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In an effort to understand obesity associated hypertension, we and others are using Dahl salt-sensitive (SS) rats fed a high fat diet as an experimental model. One reason for choosing this rat strain is that it is well-known that SS rats exhibit accelerated hypertension development not just in response to high salt intake but to numerous other stimuli as well, when compared to Dahl salt resistant (SR) rats. However, it is not known whether this general dichotomous sensitivity to hypertension development in SS and SR rats also extends to the impact of high fat feeding. Therefore, in the present study we tested the hypothesis that high fat feeding would cause a smaller increase in blood pressure in SR rats versus SS rats in both females and males (n=8 each). To explore possible strain differences in the mechanisms known to contribute to obesity associated hypertension, we also compared the activity of the renin angiotensin and sympathetic nervous systems in SS and SR rats. Rats were fed a high fat diet (60% kcal fat) from weaning. Blood pressure was measured by telemetry starting at 12 weeks of age. At 12 weeks, mean arterial pressures (MAP, mmHg) were 109±8 and 158±6 in male SR and SS rats, and 108±1 and 150±5 in female SR and SS rats, respectively. By 18 weeks MAP were 109±7 and 175±4 in male SR and SS rats, and 108±1 and 180±4 in female SR and SS rats, respectively. In males, plasma renin was lower, and aldosterone the same, in SS rats than SR rats. However, SS rats showed larger falls in blood pressure during week-long ACE inhibitor treatment and to acute sympathoinhibition with hexamethonium than did SR rats. In females, plasma renin and aldosterone both were higher in SS rats than SR rats. Female SS rats also showed larger falls in blood pressure to chronic ACE inhibition and acute ganglion blockade than did SR rats. These results confirm that both male and female SR rats are highly resistant to obesity associated hypertension, and that less robust activation by high fat diet of the renin angiotensin and sympathetic nervous systems may be a causative factor.

Dahl salt-sensitive (SS) and salt-resistant (SR) rats show dramatically different blood pressure (BP) responses to being raised on a high fat, but normal salt, diet starting at weaning. Virtually no effect on BP is seen in SR rats, whereas in SS rats mean arterial pressure (MAP) reaches over 160 mmHg by adulthood. The BP difference is similar in female and male rats. The cellular and physiological mechanisms responsible have not been completely elucidated in either sex. Dysfunctional perivascular adipose tissue (PVAT) is proposed to contribute to obesity-associated hypertension through actions on other components of the vascular wall. Here we used female rats to test the hypothesis that differences in adipose tissue amount or function in SS and SR rats play a part in the distinct BP effects of high fat diet in the two strains. Rats (n=8 per strain) were fed a high fat diet (60% kcal fat) from weaning. BP was measured with telemetry. At 18 weeks of age, MAPs (mmHg) were 108±1 and 180±4 in SR and SS rats. Body weights (g) were 274±4 and 323±4. Total and visceral adipose volumes (mm3) measured by μCT were higher in SS rats versus SR rats (visceral: 22372±927 versus 14112±1495; total: 17208±732 versus 10234±984). PVAT volume around the thoracic aorta was larger in SS rats (0.228±0.017 versus 0.167±0.006). Subcutaneous adipose tissue volumes did not differ. Plasma triglycerides and cholesterol were modestly but significantly higher in SS rats. The well-known anticontractile effect of PVAT was compared in thoracic aorta from both strains. Removal of PVAT increased the AUC of the tension/PE contraction in SR rats by 1484±226 units and by a significantly smaller amount (946±162.5 units) in SS rats. Finally, aortic stiffness was estimated from pulse wave velocity measured via Doppler in a subset (n=4 each) of rats from each strain. Pulse wave velocity (M/sec) was markedly higher in SS than SR rats (11.5±1.0 versus 6.4±0.3). We conclude that differences in adipose tissue volume, location or function could account in part for the distinct BP responses of female SS and SR rats to high fat feeding.

We have used the SHR as an animal model to understand how renal denervation (RDN) lowers blood pressure. In order to determine how concomitant antihypertensive drug therapy could affect the blood pressure response to RDN, we performed RDN both before and after chronic (several days) treatment via the drinking water with the selective alpha-1 adrenergic antagonist prazosin and the selective beta-1 adrenergic antagonist atenolol. In the presence of prazosin treatment, RDN (n=7) significantly (p

Renal nerve ablation has been shown to elicit a chronic, anti-hypertensive effect in drug-resistant hypertensive patients. Precise understanding of the mechanisms underlying the clinical success of renal denervation is currently unknown, and as a consequence, it is predicted the technology will be under-utilized until such information is uncovered. Retrospective multivariate analyses of responders suggest treatment with a central sympatholytic may correlate with a successful response to renal denervation. However, this hypothesis remains untested. This study tested the hypothesis that pretreatment with a central sympatholytic would augment the response to renal denervation (RDX) in the spontaneously hypertensive rat. In rats pre-treated for 1 week with clonidine (125ug/kg/day), MAP was significantly reduced from baseline but there was no difference in response to clonidine between groups (Sham(n=7): -21.3±0.8 vs RDX(n=7): -22.8±1.3mmHg, p>0.05). During clonidine treatment RDX significantly reduced MAP within 48hrs in RDX animals compared to shams (Sham: 145.9±2.5 vs. RDX: 135.0±1.7mmHg, p0.05). Discontinuation of clonidine caused blood pressure to rise, but once pressures stabilized, the average MAP was significantly lower in RDX treated rats (Sham:157.4 ± 0.8 vs. RDX: 146.4 ± 0.8mmHg, p

Associations between stress hormones and preterm delivery have not been fully explored. In this study, pregnant women enrolled from 52 clinics in 5 Michigan communities (1998–2004) provided urine samples for 3 days (waking and bedtime) during midpregnancy. Urinary catecholamine levels (epinephrine, norepinephrine, and dopamine) were measured in a subcohort (247 preterm and 760 term deliveries), and a 3-day median value was calculated. Polytomous logistic regression models assessed relations between catecholamine quartiles (of the median) and a 4-level outcome variable (i.e., term (referent) and 3 preterm delivery subtypes: spontaneous; premature rupture of membranes; and medically indicated). Final models incorporated other relevant covariates (e.g., creatinine, demographic, behavior). The risk of spontaneous preterm delivery was increased in the highest versus lowest quartile of norepinephrine and dopamine: norepinephrine, waking (adjusted odds ratio (AOR) ¼ 3.7, 95% confidence interval (CI): 1.8, 7.9) and bedtime (AOR ¼ 2.5, 95% CI: 1.3, 4.9); dopamine, waking (AOR ¼ 2.6, 95% CI: 1.4, 5.1) and bedtime (AOR ¼ 2.3, 95% CI: 1.2, 4.6). Adjusted odds ratios were further strengthened after removing women whose placentas showed evidence of acute infection or vascular pathology. High catecholamine levels in maternal urine may be indicative of excess stressors and/or predisposition to elevated sympathetic activation that contributes to increased risk of spontaneous preterm delivery. catecholamines; dopamine; epinephrine; gestational age; norepinephrine; pregnancy; pregnancy outcome; premature birth

Cardiopulmonary bypass (CPB) causes a systemic inflammatory response syndrome (SIRS), which can progress to an acute lung inflammation known as postperfusion syndrome. We developed a two-phase hypothesis: first, that SIRS, as indicated by elevated cytokines post-CPB, would be correlated with postoperative pulmonary dysfunction (Phase I), and second, that the cytokine interleukin-6 (IL-6) is predominantly released from the heart in CPB patients (Phase II). Blood samples were collected from patients undergoing CPB for elective cardiac surgery. In seven patients (Phase I), arterial samples were drawn before, during (5 minutes and 60 minutes), and after CPB. In 14 patients (Phase II), samples were collected from the coronary sinus, superior vena cava, and a systemic artery at the times indicated previously. Samples were analyzed with enzyme-linked immunosorbent assay: IL-1, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha were assessed in Phase I and IL-6 assessed in Phase II. In Phase I, IL-6, IL-8, and IL-10 were elevated after CPB, but only IL-6 concentrations correlated with lung function. In summary, Phase I data demonstrate that increased IL-6 levels at the end of CPB correlate with reduced lung function postoperatively. In Phase II, IL-6 elevation was similar at all sample sites suggesting that the heart is not the major source of IL-6 production. We suggest that IL-6 be implemented as a prognostic measure in patient care, and that patients with elevated IL-6 after CPB be targeted for more aggressive anti-inflammatory therapy to protect lung function.

linking cell biology to anatomy and physiology. Why the idea was necessary Students learning histology at our medical school have increased in number recently and it has become difficult to provide personal microscope time for them. In 2000 we instigated an in-house, computer-based system of histology teaching for practical classes. This was well received by students and staff, but now appears rather tired as it is a relatively static programme with little interactivity. What was done We have recently introduced a new, highly interactive, web-based digital microscope system for the viewing of histological images. This system, which we call UCL SlideSurfer, utilises very high-quality scanned images of our best microscope slides which can be viewed on class computers or online at home. This hardware and software package provides the element of real-time, dynamic microscopy and offers students a truly innovative experience in a manner analogous to that of Google Earth; they can view a tissue section on screen at a very low magnification and then zoom in on any region at progressively increasing magnifications, right down to single cells and nuclei at exceptionally high resolution. Students are led to important structures by a series of annotations on each ‘slide’, but are free to explore any part of the tissue. For this project, our extensive microscope slide collection covering the entire range of body tissues was systematically analysed and approximately 100 of the best-quality slides were chosen and dispatched to a professional provider of digital solutions, where they were scanned at very high resolution and uploaded to a website. When the quality of each scanned slide had been checked, text and questions were applied. Evaluation of results and impact Staff have found that SlideSurfer has stimulated students into learning histology. Student feedback has been exceptional; comments include: ‘I particularly like the software that is used within these practicals and I found SlideSurfer a very useful tool in helping me to cover all of the objectives’; ‘This is a fantastic way of teaching histology – the software [SlideSurfer] is brilliant’; ‘Really enjoyed using SlideSurfer and particularly the fact that we can access all the histology information from outside the labs’, and ‘Enjoyed the interactivity; maybe we could do more of that?’ Students liked having access to what is, in effect, a digital microscope with a box of our best slides at home or anywhere they have Internet access. We believe this is an innovative, engaging and effective method for teaching histology. Correspondence: G Campbell, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Tel: 00 44 207 679 7764; Fax: 00 44 207 679 7349; E-mail: g.campbell@ucl.ac.uk

Interleukin-1 beta (IL-1) is a proinflammatory cytokine which is produced within the pancreas during acute pancreatitis reaching levels which are toxic to many cell types. Since antagonism of this cytokine provides dramatic survival benefits during lethal pancreatitis, we hypothesized that IL-1 had direct secretagogue and cytolytic effects within the pancreas. The effect of IL-1 on pancreatic exocrine function and tissue viability was assessed in vivo by blockade of IL-1 with varying doses of IL-1 receptor antagonist (IL-1ra) prior to the induction of either moderate (caerulein-induced) or severe (choline deficient diet-induced) necrotizing pancreatitis. Subsequent in vitro studies were conducted to determine the direct effect of IL-1 on dispersed rat acini prepared through collagenase digestion. Amylase release was measured after a 30-min incubation with varying doses of recombinant IL-1 beta. Viability was determined in the presence of IL-1 via trypan blue exclusion at multiple time points. Blockade of the IL-1 receptor decreased pancreatic amylase release and tissue necrosis in both models of pancreatitis in a dose-dependent fashion (1.0 mg/kg, P = NS; 10 mg/kg, P < 0.05; 100 mg/kg, P < 0.05). Despite these in vivo findings, the addition of IL-1 to acini in vitro had no effect on exocrine function and failed to decrease acini viability (both, P = NS). Pancreatic amylase release and tissue necrosis are significantly attenuated during experimental pancreatitis by IL-1 antagonism. These changes do not appear to be due to the direct action of IL-1 on pancreatic acini and are likely due to more complex interactions between acini and cytokine-producing leukocytes.