Bruce N. Van Vliet

Characteristics of 24 h telemetered blood pressure in eNOS-knockout and C57Bl/6J control mice.

The purpose of the present study was to characterize in detail the 24 h blood pressure (BP) phenotype of mice lacking the gene for endothelial nitric oxide synthase (eNOS−/−) and the corresponding control strain (C57Bl/6J). Twenty‐four hour BP recordings were made in conscious 12‐ to 16‐week‐old male mice 10 days following the implantation of a BP telemeter (n= 9 per group). The BP and heart rate of both strains were markedly affected by brief locomotor activity cycles, resulting in bimodal distributions of BP and heart rate within both light and dark periods. Data from active periods were associated with the higher of the two modes, whereas data from inactive periods were associated with the lower of the two modes. In eNOS−/− mice, the 24 h average BP level was significantly elevated (+15 %, 104 ± 2 vs. 119 ± 1 mmHg), as was its daily range (+44 %), its coefficient of variation (+26 %), dark‐light difference (+48 %), and the separation of the two modes of its distribution (+41 %). Pulse pressure was also significantly greater (+23 %) in eNOS−/− mice. The 24 h heart rate level did not differ between control and eNOS−/− mice. Considerable variation was noted among previously published values of BP in eNOS−/− mice, but not in the corresponding control mice. Our results indicate that eNOS−/− mice have mild hypertension that is accompanied by more pronounced increases in BP lability and/or reactivity. Our results also demonstrate a marked effect of locomotor activity on BP in mice, which may confound short‐term measurements of BP.

Direct and indirect methods used to study arterial blood pressure.

A number of different approaches exist for assessing blood pressure in experimental animals. Here, we briefly consider the traditional indirect (rodent tail-cuff) and direct (saline-filled catheter) methods of blood pressure measurement before going on to describe our experience with blood pressure telemetry in rabbits, rats, and mice. Blood pressure telemetry offers the ability to obtain a high-fidelity recording of blood pressure continuously, for relatively long periods of time, in conscious, freely moving animals, without the limitations of restraint or anaesthesia. Since some drift in telemeter offset and sensitivity are inevitable, recalibration of the telemeter devices immediately before implantation and following explantation is essential to ensure and document the accuracy of the blood pressure measurements. For long-term implantations, verification of the calibration can be performed in vivo, at least in the case of large animals, such as rabbits. Telemetry devices suitable for small animals, such as mice, are also available now, which will facilitate the accurate characterization of blood pressure in transgenic animals. Telemeter implantation methods in mice are presently difficult, with relatively low success rates being reported. However, validation of new methods, such as the insertion of the catheter tip via the carotid artery, may make the technique more widely accessible in the near future.

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. Guytons 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 Guytons 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.

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.

Role of the sympathetic nervous system during the development of obesity-induced hypertension in rabbits ☆

We have previously reported that weight gain induced by high-fat diet (HFD) leads to an increase in mean arterial pressure (MAP, +14%) and heart rate (HR, +31%) in the adult rabbit. In the present study, we tested the hypothesis that an increased activity of the sympathetic nervous system may contribute to the development of obesity-induced hypertension. A combination of alpha- and beta-adrenergic blockers (terazosin + propranolol) was chronically administered to rabbits housed in metabolic cages for continuous monitoring of arterial pressure by telemetry, 24 h a day. After 2 weeks of adrenergic blockade under control diet, animals were switched to HFD for the next 6 weeks. HFD induced a progressive increase in body weight, but no increase in mean arterial pressure (+0.2+/-2.5%) and a slight increase in heart rate (+14+/-3%). Time-control animals fed normal diet showed no changes in MAP or HR with long-term alpha- and beta-adrenergic blockade. Our results indicate that the activation of the sympathetic nervous system may play an important role in the pathogenesis of obesity-induced hypertension.

Contribution of baroreceptors and chemoreceptors to ventricular hypertrophy produced by sino-aortic denervation in rats

1 To test whether sino‐aortic denervation (SAD)‐induced right ventricular hypertrophy (RVH) is a consequence of baroreceptor or chemoreceptor denervation, we compared the effects of aortic denervation (AD), carotid denervation (CD), SAD and a SAD procedure modified to spare the carotid chemoreceptors (mSAD), 6 weeks after denervation surgery in rats. A sham surgery group served as the control. 2 The blood pressure (BP) level was unaffected by AD, CD or SAD, but increased (9 %) following mSAD. The mean heart rate level was not affected. Short‐term BP variability was elevated following AD (81 %), SAD (144 %) and mSAD (146 %), but not after CD. Baroreflex heart rate responses to phenylephrine were attenuated in all denervation groups. 3 Significant RVH occurred only following CD and SAD. These procedures also produced high mortality (CD and SAD) and significant increases in right ventricular pressures and haematocrit (CD). 4 Significant left ventricular hypertrophy occurred following CD, SAD and mSAD. Normalized left ventricular weight was significantly correlated with indices of BP variability. 5 These results suggest that SAD‐induced RVH is a consequence of chemoreceptor, not baroreceptor, denervation. Our results also demonstrate that a mSAD procedure designed to spare the carotid chemoreceptors produced profound baroreflex dysfunction and significant left, but not right, ventricular hypertrophy.

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.

Loss of nocturnal dipping of blood pressure and heart rate in obesity-induced hypertension in rabbits

We have investigated in rabbits whether overfeeding and weight gain, which lead to hypertension, are associated with changes in circadian rhythm of blood pressure (BP) and heart rate, and whether the sympathetic nervous system is involved in these changes. In adult male rabbits, mean arterial pressure (MAP) and heart rate (HR) were monitored by telemetry 22 h a day. Daily MAP and HR records were divided into four equal intervals and used to calculate day-night differences. After a 1-week control period, animals were switched to a high-fat (HFD) ad libitum diet for 8 weeks. HFD increased whole day MAP and HR, and rapidly abolished the normal diurnal rhythm of MAP and HR. Since HFD abolished the nocturnal dip in MAP, but had little effect on daytime values, the loss of dipping appears to account for most of the hypertension in this model of obesity. In a separate set of rabbits, alpha- and beta-adrenergic blockade (terazosin + propranolol) prevented HFD-induced hypertension and attenuated the increase in HR by more than half. Adrenergic blockade alone abolished the diurnal rhythm of MAP, chiefly by preventing daytime elevation of MAP. The addition of HFD ad libitum did not further modify daily MAP or its circadian pattern. The diurnal rhythm of HR was relatively unaffected by alpha + beta blockade alone, but was abolished after switching to HFD. In conclusion, rabbits fed an HFD ad libitum develop hypertension and tachycardia associated with a loss of the normal diurnal rhythm of MAP and HR. The hypertension appears to be sympathetically mediated.

PHENOTYPING THE LEVEL OF BLOOD PRESSURE BY TELEMETRY IN MICE

1 Using telemetry, arterial blood pressure (BP) can be measured directly over long periods in freely behaving animals without recent anaesthesia or surgery. In the present review, we discuss the strengths and limitations of this method and important considerations in using the method to characterize the BP level in mice. 2 A variety of informative statistics can be used to describe the BP level and we have made available a spreadsheet template for their calculation on a routine basis. The BP level is well summarized using the average value for an entire 24 h period or for the individual light and dark phases of the day. Such long‐term averages exhibit less statistical variation than those of short recording periods. In addition, averages of the dark and light phases of the day convey information concerning circadian variations of BP. 3 The frequency distribution of BP samples provides additional information concerning the range of BP values recorded over the course of the day and can be described in terms of percentiles of the distribution that correspond with the minimum and maximum BP values and their span. 4 In mice, BP can be markedly affected by locomotor activity cycles that occur frequently throughout both the light and dark phases of the day. In addition, BP is strongly affected by ambient temperature and food intake, as well as potentially by other determinants of energy balance. Consideration of these factors may help improve accuracy and precision when phenotyping the BP level in mice.

Baroreflex stabilization of the double product

We investigated whether the baroreflex control of heart rate (HR) stabilizes the product of arterial pressure (PA) and HR, called the double product (DP), an indirect indicator of left ventricular oxygen consumption. During pharmacological increases and decreases of PA in conscious rabbits, the mean (±SE) rate of change of the DP with respect to PA(dDP/dPA) was -88 ± 36 and -20 ± 36 DP units/mmHg, respectively. Regression analysis of all peak responses obtained in individual rats produced a dDP/dPA value of 15 ± 16 DP units/mmHg. These estimates were significantly less than the dDP/dPA value predicted if HR were constant (184 ± 7 DP units/mmHg) and were not significantly different from zero. We also compared values of baroreflex sensitivity (BRS) from the literature with those calculated to provide ideal stabilization of the DP. BRS values were significantly correlated with the calculated ideal values ( R = 0.95; n = 14). BRS averaged 128 ± 24% of the ideal value in all species and 148 ± 28% in mammals and birds. Our results suggest that stabilization of the DP is a common consequence of the baroreflex control of heart rate.We investigated whether the baroreflex control of heart rate (HR) stabilizes the product of arterial pressure (P(A)) and HR, called the double product (DP), an indirect indicator of left ventricular oxygen consumption. During pharmacological increases and decreases of P(A) in conscious rabbits, the mean (+/-SE) rate of change of the DP with respect to P(A) (dDP/dP(A)) was -88 +/- 36 and -20 +/- 36 DP units/mmHg, respectively. Regression analysis of all peak responses obtained in individual rats produced a dDP/dP(A) value of 15 +/- 16 DP units/mmHg. These estimates were significantly less than the dDP/dP(A) value predicted if HR were constant (184 +/- 7 DP units/mmHg) and were not significantly different from zero. We also compared values of baroreflex sensitivity (BRS) from the literature with those calculated to provide ideal stabilization of the DP. BRS values were significantly correlated with the calculated ideal values (R = 0.95; n = 14). BRS averaged 128 +/- 24% of the ideal value in all species and 148 +/- 28% in mammals and birds. Our results suggest that stabilization of the DP is a common consequence of the baroreflex control of heart rate.