 4 μg/min (from 22.7±2.3 to 25.5±2.1 mL/min per 100 mL tissue (P < 0.01) and from 18.2±2.4 to 22.2±2.0 mL/min per 100 mL tissue (P < 0.05), respectively). No significant changes where induced by furosemide or metoprolol in response to MCh at 4 μg/min (from 19.4±2.0 to 22.9±2.8 and from 15.3±2.4 to 14.7±1.1 mL/min per 100 mL tissue, respectively). No significant changes in basal FBF or EIDV were induced by the different drugs. When the endothelial function index was calculated as the MCh : SNP FBF ratio, a significant improvement was seen only with enalaprilat (1.1±0.1 to 1.2±0.1; P < 0.01) and furosemide (1.0±0.1 to 1.3±0.4; P < 0.05).

4. In conlusion, the results of the present study show that enalaprilat and furosemide improve endothelial vasodilatory function, while no major effect was induced by digoxin or metoprolol. Thus, different direct effects on the endothelium in young normotensive subjects were induced by drugs commonly used in the treatment of hypertension or CHF.
Ouabain‐Induced Coronary Vasoconstriction In Cats Is Not Neurally Mediated
Authors: Nair Balagopalan A , Murad Yasemin Z , Brody Michael J , Gutterman David D
Published: March 2003

1. Previous reports indirectly implicate a neural mechanism for coronary constriction to centrally administered digitalis. However, autoregulatory changes in coronary resistance due to changes in arterial pressure may have influenced the interpretation of these studies.

2. We tested directly the hypothesis that cardiac sympathetic innervation is responsible for coronary constriction to ouabain by examining the effects of ouabain (intravenous (i.v.) and intracerebroventricular (i.c.v.)) before and after bilateral stellate ganglionectomy.

3. Cats were anaesthetized and instrumented for the measurement of heart rate, blood pressure and coronary blood flow velocity using an epicardial‐attached suction Doppler probe. Animals were treated with atenolol and the effects of either i.v. or i.c.v. injections of ouabain were examined.

4. In seven cats treated with atenolol, i.v. ouabain (0.11 mg/kg) produced maximal increases in arterial pressure and coronary vascular resistance index (CVRI) of 66 ± 7 mmHg and 37 ± 9%, respectively. Following bilateral stellate ganglionectomy (n = 7), ouabain produced similar increases in arterial pressure (70 ± 9 mmHg) and CVRI (39 ± 7%). A higher dose of i.v. ouabain (1.1 mg/kg) produced maximal increases in arterial pressure (115 ± 4 mmHg) and coronary resistance (86 ± 14%) in intact cats (n = 6) that were similar to responses seen in cats in which stellate ganglionectomy had been performed (n = 6; arterial pressure 104 ± 13 mmHg; coronary resistance 114 ± 6%). The increases in coronary resistance to ouabain at both doses were significantly greater than increases in coronary resistance to passive elevation of arterial pressure during aortic constriction. Thus, autoregulation does not explain fully the coronary constriction to ouabain.

5. To further examine a central mechanism, i.c.v. perfusion with 0.3 mmol/L ouabain was performed in six cats, resulting in increases in arterial pressure (122 ± 7 mmHg) and coronary resistance (58 ± 14%). Similar increases in arterial pressure (117 ± 16%) and coronary resistance (84 ± 20%) were seen in separate studies (n = 6) following stellate ganglionectomy.

6. These results indicate that coronary constriction to ouabain does not require intact cardiac sympathetic innervation, but probably involves a direct or humorally mediated effect.
Mechanisms Of Endothelin‐1‐Induced Potentiation Of Noradrenaline Response In Rat Mesenteric Artery
Authors: Matsumura Yasuo , Kita Satomi , Okui Tomoko
Published: March 2003

1. Subthreshold concentrations of endothelin (ET)‐1 enhance the contractile responses to noradrenaline (NA). We investigated possible mechanisms underlying the ET‐1‐induced enhancement of vasoconstrictor responses to NA in rat perfused mesenteric arteries.

2. Perfusion of arteries with subpressor dose of ET‐1 (3 × 10–10 mol/L) significantly potentiated the pressor responses to NA (10–6, 3 × 10–6 and 10–5 mol/L) and this action of ET‐1 was endothelium independent.

3. The protein kinase C (PKC) inhibitors staurosporine (10–8 mol/L) and calphostin C (10–7 mol/L) markedly attenuated the ET‐1‐induced enhancement of NA responses. Vasoconstrictor responses to NA were potentiated when vessels were perfused with phorbol 12‐myristate 13‐acetate (10–8 mol/L).

4. The potentiating effect of ET‐1 was efficiently suppressed by Y‐27632 (10–6 mol/L), a selective Rho‐kinase inhibitor. In the presence of both staurosporine and Y‐27632, contractile responses to NA alone were decreased markedly and ET‐1‐induced potentiation was abolished.

5. Both staurosporine and Y‐27632 decreased contractile responses to NA in arteries of deoxycorticosterone acetate (DOCA)‐salt hypertensive rats to levels observed in normotensive control animals.

6. These findings suggest that ET‐1‐mediated potentiation of responses to NA occurs through activation of either PKC or Rho‐kinase. This mechanism seems to contribute to the enhanced vasoconstrictor responces to NA observed in DOCA‐salt hypertensive rats, in which the responses to NA are enhanced tonically by endogenous vascular ET‐1.
Circumventricular Organs: Gateways to the BrainLeptin Receptors In Hypothalamus And Circumventricular Organs
Authors: Meister Björn , Håkansson Marie‐Louise
Published: March 2003

1. The adipose tissue‐derived hormone leptin reduces food intake and bodyweight via leptin receptors (Ob‐R) in the hypothalamus.

2. Leptin receptor immunoreactivity, demonstrated with an antiserum recognizing all Ob‐R isoforms, is present in hypothalamic neurons of the medial and lateral preoptic area, organum vasculosum lamina terminalis, subfornical organ, periventricular, suprachiasmatic, supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial, ventromedial hypothalamic and tuberomammillary nuclei and lateral hypothalamic area. In the brainstem, Ob‐R immunoreactivity is present in the area postrema, nucleus tractus solitarius, hypoglossal nucleus and dorsal motor nucleus of the vagus nerve.

3. Leptin receptor immunoreactivity is present in magnocellular vasopressin and oxytocin neurons of the SON and PVN, in parvocellular corticotropin‐releasing hormone neurons of the PVN, neuropeptide Y and pro‐opiomelanocortin neurons of the ARC and in melanin‐concentrating hormone neurons of the lateral hypothalamic area.

4. The passage of leptin across the blood–brain barrier and the chemical mediators of the action of leptin in the hypothalamus are discussed.
Lack Of Association Between Qt Dispersion And Blood Pressure Response During Dental Surgery
Authors: Matsumura Kiyoshi , Miura Keiko , Kurokawa Hideo , Abe Isao , Takata Yutaka
Published: March 2003

1. It is well known that dental surgery induces increases in blood pressure. However, the factors influencing this increase are not yet fully understood. We have determined the relationship between QTc (= QT/RR1/2, with RR being the R‐R interval in seconds) dispersion, measured with a 12‐lead surface electrocardiogram, and changes in blood pressure during tooth extraction.

2. Both QTc dispersion and the power spectrum of R‐R variability were determined before the dental surgery was undertaken. The low‐frequency (LF; 0.041–0.140 Hz), high‐ frequency (HF; 0.140–0.500 Hz) and total spectral powers (TF; 0.000–4.000 Hz) were calculated and the ratio of LF to HF and the percentage of HF relative to TF (%HF; HF/TF × 100) were used as indices of sympathovagal balance and parasympathetic activities, respectively.

3. In the present study, QTc dispersion failed to correlate with LF/HF and %HF. Systolic blood pressure and pulse rate increased significantly during tooth extraction; however, changes in these variables failed to correlate with QTc dispersion.

4. These results suggest that QTc dispersion is not associated with the power spectrum of R‐R variability and that it does not affect the blood pressure response during tooth extraction.
Vitamin C Prevents Radiation‐Induced Endothelium‐Dependent Vasomotor Dysfunction And De‐Endothelialization By Inhibiting Oxidative Damage In The Rat
Authors: On Young‐Keun , Kim Hyo‐Soo , Kim Seok‐Yeon , Chae In‐Ho , Oh Byung‐Hee , Lee Myoung‐Mook , Park Young‐Bae , Choi Yun‐Shik , Chung Myung‐Hee
Published: March 2003

1. The present study was undertaken to determine whether endothelial function or morphology was altered in aortic rings of rats after irradiation, to investigate the mechanism of radiation effects on the endothelium and to examine the effect of vitamin C treatment against radiation‐induced damage of the endothelium.

2. Female Sprague‐Dawley rats were randomized into four groups (control, radiation, radiation + vitamin C, radiation + vitamin C + NG‐nitro‐L‐arginine methyl ester (L‐NAME); n = 10 for each group and n = 7 for the control group) and were irradiated with 10 Gy of 137Cs as a radiation source. Segments of the thoracic aorta were obtained and isometric tension, levels of 8‐hydroxydeoxyguanosine (OH‐dG) and immunohistochemical staining were measured.

3. Irradiation significantly impaired the acetylcholine‐induced vasodilation of aortic segments, an effect that could be prevented by pretreatment with vitamin C (500 mg/kg per day). This beneficial effect of vitamin C was abolished by the addition of L‐NAME (100 μg/kg per day), an inhibitor of nitric oxide (NO) synthesis. Irradiation significantly increased the level of OH‐dG in the aorta (1.02 ± 0.27 vs 2.61 ± 0.78 OH‐dG/105 deoxyguanosine (dG) for control and irradiated tissues, respectively; P < 0.01), an increase that was prevented by vitamin C treatment (1.59 ± 0.23 OH‐dG/105 dG; P < 0.01). Irradiation caused significant de‐endothelialization (von Willebrand factor (vWF) staining was 93 ± 7 vs 100% in irradiated and control tissues, respectively; P < 0.05) and this was prevented by vitamin C treatment (vWF staining 98 ± 3%; P < 0.05).

4. Radiation caused endothelial damage and impaired NO production through oxidative injury, resulting in a selective impairment of endothelial‐dependent vasodilation that could be prevented by vitamin C, partly through anti‐oxidant mechanisms.
Effect Of Enalapril On Diabetic Nephropathy In Oletf Rats: The Role Of An Anti‐Oxidative Action In Its Protective Properties
Authors: Sugimoto Koh‐ichi , Tsuruoka Shuichi , Fujimura Akio
Published: March 2003

1. We have evaluated the effects of the angiotensin‐converting enzyme inhibitor enalapril on renal function and oxidative status in the kidney of Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous onset of type 2 diabetes mellitus.

2. Enalapril (5 mg/kg) or vehicle (distilled water) was given once daily by gavage to 22‐week‐old male OLETF rats for 32 weeks. Long‐Evans Tokushima Otsuka (LETO) rats, the control animals for OLETF rats, received vehicle alone (n = 10 in each group).

3. Enalapril attenuated the rise in blood pressure mildly, but significantly. Enalapril significantly blunted the development of proteinuria without a significant effect on creatinine clearance. At the end of the study period, the lipid peroxide content in the renal cortex was significantly increased in OLETF compared with LETO rats, in which enalapril had no effect on lipid peroxide content. Enalapril enhanced the activity of catalase in the renal cortex of OLETF rats, but had no effect on the activity of either superoxide dismutase or glutathione peroxidase.

4. These results suggest that oxidative stress may be involved in the development of nephropathy in type 2 diabetes. Enalapril exhibited renoprotective effects without changing lipid peroxides in the kidney, suggesting that the beneficial effects of the compound on diabetic renal damage in OLETF rats may not be mediated through an anti‐oxidative action.
Prenatal Exposure To Magnetic Field Increases Dopamine Levels In The Striatum Of Offspring
Authors: Lee Byung‐Cheon , Bing Guoying , Jhoo Wang‐Kee , Yoon Joo‐Mae , Kang Kee‐Seok , Shin Eun‐Joo , Kim Won‐Ki , Ko Kwang Ho , Kim Hyoung‐Chun
Published: March 2003

1. The putative effects of prenatal exposure to magnetic field (MF) have recently received much interest. In the present study, mice were exposed to a MF of 50 mT during gestation (0–19 days).

2. After the exposure was terminated, mothers and offspring were returned to normal laboratory conditions. We then determined changes in striatal levels of dopamine (DA) and its metabolite 3,4‐dihydroxyphenylacetic acid (DOPAC) in the offspring.

3. Our results indicate that prenatal exposure to MF increases levels of DA and DOPAC in the striatum at 4, 8 and 12 weeks postnatally.
Design Of Clinical Pharmacology Trials
Authors: Duffull Stephen B
Published: March 2003

1. There are a variety of methods that could be used to increase the efficiency of the design of experiments. However, it is only recently that such methods have been considered in the design of clinical pharmacology trials.

2. Two such methods, termed data‐dependent (e.g. simulation) and data‐independent (e.g. analytical evaluation of the information in a particular design), are becoming increasingly used as efficient methods for designing clinical trials. These two design methods have tended to be viewed as competitive, although a complementary role in design is proposed here.

3. The impetus for the use of these two methods has been the need for a more fully integrated approach to the drug development process that specifically allows for sequential development (i.e. where the results of early phase studies influence later‐phase studies).

4. The present article briefly presents the background and theory that underpins both the data‐dependent and ‐independent methods with the use of illustrative examples from the literature. In addition, the potential advantages and disadvantages of each method are discussed.
Renal And Cardiac Sympathetic Baroreflexes In Hypertensive Rabbits
Authors: Head Geoffrey A , Burke Sandra L
Published: March 2003

1. The purpose of the present study was to assess the changes to renal sympathetic nerve activity (RSNA) baroreflexes during the development of hypertension after renal clipping in conscious rabbits.

2. Rabbits were fitted with a clip on the right renal artery or underwent a sham operation under halothane anaesthesia. A recording electrode was implanted on the left renal nerve 1 week before the experiment, 3 or 6 weeks after the initial operation. During the experiment, drug‐induced ramp rises and falls in mean arterial pressure (MAP) were used to produce RSNA and heart rate (HR) baroreflex curves. The RSNA for each experiment was calibrated against maximum RSNA evoked by stimulation of baroreceptor‐independent trigeminal afferents.

3. Mean arterial pressure was 20 and 36% higher 3 and 6 weeks after clip implantation, respectively. Renal sympathetic nerve activity baroreflex curves were reset rightwards accordingly, but the shape of the RSNA curves was differentially affected.

4. At both hypertensive periods, MAP–HR baroreflex gain was markedly reduced due to a reduction in curvature. The HR baroreflex range was increased. The RSNA baroreflex gain was reduced at 3 weeks, which was due to a 35% lower RSNA baroreflex range, but was similar to sham animals at 6 weeks.

5. The results show that, in established two kidney, one clip hypertension in rabbits, the sympathetic baroreflex is relatively well preserved but sensitivity of cardiac baroreflexes is attenuated. Therefore, the short‐term inhibition of RSNA baroreflexes is not related to the level of blood pressure or the development of secondary changes, such as cardiac or vascular hypertrophy, but may be related to circulating angiotensin, which is known to increase at this time.
Inhibitory Effects Of Angiotensin Ii On Barosensitive Rostral Ventrolateral Medulla Neurons Of The Rat
Authors: Bertram Delphine , Coote John H
Published: March 2003

1. The brain renin–angiotensin system can influence arterial baroreceptor reflex control of blood pressure (BP) through both direct and indirect effects on sympathetic premotor neurons of the rostral ventrolateral medulla (RVLM). The present study examined the direct effect of angiotensin (Ang) II applied by microiontophoresis on the ongoing activity of single RVLM neurons.

2. In 26 urethane‐anaesthetized Wistar rats, recordings of single unit activities of barosensitive RVLM neurons were made from one barrel of a six‐barrel micropipette assembly. The other five barrels were filled with eitherL‐glutamate, AngII, valsartan (an AT1receptor antagonist), PD 123177 (an AT2receptor antagonist) and saline. All drugs were applied by microiontophoresis.

3. Mean BP was 83±3 mmHg. Application of AngII inhibited the ongoing activity of RVLM neurons, identified as barosensitive because their activity was inhibited by a phenylephrine‐ induced increase in BP, from 12.6±1.5 to 5.4±1.1 Hz (n= 24;P< 0.001). Angiotensin II also inhibited the glutamate‐evoked excitation of barosensitive RVLM neurons from 15±3 to 5.8±2.0 Hz (n= 6;P< 0.001). Valsartan significantly increased neuronal activity from 9.5±2.3 to 13.5±3.2 Hz (n= 7,P< 0.01), whereas PD 123177 significantly decreased neuronal activity from 13.5±3.5 to 9.9±2.8 Hz (n= 13;P< 0.01).

4. The results suggest that AngII exerts a tonic inhibitory effect on barosensitive RVLM neurons, which is presumably mediated through AT1receptor stimulation.
Glucocorticoid‐Induced Hypertension: From Mouse To Man
Authors: Whitworth Judith A , Schyvens Christopher G , Zhang Yi , Mangos George J , Kelly John J
Published: March 2003

1. Adrenocorticotrophic hormone (ACTH) raises blood pressure in humans, sheep, rat and mouse. In rat and humans, but not sheep, the hypertension can be explained by glucocorticoid excess.

2. In both rat and humans, the hypertension is associated with a rise in cardiac output and renal vascular resistance.

3. In both rat and humans, the nitric oxide system is implicated in glucocorticoid hypertension.

4. In both rat and humans, hypertension due to naturally occurring glucocorticoids is not prevented by drugs that block classical glucocorticoid or mineralocorticoid receptors.

5. Abnormalities in glucocorticoid metabolism may contribute to some forms of ‘essential’ hypertension.
Impact Of Physical And Physiological Factors On Arterial Function
Authors: McGrath BP , Liang Y‐L , Kotsopoulos D , Cameron JD
Published: March 2003

1. Arterial function measurements are increasingly used as surrogate markers of cardiovascular disease and it is important to define which non‐pathological factors may influence these measurements.

2. The present study examined the influence of gender, height, body mass index (BMI), waist : hip ratio, heart rate and arterial pressure on pulse wave velocity (PWV), systemic arterial compliance (SAC) and central pressure augmentation index (AI) in 285 normal subjects, 98 males and 187 females, aged 50–82 years.

3. There were significant gender differences in PWV (higher in men), SAC (higher in men) and central pressure AI (lower in men).

4. Both SAC and AI were correlated with height in men and women and height largely accounted for gender differences.

5. Systemic arterial compliance was positively, whereas AI was negatively, correlated with BMI.

6. Both PWV and AI were significantly correlated with heart rate and central pulse pressure.

7. These findings may have implications for cardiovascular disorders. Reduced central arterial compliance and increased central pressure augmentation are potential mediators for the increased cardiovascular risk of short stature. A slow heart rate may contribute to increased central arterial pressure with potentially adverse consequences in older subjects.
Acute Effects Of L‐ And T‐Type Calcium Channel Antagonists On Cardiovascular Reflexes In Conscious Rabbits
Authors: Devlin Mark G , Angus James A , Wilson Kathryn M , Wright Christine E
Published: March 2003

1. The effects of the relatively selective T‐type voltage‐ operated calcium channel (VOCC) antagonist mibefradil were compared with verapamil, an L‐type VOCC antagonist, on a range of autonomic reflexes in conscious rabbits.

2. Mean arterial pressure (MAP), heart rate (HR), the baroreceptor–HR reflex, postural adaptation reflex (90°head‐up tilt), Bezold–Jarisch‐like reflex and the vasoconstrictor component of the nasopharyngeal reflex were assessed before and during i.v. infusion of vehicle (saline), mibefradil or verapamil. Doses of mibefradil that gave low (M1; 0.45±0.02μg/mL) and high (M2; 0.93±0.05μg/mL) plasma concentrations, or verapamil (0.059±0.004μg/mL;n= 6 each) were chosen to mimic clinically observed therapeutic levels.

3. At steady state infusion over 30–90 min, MAP was significantly lower in M2 (– 7 mmHg) and verapamil (– 6 mmHg) treatments, but only verapamil caused a significant tachycardia (+ 31 b.p.m.) compared with vehicle. Mibefradil (M2) and verapamil decreased the HR range of the baroreflex by 27 and 29%, respectively, but neither treatment affected the vagal or sympathetic constrictor components of the Bezold–Jarisch‐like and nasopharyngeal reflexes, respectively.

4. In response to 90°tilt, vehicle‐ and verapamil‐treated rabbits responded with small rises in MAP of 4±2 and 8±2 mmHg, respectively, 5 s into the upright posture, while M1 and M2 caused falls in MAP of 6±4 and 9±3 mmHg, respectively, at 5 s.

5. Thus, both L‐ and T‐type VOCC antagonists, at plasma concentrations in the clinical range, lowered MAP in the conscious rabbit, but only mibefradil caused postural hypotension. We conclude that T‐type VOCC may play an important role in the venoconstrictor reflex in response to tilt in the rabbit.
Inhibition Of Proliferation And Signalling Mechanisms In Human Lymphocytes By Fluvastatin
Authors: Hillyard Dianne Z , Cameron Angus JM , McIntyre Alan H , Hadden Mark H , Marshall Hilary E , Johnston Nicola , Jardine Alan G
Published: March 2003

1. Inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (statins) reduce serum cholesterol and have proven benefits in the treatment of cardiovascular disease. However, recent work suggests that statins may exert immunosuppressive effects in isolated lymphocytes and in solid organ transplant recipients. Fluvastatin does not interfere with the metabolism of commonly used immunosuppressive agents and, therefore, may have benefits in transplant recipients.

2. The aim of the present study was to investigate the potential immunomodulatory effects of fluvastatinin vitroin human lymphocytes and the underlying effects on signal transduction.

3. In vitro, fluvastatin (10μmol/L) caused a time‐dependent inhibition of T cell proliferation in response to cross‐linking of CD3.

4. Thymidine incorporation was reduced by 22, 81 and 92% at days 1, 3 and 5, respectively.

5. Mevalonate (1μmol/L) treatment for 4 or 24 h significantly reduced the inhibitory effects of fluvastatin; the reversal was abrogated by simultaneous exposure to mevalonate and a farnesyl transferase inhibitor.

6. At a subcellular level, fluvastatin treatment was associated with reduced functional activity of Ras‐dependent extracellular signal‐regulated kinase pathways and of Rho‐dependent p38 activation.

7. These data suggest that the potential immunosuppressive actions of statins involve inhibition of subcellular pathways dependent on isoprenylation of signal peptides, including Ras, Rho and related G‐proteins.
Effects of indomethacin on responses of regional kidney perfusion to vasoactive agents in rabbits
Authors: Oliver Jeremy J , Rajapakse Niwanthi W , Evans Roger G
Published: March 2003

1. To determine whether differential release of products of arachidonic acid metabolism, via the cyclo‐oxygenase pathway, underlies the diversity of responses of regional kidney perfusion to vasoactive agents, we tested the effects of intravenous indomethacin on responses to renal arterial bolus doses of vasoactive agents in pentobarbitone‐anaesthetized rabbits.

2. Total renal blood flow (RBF) and regional kidney perfusion were determined by transit time ultrasound flowmetry and laser‐Doppler flowmetry, respectively.

3. Responses of regional kidney blood flow to vasoactive agents were diverse: noradrenaline reduced cortical but not medullary perfusion, [Phe2,Ile3,Orn8]‐vasopressin reduced medullary perfusion more than cortical perfusion, endothelin‐1 and angiotensin II increased medullary perfusion in the face of reduced cortical perfusion, while acetylcholine, bradykinin and the nitric oxide donor methylamine hexamethylene methylamine (MAHMA) NONOate all increased both cortical and medullary perfusion.

4. Indomethacin administration was followed by reductions in total RBF (17 ± 6%), cortical perfusion (13 ± 5%) and medullary perfusion (40 ± 8%). Angiotensin II‐ and endothelin‐1‐induced increases in medullary perfusion were abolished by indomethacin, but indomethacin had no significant effects on responses of regional kidney perfusion to acetylcholine, bradykinin, MAHMA NONOate, noradrenaline and [Phe2,Ile3,Orn8]‐vasopressin.

5. Our results suggest that vasodilator cyclo‐oxygenase products contribute to the maintenance of resting renal vascular tone, particularly in vascular elements controlling medullary perfusion. Cyclo‐oxygenase products also appear to mediate endothelin‐1‐ and angiotensin II‐induced increases in medullary perfusion. However, regionally specific engagement of cyclo‐oxygenase‐dependent arachidonic acid metabolism does not appear to contribute to the differential effects of noradrenaline and [Phe2,Ile3,Orn8]‐vasopressin on cortical and medullary perfusion.
Neural control of the renal vasculature in angiotensin II‐induced hypertension
Authors: Ramchandra Rohit , Barrett Carolyn J , Guild Sarah‐Jane , Malpas Simon C
Published: March 2003

1. Chronic administration of angiotensin (Ang) II causes an increase in blood pressure via a multitude of actions, including direct vasoconstriction, hypertrophy and increased sympathetic nerve activity. In the present study, we assessed whether the hypertension resulting from chronic AngII alters the ability of the renal vasculature to respond to sympathetic activity.

2. Angiotensin II was administered for 7 weeks via an osmotic minipump at a dose of 50 ng/kg per min, i.v., to a group of six rabbits. Blood pressure, measured at 0, 1, 2 and 6 weeks after insertion of the pump, increased from 76 ± 2 to 104 ± 6 mmHg at the end of 6 weeks, without any significant change in heart rate. The blood pressure in the control group remained constant at 76 ± 2 mmHg.

3. After 7 weeks, rabbits were anaesthetized and the renal nerves were stimulated at 0.5, 1, 1.5, 2, 3, 5 or 8 Hz for 3 min at their supramaximal voltage (5.5 ± 1.0 V in the normotensive group and 6.5 ± 1.5 V in the hypertensive group) while the renal blood flow (RBF) response was recorded. Under anaesthesia, there was no difference in mean arterial pressure between the normotensive and hypertensive animals (77 ± 2 and 80 ± 7 mmHg, respectively). The resting RBF under these conditions was not significantly different in the hypertensive group (30 ± 4 vs 26 ± 5 mL/min in the normotensive vs hypertensive group, respectively).

4. Stimulation at increasing frequencies was associated with increasing reductions in RBF (e.g. 36 ± 8% at 2 Hz in normotensive rabbits and 48 ± 7% at 2 Hz in hypertensive rabbits). However, there were no significant differences between RBF responses in normotensive and hypertensive rabbits.

5. We conclude that hypertension associated with chronic AngII administration does not alter the response in RBF to electrical stimulation of the nerves.
Propofol differently alters vascular reactivity in normotensive and hypertensive rats
Authors: Samain Emmanuel , Clichet Adeline , Bouillier Hélène , Chamiot‐Clerc Philippe , Safar Michel , Marty Jean , Renaud Jean‐François
Published: March 2003

1. The effect of propofol on arterial tone in hypertension is poorly understood. We examined the effect of increasing concentrations of propofol (5.6 × 10−8 to 2.8 × 10−3 mol/L) on isometric tension developed by noradrenaline (10−7 mol/L)‐contracted aortic rings from 12‐week‐old Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).

2. In both WKY rats and SHR, propofol induced a dose‐dependent inhibition of contraction induced by noradrenaline, but the amplitude of relaxation was larger in the SHR than in WKY rats.

3. The effects of propofol was endothelium independent in WKY rats, whereas in SHR relaxation induced by propofol was greater in endothelium‐intact than in endothelium‐denuded rings.

4. In conclusion, we found significant differences in the effect of propofol in hypertensive rats, which may be related to differences in structural and functional properties of the arterial wall observed in hypertension.
Effect of oestrone on membrane fluidity of erythrocytes is mediated by a nitric oxide‐dependent pathway: An electron paramagnetic resonance study
Authors: Tsuda Kazushi , Kinoshita‐Shimamoto Yukiko , Kimura Keizo , Nishio Ichiro
Published: March 2003

1. It has been recognized that hormone replacement therapy (HRT) may have a beneficial effect on protection against cardiovascular diseases. Oestrone is the major component of conjugated equiline oestrogens, which are commonly used in HRT. The present study was performed in order to investigate the effects of oestrone on the membrane fluidity of erythrocytes by means of an electron paramagnetic resonance (EPR) and spin‐labelling method.

2. In an in vitro study, oestrone significantly decreased the order parameter (S) for 5‐nitroxide stearate (5‐NS) and the peak height ratio (ho/h‐1) for 16‐nitroxide stearate (16‐NS) obtained from EPR spectra of erythrocyte membranes. This finding indicated that oestrone may increase the membrane fluidity and improve the membrane microviscosity of erythrocytes.

3. The effect of oestrone was significantly potentiated by the nitric oxide (NO) donor s‐nitroso‐N‐acetylpenicillamine and the cGMP analogue 8‐bromo‐cGMP.

4. In contrast, the change in membrane fluidity induced by oestrone was antagonized by the NO synthase inhibitors NG‐nitro‐l‐arginine methyl ester and asymmetric dimethyl‐l‐arginine.

5. The results of the present study show that oestrone significantly increases membrane fluidity and improves the rigidity of cell membranes, which is partially mediated by a NO‐ and cGMP‐dependent pathway. Furthermore, the data may be consistent with the hypothesis that oestrone could have a beneficial effect on the rheological behaviour of erythrocytes and have a crucial role in the regulation of the microcirculation.