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Abstract
Abstract We recently reported that high dietary NaCl exposure significantly increases both daytime and nighttime mean arterial pressure in male spontaneously hypertensive rats (SHR) but only nighttime values in male normotensive Wistar-Kyoto rats (WKY). In the present study we used a telemetry monitoring system to evaluate the effects of high dietary NaCl exposure on diurnal variation of mean arterial pressure and heart rate in male and female SHR and WKY. After implantation of a radio-frequency transducer, rats were fed either high (8%) or basal (1%) NaCl diets for 2 weeks. High dietary NaCl ingestion significantly increased both daytime and nighttime mean arterial pressure in male SHR compared with males receiving a basal NaCl diet, resulting in greater 24-hour values (163±1 versus 154±1 mm Hg, high versus basal NaCl diet; P<.05). High dietary NaCl ingestion significantly increased only nighttime blood pressure in male WKY, with no significant effect on 24-hour mean arterial pressure (102±2 versus 101±3 mm Hg, high versus basal). High dietary NaCl exposure did not affect daytime or nighttime mean arterial pressure in female SHR (24-hour mean arterial pressure, 144±2 versus 141±2 mm Hg, high versus basal NaCl diet). Twenty-four-hour mean arterial pressure tended to be lower in female WKY receiving a high NaCl diet than females ingesting a basal diet (101±3 versus 106±1 mm Hg), but the difference was not significant. These results indicate a sexually dimorphic response to dietary NaCl ingestion, with males of both strains manifesting some degree of NaCl sensitivity, whereas females are NaCl resistant.
Because telemetry monitoring allows for 24-hour measurement of BP and HR in freely moving, untethered animals, it is much more sensitive in identifying small but significant changes in BP and HR than conventional methods of BP measurement. The latter, including indirect measurements with tail-cuff plethysmography and direct measurements from indwelling arterial cannulas, have been limited to daytime assessments when animals are asleep and require animals to be restrained or tethered.
Using a telemetry system to record MAP continuously, our laboratory recently reported that 2 weeks of high dietary NaCl exposure significantly increases daytime and nighttime MAP in male SHR.1 The greatest increase occurs at nighttime when the rats are active and feeding. Male WKY, in contrast, manifest only a small nighttime increase in MAP when exposed to a high NaCl diet for 2 weeks, with no net effect on 24-hour MAP. Previously, using indwelling femoral artery cannulas to measure MAP, we had not seen significant increases in daytime MAP and therefore had characterized male WKY as NaCl resistant.2 3 The results of 24-hour monitoring, however, demonstrate that male WKY are acutely sensitive to nocturnal NaCl ingestion but have sufficient compensatory mechanisms to avoid sustained diurnal increases in MAP. Such compensatory mechanisms are lacking in male SHR.
Studies from several laboratories suggest that male rats are more sensitive to short-term dietary NaCl exposure than females.4 5 6 These studies, however, relied on daytime measurements of BP in either restrained or tethered rats. We hypothesized that there is a sexual dimorphism in the NaCl sensitivity of BP in SHR and WKY. Specifically, we hypothesized that female SHR, like male WKY, are acutely sensitive to NaCl ingestion and manifest nocturnal elevations in BP that are compensated for by mechanisms that cause BP to fall during the day, resulting in no net change in 24-hour BP. We also hypothesized that these compensatory mechanisms are most efficient in female WKY. Testing this hypothesis required use of a telemetry monitoring system that allowed for both daytime and nighttime BP measurement.
Methods
Rat Strains and Environmental Conditions
Male and female SHR (IBU3 colony) and WKY were obtained from Taconic Farms, Germantown, NY, at 10 weeks of age. The rats were acclimated to a 12-hour light (6 am to 6 pm)/dark (6 pm to 6 am) cycle for 1 week. During this period all rats were maintained on normal (1%) rat chow (Purina Test Diets) and allowed tap water ad libitum. These studies were conducted in accordance with University of Alabama at Birmingham Institutional Animal Care and Use Committee guidelines.
Telemetry and Data Acquisition
We used the Dataquest IV system (Data Sciences Inc) to measure telemetrically SBP, diastolic BP, MAP, and HR.7 8 The monitoring system consists of a transmitter (radio-frequency transducer), receiver panel, consolidation matrix, and IBM-compatible personal computer with accompanying software.
At 10 weeks of age during pentobarbital general anesthesia, the flexible catheter of the transmitter was surgically secured into the abdominal aorta of rats just below the renal arteries. The transmitter was sutured to the abdominal wall. Rats were housed in individual cages postoperatively. Each cage was placed over a receiver panel that was connected to the personal computer for storage of data onto the hard drive. With the Dataquest system the rats are completely unrestrained and free to move within their individual cages. Hemodynamic data were sampled every 4 minutes in each rat as a waveform curve for 10 seconds. After regaining their preoperative weight (2 weeks after surgery), the rats were maintained on either high (8%) (ISCN Biochemicals Purina chow with 8% NaCl) or basal (1%) NaCl rat chow for 2 weeks.
Data Analysis
Twenty-four-hour mean values and mean values of the 6-hour day/night periods for MAP and HR for each of the various diet/strain/sex groups were compared by ANOVA (P<.05 considered significant) and Newman-Keuls post hoc analysis.
Results
Male SHR and WKY were heavier than their female counterparts (Table 1⇓). High dietary NaCl exposure did not significantly affect weight gain in either strain. At baseline, MAP was greater in male than female SHR, whereas MAP in female WKY was slightly greater than in male WKY. After 2 weeks of dietary exposure 24-hour MAP was significantly greater in male SHR receiving the 8% NaCl diet than in male SHR fed 1% NaCl (163±1 versus 154±1 mm Hg, SHR 8% versus SHR 1%; an increase of 5.8%) (Table 1⇓, Fig 1⇓). MAP tended to be higher in the female WKY fed 1% NaCl compared with those fed 8% NaCl, but the difference was not statistically significant (101±3 versus 106±1 mm Hg, 1% versus 8%).
Line graphs show 24-hour MAP in male and female SHR and WKY during 8% and 1% NaCl diets. See Table 1⇓ for statistical analysis of differences between diet/strain/sex groups at baseline and the end of the dietary intervention period.
Body Weight and Hemodynamic Characteristics at Baseline and After 2 Weeks of Dietary Intervention
At baseline, 24-hour HR was significantly greater in male rats of both strains than in females (Table 1⇑). Two weeks of high NaCl diet significantly decreased 24-hour mean HR in both sexes and strains compared with 1% NaCl diet groups. In the female rats these decreases in HR occurred independent of significant changes in BP.
High dietary NaCl exposure significantly increased both nighttime and daytime MAP in male SHR (Table 2⇓, Fig 2⇓). The increase was greatest during the 6-hour interval from midnight to 6 am (172±1 versus 158±1 mm Hg, SHR 8% versus SHR 1%, an increase of 8.9%; P<.05). NaCl-induced increases in nighttime MAP were smaller in male WKY than male SHR but were statistically significant (105±1 versus 100±1 mm Hg, WKY 8% versus WKY 1% during the midnight to 6 am period, an increase of 5%; P<.05). NaCl-related differences in daytime MAP in male WKY were not statistically significant (95±1 versus 95±1 mm Hg, 8% versus 1% NaCl groups). Neither daytime nor nighttime MAP in female WKY was affected by high dietary NaCl exposure except for the noon to 6 pm period, when MAP was slightly lower in the 8% NaCl diet group than in the 1% diet group (105±2 versus 101±1 mm Hg, 1% versus 8% NaCl groups, a decrease of 4%; P<.05).
Line graphs show circadian profiles plotted by 6-hour intervals of MAP in male and female SHR and WKY maintained on 8% or 1% NaCl diets for 2 weeks. Telemetric data used for analysis were obtained during the last 3 days of dietary exposure. Light/dark periods are indicated by white/black segments along the top x axis. See Table 2⇓ for statistical analysis of differences between diet/strain/sex.
Six-Hour Hemodynamic Values at End of 2-Week Dietary Intervention Period
High dietary NaCl exposure significantly reduced HR in SHR of both sexes during all nighttime and daytime periods except for the midnight to 6 am period in female SHR (Table 2⇑, Fig 3⇓). HR was also significantly reduced by high dietary NaCl exposure in male WKY during all nighttime and daytime periods. High dietary NaCl exposure reduced HR in female WKY during daytime periods but not at night.
Line graphs show circadian profiles plotted by 6-hour intervals of HR in male and female SHR and WKY maintained on 8% or 1% NaCl diet for 2 weeks. Telemetric data used for analysis were obtained during the last 3 days of dietary exposure. Light/dark periods are indicated by white/black segments along the top x axis. See Table 2⇑ for statistical analysis of differences between diet/strain/sex.
Discussion
The results of the current study support our hypothesis that there is a sexual dimorphism in the BP response to high dietary NaCl exposure in both SHR and WKY. A 2-week exposure to high dietary NaCl did not significantly increase either daytime or nighttime MAP in female rats of either strain, whereas male SHR manifested both daytime and nighttime increases in MAP, and male WKY manifested only nighttime increases in nighttime MAP, as we had shown in a previous study.1 Thus, unlike male SHR and WKY, which manifest some degree of acute NaCl sensitivity, female SHR and WKY are truly resistant to the BP-elevating effects of short-term high dietary NaCl exposure. In fact, dietary NaCl supplementation was associated with a reduction in daytime BP in female WKY, causing a tendency for 24-hour MAP to be lower in rats fed 1% NaCl. Thus, compensatory mechanisms that respond to dietary NaCl supplementation used to lower BP appear to be exaggerated in female rats of both strains compared with males.
Gender differences in the NaCl sensitivity of BP have received little investigative attention. Ouchi et al9 reported that 6 weeks of DOCA-salt exposure induced greater increases in SBP in male than female Sprague-Dawley rats (190±8 versus 163±7 mm Hg, respectively). Fluid intake and urinary sodium excretion were increased in both sexes by DOCA-salt treatment, but the increases were greater in females. These results are consistent with the findings of Crofton et al10 that SBP after 3 weeks of DOCA-salt exposure was 30 to 40 mm Hg higher in intact male than intact female Sprague-Dawley rats. In addition, these authors observed that ovariectomy increased SBP by 15 to 25 mm Hg in the female rats, suggesting that ovarian hormones blunted the sensitivity to DOCA-salt. Wambach and Higgins11 reported that long-term administration of progesterone prevented DOCA-salt–induced increases in BP in male Sprague-Dawley rats. At 4 weeks of treatment, mean SBP in the DOCA-salt–treated rats was 135±2 versus 121±3 mm Hg in male rats receiving both DOCA-salt and progesterone treatment. The progesterone-treated rats had greater urine output and urinary sodium excretion than rats receiving only DOCA-salt. The above studies suggest that endogenous progesterone may blunt the sensitivity of female rats to DOCA-salt exposure through its antimineralocorticoid effects in the kidney.
Susic et al12 produced NaCl-induced hypertension by NaCl loading partially nephrectomized rats. They found that the long-term administration of progesterone blunted the NaCl-induced increase in SBP in this model. The progesterone-related decrease in BP was accompanied by a decrease in total peripheral resistance, suggesting that progesterone has antihypertensive effects independent of its antimineralocorticoid properties.
Like DOCA-salt and reduced kidney mass–salt hypertension, NaCl-sensitive hypertension in SHR has a sexually dimorphic pattern. Blizzard et al5 maintained 7-week-old SHR on high (8%) or low (0.3%) NaCl diet. Male SHR reached an SBP level of 170 mm Hg in 16 days, whereas female SHR did not achieve that level until 28 days. Reduced NaCl sensitivity of female SHR was confirmed by Wyss et al,6 who reported that female SHR manifested no significant increase in MAP after 2 weeks of high (8%) dietary NaCl exposure compared with controls receiving a 1% NaCl diet. Chen13 reported that the greater NaCl sensitivity of male SHR is not related to testosterone. In this study, intact, castrated, and testosterone-replaced castrated male SHR were maintained on high (8%) or basal (1%) NaCl diets for 18 weeks. All rats manifested significant increases in SBP when fed the high NaCl diet, with the castrated rats manifesting the largest increase. The relationship of ovarian hormones to NaCl sensitivity in female SHR has not been studied.
The current study demonstrates that female SHR are resistant to short-term dietary NaCl exposure. Studies of DOCA-salt and reduced renal mass hypertension, as discussed above, suggest that progesterone protects female rats from salt-induced increases in BP. Whether progesterone likewise protects female SHR from NaCl-induced increases in BP is of interest, because the hypertension occurring in SHR is thought to be pathophysiologically similar to human primary hypertension. Ongoing studies in our laboratory are addressing this issue.
Selected Abbreviations and Acronyms
| BP | = | blood pressure |
| DOCA | = | deoxycorticosterone acetate |
| HR | = | heart rate |
| MAP | = | mean arterial pressure |
| SBP | = | systolic blood pressure |
| SHR | = | spontaneously hypertensive rat(s) |
| WKY | = | Wistar-Kyoto rat(s) |
Acknowledgments
This work has been supported by National Heart, Lung, and Blood Institute grants HL-07457, HL-37722, HL-47081, and HL-54618; Grants-in-Aid from the American Heart Association; and a grant-in-aid from the Upjohn Co, Kalamazoo, Mich. Dr Calhoun is a recipient of a Physician-Scientist Award (HL-02568) from the National Heart, Lung, and Blood Institute.
- Received March 17, 1995.
- Revision received April 11, 1995.
- Accepted May 14, 1995.
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- Gender and Dietary NaCl in Spontaneously Hypertensive and Wistar-Kyoto Rats
