Intrauterine growth-restricted Yucatan miniature pigs experience early catch-up growth, leading to greater adiposity and impaired lipid metabolism as young adults.

Early nutrition has critical influences on cardiovascular disease risk in adulthood. The study objectives were to evaluate the impact of low birth weight on fasting and postprandial lipid metabolism and endothelium function in Yucatan miniature pigs. Intrauterine growth-restricted (IUGR) piglets (n = 6; 3 days old, 0.73 ± 0.04 kg) were paired with normal-weight (NW) same-sex littermates (n = 6; 1.11 ± 0.05 kg) and fed milk replacer ad libitum for 4 weeks. Thereafter, all pigs were fed a standard diet ad libitum for 5 h/day with growth, intakes, and blood samples collected for 8 months. At 9 months old, pigs were surgically fitted with venous catheters and an oral fat tolerance test was performed. At 10 months old, pigs were killed and endothelium-dependent and -independent vasodilations of isolated coronary arteries were measured using wire-myographs. IUGR pigs demonstrated catch-up growth (P < 0.05) in body weight and abdominal circumference prior to sexual maturity (<7 months old) and had more (P < 0.05) subcutaneous fat at 10 months old compared with NW pigs. IUGR pigs had consistently higher fasting plasma triglyceride concentrations from 5 to 10 months old and higher liver triglyceride and total cholesterol concentrations at 10 months old (P < 0.05). The fat tolerance test revealed delayed postprandial triglyceride clearance in IUGR pigs, but no differences in plaque formation or vascular reactivity. To conclude, IUGR and early postnatal catch-up growth are associated with increased overall body fat deposition and altered triglyceride metabolism in adult Yucatan miniature swine.

Uninephrectomy-Induced Lipolysis and Low-Grade Inflammation Are Mimicked by Unilateral Renal Denervation.

Uninephrectomy (UniNX) in rats on a fixed food intake leads to increased lipolysis and a low-grade inflammation with an increased subset of circulating cytokines. Because UniNX ablates renal nerves on the side of the removed kidney, we tested the contribution of unilateral renal denervation in the phenotype of UniNX. We compared Sham-operated controls, left nephrectomy (UniNX) and unilateral left kidney denervation (uDNX) in rats 4 weeks after surgery. uDNX did not affect kidney weight and function. In general, the uDNX phenotype was similar to the UniNX phenotype especially for lipolysis in fat pads and increased low-grade inflammation. uDNX led to decreased fat pad weight and increased hormone sensitive lipase and adipocyte triglyceride lipase mRNA levels in epididymal and inguinal adipose tissue, as well as increased circulating lipolysis markers ß-hydroxybutyrate and glycerol. Measured circulating hormones such as leptin, T3 and insulin were similar amongst the three groups. The lipolytic cytokines interferon-gamma and granulocyte macrophage colony stimulating factor were increased in the circulation of both uDNX and UniNX groups. These two cytokines were also elevated in the spleen of both groups, but contrastingly they were decreased in fat pads, liver, and kidneys. Both uDNX and UniNX similarly increased noradrenaline content in fat pads and spleen. Melanocortin 4 receptor mRNA levels were increased in the brains of both uDNX and UniNX compared to Sham and may contribute to increased tissue noradrenaline levels. In addition, the farnesoid x receptor (FXR) may contribute to changes in tissue metabolism and inflammation, as anti-inflammatory FXR was decreased in the spleen but increased in other tissues in uDNX and UniNX compared to Sham. In summary, both uDNX and UniNX in rats promote metabolic and immunological alterations by mechanisms that seem to implicate modification of unilateral renal nerve pathways as well as central and peripheral neural pathways.

A maternal high salt diet disturbs cardiac and vascular function of offspring.

AIMS: High salt intake is an environmental factor that promotes increased blood pressure. We previously demonstrated that high salt diet causes aggravation of hypertension and impaired vasodilation in response to nitric oxide (NO) in young spontaneously hypertensive rats (SHR), which exhibit low sensitivity to salt in adulthood. Changes in offspring blood pressure and cardiovascular structures have been reported. However, it remains unclear to what extent a maternal high salt intake may affect cardiac and/or vascular function in offspring. Therefore, we investigated influence of exposure to a maternal high salt diet during gestation and lactation on offspring's cardiac and arterial functions in SHR. MAIN METHODS: SHR dams were fed either a high salt diet or a control diet. After weaning, the offspring were fed the high salt diet or control diet for 8weeks. KEY FINDINGS: Compared with offspring of control diet-fed dams, at 12weeks of age, offspring of the high-salt diet-fed dams had lower blood pressure, heart rate, indices of both left ventricular systolic and diastolic function, and a decreased aortic vasodilation response to NO. Postnatal high salt intake did not affect blood pressure, vasodilatory response, or cardiac function in offspring of high-salt diet-fed dams. Neither maternal nor postnatal dietary salt altered levels of lipid peroxide, superoxide dismutase, or angiotensinogen mRNA in serum and ventricle of the offspring. SIGNIFICANCE: Exposure to high maternal dietary salt induces cardiac and vascular dysfunction in offspring. These results point to the possible importance of avoiding excess dietary salt during gestation and lactation.

Effects of a diet high in salt, fat, and sugar on telemetric blood pressure measurements in conscious, unrestrained adult Yucatan miniature swine (Sus scrofa).

Radiotelemetry was used to evaluate diet-related elevation of blood pressure in adult Yucatan miniature swine. Systolic arterial blood pressure (SAP), diastolic atrial blood pressure (DAP), heart rate, and locomotor activity were assessed in 9- or 11-mo-old Yucatan miniature pigs fed a standard diet or a North American-type diet high in salt, fat, and sugar (HSFS). Compared with pigs fed standard diet, pigs fed HSFS diet showed markedly elevated SAP (132 ± 3 compared with 156 ± 6 mm Hg), whereas DAP was unchanged (92 ± 2 compared with 99 ± 5 mm Hg). In addition, all pigs were modestly sensitive to short-term changes in dietary salt, as indicated by a 6% to 7% response in blood pressure parameters. According to these data, the increase in SAP for pigs on the HSFS diet was too large to be explained by the NaCl content of the diet alone. We found no evidence of endothelial dysfunction, and the relaxation responses of isolated coronary arteries actually were enhanced in the HSFS group. In conclusion, in a Yucatan miniature pigs model chronically fed a HSFS diet, DAP did not increase, but SAP and pulse pressure appeared to be affected by high dietary levels of fat or sugar (or both).

Early programming of adult blood pressure in the low birth weight Yucatan miniature pig is exacerbated by a post-weaning high-salt-fat-sugar diet.

We previously demonstrated that intra-uterine growth-restricted (IUGR) Yucatan miniature pigs develop modestly elevated blood pressure (BP) as young adults. The present study evaluated the effects of a post-weaning Western-style, high-salt-fat-sugar (HSFS) diet on early programming of BP. IUGR piglets (3 d old, 0·77 (sem 0·04) kg, n 6) were paired with normal weight (NW) same-sex littermates (1·14 (sem 0·03) kg, n 6) and fed milk replacer for 4 weeks. A third littermate was left with the sow (SF; 1·01 (sem 0·05) kg, n 6). When 4 weeks old, all pigs were placed on a HSFS diet ad libitum for 5 h/d. When 11 months old, telemeters were implanted to measure BP in pigs before (4·5% NaCl) and after (0·5% NaCl) a 7 d reduced salt challenge. At necropsy, nephron numbers were determined. Before sexual maturity, IUGR pigs had greater relative feed intake (P<0·05), and experienced catch-up growth with greater adiposity, with correlations between adiposity and BP (P<0·05). Adult IUGR pigs had 26-34% fewer nephrons and higher diastolic BP (107·7 (sem 4·9) mmHg, P = 0·044) than NW (97·2 (sem 1·8) mmHg) and SF (98·9 (sem 5·3) mmHg) pigs. Systolic BP was similar among the three groups, but was significantly elevated compared with levels previously reported for a control diet. Salt restriction reduced BP in all groups (P<0·05), but with no differences (P>0·05) in the degree of salt sensitivity among groups. In conclusion, a post-weaning Western-style diet exacerbates early programming of diastolic BP in Yucatan miniature swine, whereas systolic BP is more sensitive to postnatal diet.

Efforts to reduce sodium intake in Canada: why, what, and when?

This review addresses the rationale for lowering dietary sodium intake in Canada and recent progress in this direction. Data from trials involving moderate and sustained (≥ 4 weeks) reductions in sodium intake demonstrated significant dose-dependent effects on blood pressure (BP) with larger effects in hypertensive individuals. Average sodium intake in Canada (approximately 3500 mg per day) is well above currently recommended intake targets (≤ 1500 mg per day). Approximately one-eighth of sodium intake is a natural component of food, with the remainder added by food industries (approximately 3/4) or at home (approximately 1/8). Modelling results suggest that lowering Canadian sodium intake to near recommended levels would reduce hypertension prevalence by approximately 30%, prevent approximately 15,500 cardiovascular events per year, and yield savings of approximately CAD$2 billion per year. These estimates do not include the potential additional benefits of long-term sodium restriction on BP, nor BP-independent effects. Actions to facilitate lower sodium intakes in Canada included dietary intake recommendations, mandatory nutritional labelling, a national intake survey, and recommendations of a Government-appointed Sodium Working Group (SWG) that aims to reduce Canadian intakes below 2300 mg per day by 2016. SWG strategies included voluntary reductions in sodium added by food industries, increased education, and research. However, the SWG has recently been disbanded, its responsibilities passed to a Federal-Provincial-Territorial Committee and to a new Food Regulatory Advisory Committee, and the significance for implementing recommendations is unclear. Health care practitioners are encouraged to promote lower dietary sodium intake in their patients and to advocate continued Government efforts to reduce the sodium content of the Canadian food supply.

Low birth weight is associated with reduced nephron number and increased blood pressure in adulthood in a novel spontaneous intrauterine growth-restricted model in Yucatan miniature Swine.

BACKGROUND: Impaired fetal growth and rapid postnatal growth are associated with programming of hypertension and metabolic syndrome in adulthood. OBJECTIVES: This study evaluated this phenomenon in a novel spontaneous intrauterine growth-restricted (IUGR) model in Yucatan miniature pigs. METHODS: IUGR piglets (n = 6, 3 days old, 0.73 ± 0.11 kg) were paired with a normal weight (NW) same-sex littermate (n = 6, 1.11 ± 0.13 kg), fed milk replacer for 4 weeks followed by a standard diet ad libitum for 5 h/day. At 9 months of age, arterial blood pressure (BP) telemeters were implanted to assess BP before (0.5% NaCl) and after (4.5% NaCl) a 7-day salt-loading period. At 10 months of age, nephron numbers were determined. RESULTS: Prior to sexual maturity, IUGR pigs showed greater (p < 0.05) relative feed intake and experienced significant catch-up growth. Adult IUGR pigs also had higher BP (diastolic BP: 93.8 ± 5.5 vs. 90.0 ± 8.7 mm Hg, p < 0.05) and 43% fewer nephrons per kidney (p < 0.05). Nephron number was positively associated with birth weight and negatively correlated with BP (p < 0.05). Acute salt loading increased BP in both groups (p < 0.05); however, the degree of salt sensitivity was similar between groups (p > 0.05). CONCLUSIONS: In conclusion, IUGR piglets have reduced nephron endowment associated with a modest BP increase in early adulthood. This new model can be used to conduct longitudinal mechanistic studies on the early programming phenomenon.

Graphical simulation environments for modelling and simulation of integrative physiology.

Guyton's original integrative physiology model was a milestone in integrative physiology, combining significant physiological knowledge with an engineering perspective to develop a computational diagrammatic model. It is still used in research and teaching, with a small number of variants on the model also in circulation. However, though new research has added significantly to the knowledge represented by Guyton's model, and significant advances have been made in computing and simulation software, an accepted common platform to integrate this new knowledge has not emerged. This paper discusses the issues in the selection of a suitable platform, together with a number of current possibilities, and suggests a graphical computing environment for modelling and simulation. By way of example, a validated version of Guyton's 1992 model, implemented in the ubiquitous Simulink environment, is presented which provides a hierarchical representation amenable to extension and suitable for teaching and research uses. It is designed to appeal to the biomedical engineer and physiologist alike.

A 5-component mathematical model for salt-induced hypertension in Dahl-S and Dahl-R rats.

Salt-induced hypertension has been demonstrated in a variety of species including rats, monkeys, chimpanzees and humans. Until recently, the multiple phases of this blood pressure increase due to high salt intake had not been closely studied. This work builds upon a recent study, which developed a grey-box multi-component model of salt-induced hypertension in the Dahl-S rat. The previous 3-component model has been extended here to include additional model dynamics to improve the model fit and add new important elements to the model response. The model was optimised using numerical techniques with experimental data from 4 different protocols with Dahl-S, Dahl-R and FF2 hybrid rats. Results show a marked improvement over the previous model and confirm the merit of the 5-component model structure. A comparison between the model dynamics for different rat strains has also been included.

Frequency response of implantable blood pressure telemetry systems.

1. Measurement of blood pressure via telemetry in a variety of animal species has become an indispensable part of cardiovascular physiology, drug development and safety pharmacology. 2. These telemetry systems use fluid-filled catheters, which differ from commonly encountered indwelling catheters by virtue of their short length, high durometer, variable inner diameter and the use of a gel interface at the distal tip. 3. Despite the widespread use of blood pressure telemetry, there is little information describing the frequency response of these systems. The frequency response is of importance because it determines how well the waveform dynamics, such as pulse pressure, are captured. 4. For this reason, we measured the frequency responses of commonly used telemeters manufactured by Data Sciences International (St Paul, MN, USA; namely PA-C10, PA-C40 and PA-D70) and Telemetry Research (TR43P). The mean (+/- SEM) -3 dB frequencies measured for the PA-C10, PA-C40, PA-D70 and TR43P telemeters were 57 +/- 2 Hz, 40 +/- 6 Hz, 32 +/- 2 Hz and 173 +/- 3 Hz, respectively. 5. Simulation of the devices' dynamic performance by applying their frequency responses to a high-fidelity recording of arterial pressure demonstrated that the devices have sufficient bandwidth to accurately record arterial waveform dynamics. Experiments were also performed to determine how routine laboratory use and maintenance of the catheter affects the frequency response of the telemeters. Provided no air bubbles were introduced, these showed that the telemeters' frequency responses were robust to the maintenance procedures of tip removal and gel application. 6. The frequency response measurements, combined with simulation results, demonstrate that the systems tested have adequate dynamic performance to record arterial pressure.

Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms.

Alterations in the circadian blood pressure pattern are frequently observed in hypertension and lead to increased cardiovascular morbidity. However, there are no studies that have investigated a possible implication of the Period2 gene, a key component of the molecular circadian clock, on the circadian rhythms of blood pressure and heart rate. To address this question, we monitored blood pressure, heart rate, and locomotor activity 24 h a day by telemetry in mice carrying a mutation in the Period2 gene and in wild-type control mice. Under a standard 12:12-h light-dark cycle, mutant mice showed a mild cardiovascular phenotype with an elevated 24-h heart rate, a decreased 24-h diastolic blood pressure, and an attenuation of the dark-light difference in blood pressure and heart rate. Locomotor activity was similar in both groups and did not appear to explain the observed hemodynamic differences. When mice were placed under constant darkness during eight consecutive days, wild-type mice maintained 24-h rhythms, whereas there was an apparent progressive loss of 24-h rhythm of blood pressure, heart rate, and locomotor activity in mutant mice. However, a chi square periodogram revealed that circadian rhythms were preserved under complete absence of any light cue, but with shorter periods by approximately 40 min, leading to a cumulative phase shift toward earlier times of approximately 5 h and 20 min by the end of the 8th day. When heart rate, mean arterial pressure, and activity were recalculated according to the endogenous circadian periods of each individual mouse, the amplitudes of the circadian rhythms ("subjective night"-"subjective day" differences) were maintained for all variables studied. Our data show that mutation of the Period2 gene results in an attenuated dipping of blood pressure and heart rate during both light-dark cycles and constant darkness, and in shorter circadian periods during constant darkness.

Quantifying sympathetic nerve activity: problems, pitfalls and the need for standardization.

Since the first recording of sympathetic nerve activity (SNA) early last century, numerous methods for presentation of the resulting data have developed. In this paper, we discuss the common ways of describing SNA and their application to chronic recordings. Suggestions on assessing the quality of SNA are made, including the use of arterial pressure wave-triggered averages and nasopharyngeal stimuli. Calculation of the zero level of the SNA signal from recordings during ganglionic blockade, the average level between bursts and the minimum of arterial pressure wave-triggered averages are compared and shown to be equivalent. The use of normalization between zero and maximal SNA levels to allow comparison between groups is discussed. We recommend that measured microvolt levels of integrated SNA be presented (with the zero/noise level subtracted), along with burst amplitude and frequency information whenever possible. We propose that standardization of the quantifying/reporting of SNA will allow better comparison between disease models and between research groups and ultimately allow data to be more reflective of the human situation.

A multi-component model of the dynamics of salt-induced hypertension in Dahl-S rats.

BACKGROUND: In humans, salt intake has been suggested to influence blood pressure (BP) on a wide range of time scales ranging from several hours or days to many months or years. Detailed time course data collected in the Dahl salt-sensitive rat strain suggest that the development of salt-induced hypertension may consist of several distinct phases or components that differ in their timing and reversibility. To better understand these components, the present study sought to model the dynamics of salt-induced hypertension in the Dahl salt sensitive (Dahl-S) rat using 3 sets of time course data. RESULTS: The first component of the model ("Acute-Reversible") consisted of a linear transfer function to account for the rapid and reversible effects of salt on BP (ie. acute salt sensitivity, corresponding with a depressed slope of the chronic pressure natriuresis relationship). For the second component ("Progressive-Irreversible"), an integrator function was used to represent the relatively slow, progressive, and irreversible effect of high salt intake on BP (corresponding with a progressive salt-induced shift of the chronic pressure natriuresis relationship to higher BP levels). A third component ("Progressive-Reversible") consisted of an effect of high salt intake to progressively increase the acute salt-sensitivity of BP (ie. reduce the slope of the chronic pressure natriuresis relationship), amounting to a slow and progressive, yet reversible, component of salt-induced hypertension. While the 3 component model was limited in its ability to follow the BP response to rapid and/or brief transitions in salt intake, it was able to accurately follow the slower steady state components of salt-induced BP changes. This model exhibited low values of mean absolute error (1.92 +/- 0.23, 2.13 +/- 0.37, 2.03 +/- 0.3 mmHg for data sets 1 - 3), and its overall performance was significantly improved over that of an initial model having only 2 components. The 3 component model performed well when applied to data from hybrids of Dahl salt sensitive and Dahl salt resistant rats in which salt sensitivity varied greatly in its extent and character (mean absolute error = 1.11 +/- 0.08 mmHg). CONCLUSION: Our results suggest that the slow process of development of salt-induced hypertension in Dahl-S rats over a period of many weeks can be well represented by a combination of three components that differ in their timing, reversibility, and their associated effect on the chronic pressure natriuresis relationship. These components are important to distinguish since each may represent a unique set of underlying mechanisms of salt-induced hypertension.

Understanding the contribution of Guyton's large circulatory model to long-term control of arterial pressure.

With the publication in 1972 of a large computer model of circulatory control, Guyton and colleagues challenged the then prevailing views on how blood pressure and cardiac output were controlled. At that time, it was widely accepted that the heart controlled cardiac output and that peripheral resistance controlled arterial blood pressure. By incorporating the empirically demonstrated concepts of blood flow autoregulation and the pressure-natriuresis relationship into their mathematical model, Guyton and colleagues were able to develop a number of revolutionary concepts. Guyton's circulatory model was particularly instrumental in exploring the linkage between blood pressure and sodium balance and in demonstrating an overriding importance of renal salt and water balance in setting the long-term blood pressure level. In both the model and experimental data, any long-lasting imbalance between salt intake and salt excretion leads to a progressive alteration of the degree of filling of the vascular system and thus to parallel changes in blood pressure. In turn, changes in blood pressure alter sodium excretion, opposing the initial salt imbalance. Although Guyton's model does not include the most recent cardiovascular discoveries, the concepts underlying the basic functioning of the cardiovascular system can serve as a well-built basis for the development of new, large and integrative cardiovascular models.

Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2) knockout mice.

BACKGROUND: In this study we used radiotelemetry to measure hemodynamic variables and locomotor activity in conscious unrestrained male Protease-Activated Receptor 2 (PAR-2) knockout mice in order to provide a detailed assessment of their blood pressure phenotype. In addition we tested for an influence of PAR-2 on salt-sensitivity (8% versus 0.5% NaCl diet, 2.5 weeks) and angiotensin II-induced hypertension (1 microg Ile5-angiotensin II/kg/min versus 0.25 microl/h saline, 2 weeks). RESULTS: Systolic arterial pressures of PAR-2 -/- (129 +/- 1 mmHg, n = 21, P < 0.05) were statistically higher than those of C57BL/6J (124 +/- 1 mmHg, n = 33) throughout the 24 h period under baseline conditions. Pulse pressures in PAR-2 -/- were also significantly elevated (33 +/- 1 mmHg versus 30 +/- 1 mmHg, P < 0.05), whereas diastolic arterial pressures were not. Heart rates in PAR-2 -/- were not significantly different than controls, with the exception that heart rate of PAR-2 -/- was 23 beats per min higher than controls (P < 0.001) during periods of nocturnal activity. The diurnal pattern and intensity of locomotor activity were not found to differ between strains. A high salt diet led to increased blood pressures, decreased heart rates, increased time spent active and decreased intensity levels of locomotor activity. Salt-induced changes in systolic and pulse pressures in PAR-2 -/- were less than in C57B/6J. Angiotensin II treatment increased pressures, decreased heart rates, decreased time spent active and decreased intensity levels of activity of PAR-2 -/-, all to the same extent as C57BL/6J. A trend of lower blood pressures during the middle period of angiotensin II treatment period was observed in individual PAR-2 -/-. CONCLUSION: The data indicated gene knockout of PAR-2 was associated with a modest change in blood pressure phenotype. PAR-2 -/- mice exhibited moderate elevation of systolic arterial and pulse pressures, yet no increased diastolic arterial pressure, no increased blood pressure responses to high salt diet and a subtle difference in the time course of the blood pressure responses to angiotensin II infusion.

Sampling of cardiovascular data; how often and how much?

Long-term measurement of cardiovascular variables by telemetry in laboratory animals has become indispensable in recent years. However, limited battery life and management of large volumes of recorded data are major drawbacks. These limitations can often be overcome by intermittent sampling of data. The question is, how much data does one need to collect to accurately reflect the underlying average value? To investigate this, 24-h continuous recordings of rabbit heart rate, arterial pressure, and integrated renal sympathetic nerve activity (RSNA) were resampled using a variety of protocols that differed with respect to the number of individual sampling periods used and the total amount of time that was sampled. The absolute percentage errors of estimates of the daily mean, standard deviation, and interquartile range were calculated for each sampling protocol. A similar analysis was repeated using arterial pressure data from rats. The results show that the number of sampling periods spread throughout the day had more effect than the total amount of data recorded. For example, just 2 h of total sampling time spread over 12 evenly spaced 10-min periods gave estimates of the daily mean of blood pressure and heart rate with <1% error and RSNA with <3% error. We show that accurate estimates of the daily mean of arterial pressure, heart rate, and RSNA can all be made using scheduled recording, and we recommend recording a minimum of 2 h/day spread over a number of periods throughout the day.

Hemodynamic consequences of chronic parasympathetic blockade with a peripheral muscarinic antagonist.

Whereas the sympathetic nervous system has a well-established role in blood pressure (BP) regulation, it is not clear whether long-term levels of BP are affected by parasympathetic function or dysfunction. We tested the hypothesis that chronic blockade of the parasympathetic nervous system has sustained effects on BP, heart rate (HR), and BP variability (BPV). Sprague-Dawley rats were instrumented for monitoring of BP 22-h per day by telemetry and housed in metabolic cages. After the rats healed from surgery and a baseline control period, scopolamine methyl bromide (SMB), a peripheral muscarinic antagonist, was infused intravenously for 12 days. This was followed by a 10-day recovery period. SMB induced a rapid increase in mean BP from 98 +/- 2 mmHg to a peak value of 108 +/- 2 mmHg on day 2 of the SMB infusion and then stabilized at a plateau value of +3 +/- 1 mmHg above control (P < 0.05). After cessation of the infusion, the mean BP fell by 6 +/- 1 mmHg. There was an immediate elevation in HR that remained significantly above control on the last day of SMB infusion. SMB also induced a decrease in short-term (within 30-min periods) HR variability and an increase in both short-term and long-term (between 30-min periods) BPV. The data suggest that chronic peripheral muscarinic blockade leads to modest, but sustained, increases in BP, HR, and BPV, which are known risk factors for cardiovascular morbidity.

Dietary sodium and cardiovascular outcomes: a rational approach.

Hypertension, the leading risk factor for mortality in the world, affects nearly one in four Canadians. There is substantive evidence that high dietary sodium contributes to hypertension. Animal studies consistently demonstrate increased blood pressure and cardiovascular morbidity and mortality with high dietary sodium intake. Evidence of the adverse health effects in humans associated with increased sodium intake is accumulating rapidly. Previously, limitations on sodium consumption were recommended only for those identifiable groups of people shown to be at higher risk. With the lifetime risk of developing hypertension being more than 90% in an average lifespan, the need for a population-based approach to reducing hypertension is clear. The present paper reviews the evidence of sodium and cardiovascular disease, resulting in the 2007 Canadian Hypertension Education Program recommendation of daily intake of less than 100 mmol of sodium in both normotensive and hypertensive adults.

Persistence of PAR-2 vasodilation despite endothelial dysfunction in BPH/2 hypertensive mice.

This study investigated relaxation of vascular smooth muscle by acetylcholine, bradykinin and protease-activated receptor 2 (PAR-2) to characterise endothelial dysfunction in spontaneously hypertensive mice (BPH/2). We hypothesised that PAR-2 induced vasodilation would be preserved in BPH/2 despite the presence of hypertension and impaired vasodilator responses to acetylcholine and bradykinin. Mean arterial blood pressure (MAP), heart rate and locomotor activity were assessed in conscious mice over 24-h periods by radiotelemetry. Relaxation responses of small mesenteric arteries to acetylcholine, bradykinin and the PAR-2 agonist, 2-furoyl-LIGRLO-amide (2fly), were assessed using wire myographs. MAP and heart rate of BPH/2 were 15 and 18%, respectively, higher than in controls (BPN/3). BPH/2 also exhibited increased locomotor activity. Maximal relaxations of arteries by acetylcholine and bradykinin in BPH/2 were reduced by 25-50% relative to BPN/3. In contrast, relaxation responses to 2fly were only slightly (6%), albeit significantly, reduced. Sodium nitroprusside-induced relaxations were not different between strains. Treatment of BPH/2 arteries with inhibitors of calcium-activated K(+) channels was sufficient to block persistent 2fly- and residual ACh- and bradykinin-induced relaxations, whereas NO synthase inhibitor failed to inhibit these relaxations. In BPH/2 mice, vascular smooth muscle relaxation by PAR-2 is well preserved despite the presence of hypertension and impaired vasodilation responses to acetylcholine and bradykinin.