(Hypertension. 1995;26:452-459.)
© 1995 American Heart Association, Inc.
Articles |
Blood Pressure in Genetically Hypertensive Rats
Influence of the Y Chromosome
From the Departments of Medicine and Therapeutics (A.O.D., A.W.K., J.L.R., A.F.D.) and Surgery (B.C.J.), and the Laboratory of Genetics IBLS (R.G.S.), The University of Glasgow (Scotland); and Department of Genetics, Case Western Reserve University, Cleveland, Ohio (N.S.).
Correspondence to Dr Anna F. Dominiczak, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, UK. E-mail gona41@udcf.gla.ac.uk.
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Abstract |
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Abstract We used a cross between the stroke-prone spontaneously hypertensive rat (SHRSP) strain and the Wistar-Kyoto (WKY) normotensive strain to elucidate the genetic basis of hypertension. Previous studies have reported conflicting evidence for the contribution of the Y chromosome to hypertension in these models. To investigate further the role of the Y chromosome in hypertension, we performed two large reciprocal crosses: one with the SHRSP as a male progenitor of the cross, yielding 60 F2 rats, and another with the WKY as a male progenitor, yielding 83 F2 rats. The resulting F2 hybrids were phenotyped with the use of a radiotelemetry system (Data Sciences) for measurement of systolic, diastolic, and mean arterial pressures as well as heart rate and motor activity continuously for 96 hours at baseline and after 1% NaCl was added to the rats' drinking water for 12 days. Male F2 hybrids with the SHRSP grandfather had significantly higher average systolic, diastolic, and mean arterial pressures at baseline compared with male F2 hybrids with the WKY grandfather (188.7±18.1 versus 168.9±11.5, 130.3±14 versus 115.7±7.3, and 159.1±15.8 versus 141.5±9.4 mm Hg, respectively). These differences were also observed after salt loading (197.9±22.1 versus 176.8±11.7, 136.5±17.3 versus 120.7±7.6, and 166.7±19.5 versus 148±9.7 mm Hg, respectively; P<.0001 for each comparison). These results suggest that the SHRSP Y chromosome contains a locus or loci that contribute to hypertension in SHRSP/WKY F2 hybrids.
Key Words: hypertension, genetic • rats, inbred strains • Y chromosome • telemetry
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The stroke-prone spontaneously hypertensive rat (SHRSP) is generally regarded as an excellent experimental model of human essential hypertension.1 As in humans, male SHRSP have higher blood pressure than females.2 The same is true of the more commonly used animal model, the spontaneously hypertensive rat (SHR).3 4 5
Genetic crosses between Wistar-Kyoto rats (WKY) and SHR or SHRSP have been used to elucidate the genetic basis of hypertension.6 7 8 9 One of these studies found that the blood pressure of F2 hybrid offspring depended on the strain of the male progenitor of the cross; male offspring with an SHR male progenitor had significantly higher pressures than male offspring with a WKY male progenitor.9 This observation suggested that there are two major components of SHR hypertension: a genetic locus on the SHR Y chromosome and an autosomal locus or loci.9 These results were confirmed by Turner and colleagues10 through the development of two new SHR/WKY substrains (congenic strains) that permitted the separation of the Y chromosome and the autosomal loci of the SHR. The first substrain, SHR/y, contains an SHR Y chromosome and 99.9% autosomal genes and an X chromosome of WKY origin; the second substrain, SHR/a, contains 99.9% autosomal loci and an X chromosome of SHR origin and a WKY Y chromosome.10 11 A recent study examining these substrains proposed that a gene on the SHR Y chromosome (Tty) is responsible for the timing of testosterone in development.12
The results of Ely et al11 and Turner et al10 were not confirmed in a recent cross described by Vincent et al.13 This study failed to demonstrate a differential effect of the SHR Y chromosome on blood pressure, despite study of an SHRxWKY cross similar to that of Ely and Turner. The reasons for the discrepant results have not been clarified although genetic heterogeneity of WKY and SHR from different sources has been suggested as the cause.14 It is also conceivable that the methods used to phenotype rats in the individual crosses may have influenced the final results. We have recently characterized two large reciprocal crosses of SHRSPxWKY using a radiotelemetry system for blood pressure monitoring. The aim of the present study was to assess the effect of the Y chromosome on blood pressure in an SHRSP/WKY intercross.
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Methods |
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Experimental Rats and Genetic Crosses
Thirteen SHRSP and 13 WKY (6 males and 7 females of each) were obtained from the colonies maintained in the University of Michigan, which had obtained their breeding stocks from the National Institutes of Health (personal communication, Dr DF Bohr, Department of Physiology, University of Michigan). These rats were brotherxsister mated in Glasgow to provide an SHRSP colony and a WKY colony as previously described.15
For the two reciprocal genetic crosses 1 male SHRSP was mated with 2 WKY females (cross 1) and 1 male WKY with 2 SHRSP females (cross 2) (Fig 1). From the F1 rats of each cross, 3 males and 6 females were brotherxsister mated to generate F2 rats (60 in cross 1 and 83 in cross 2). All rats were housed under controlled conditions of temperature (21°C) and light (12-hour light/dark cycle; 7 AM to 7 PM) and were maintained on normal rat chow (rat and mouse No. 1 maintenance diet, Special Diet Services) and water ad libitum. Litters were weaned and sexed after 3 weeks and maintained by sibling group and sex thereafter. Three rats were kept in a cage until the time of the telemetry experiment.
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Blood Pressure Measurements
Indirect blood pressure was measured in conscious rats by tail
plethysmography as previously described.16 Rats were
prewarmed to 34°C for 10 to 15 minutes before measurements, which
were taken either between 9 AM and 1 PM or
between 2 PM and 5 PM. Special care was taken
to perform measurements in both the morning and afternoon in each rat
at a given age. Measurements were made at 16 weeks of age in all rats
studied. In addition, F2 hybrids from cross 2, parental
SHRSP, and parental WKY also underwent indirect blood pressure
measurements at 8 and 12 weeks of age. At each age at least three
measurements were taken, and the average of all recordings was
taken as the value for that age.
The Dataquest IV telemetry system (Data Sciences International) was used for measurement of systolic pressure, diastolic pressure, mean arterial pressure, heart rate, and motor activity.17 The monitoring system consists of a transmitter (radio frequency transducer model TA11PA), receiver panel, consolidation matrix, and personal computer with accompanying software. Before the device was implanted, calibrations were verified to be accurate within 3 mm Hg. Rats at 16 weeks of age were anesthetized with halothane, and the flexible catheter of the transmitter was surgically secured in the abdominal aorta just below the renal arteries and pointing upstream (against the flow). The transmitter was sutured to the abdominal wall. Rats were housed in individual cages after the operation. Each cage was placed over a receiver panel that was connected to the personal computer for data acquisition. The rats were unrestrained and free to move within their cages. Hemodynamic data were sampled every 5 minutes for 10 seconds. Preliminary experiments showed that blood pressure and heart rate took up to 12 days to stabilize postoperatively. Experimental observations were therefore collected from day 12 to day 16 after surgery as "baseline hemodynamic measurements." Previously published data suggested that salt-loaded blood pressure may be used as a separate phenotype for genetic studies.7 8 In the evening of day 16 the rats received 1% NaCl in their drinking water, and this was continued until day 28 when they were euthanized. The measurements collected between day 25 and day 28 constituted "hemodynamic measurements on 1% NaCl" or "salt-loaded measures." Systolic and diastolic pressures and heart rate values were calculated by the Dataquest software. Mean values were calculated for intervals of 60 minutes and exported from the Dataquest program in an ASCII format.
The experiments were approved by the Home Office according to regulations regarding experiments in animals in the United Kingdom. These regulations meet all the requirements of the American Physiological Society.
Statistical Analysis
The statistical methods used to analyze the telemetry
data included standard two-sample t tests, ANOVA
methods, and nonparametric two- and multiple-sample
median tests.18 Nonparametric tests were used
in conjunction with parametric tests because data collected at
some time points during data collection showed departures from
normality, and the variances between groups tested tended to be
unequal. Analysis of telemetry data was carried out in two
ways: (1) using the aggregate measures of telemetry data computed for
each individual rat (ie, mean and coefficient of variation over the 96
hours), and (2) treating each time point in isolation and investigating
group differences. For this second method, all test statistics were
corrected for multiple comparisons. Since 96 time points were
investigated and an overall significance level of .05 was assumed, only
test statistics achieving values of P<.05/96=.0005 were
taken to be significant. This strategy is conservative in that it
ignores the correlations between test statistics computed at
neighboring time points. However, since the purpose of this study was
to investigate the effect of the SHRSP Y chromosome, we have left for
future investigations time-series analyses and a general
characterization of the diurnal variation exhibited over the data
collection time period.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Indirect Blood Pressure Measurements
Tail-cuff systolic pressures measured in SHRSP and WKY of the Glasgow colonies at 8, 12, and 16 weeks of age are shown in Fig 2, top. Male SHRSP had higher blood pressures than female SHRSP at each time point (P<.001 for each comparison). Mean indirect systolic pressure of the F2 hybrids of cross 1 (with the SHRSP Y chromosome, Ys) at 16 weeks of age and mean indirect systolic pressures of the F2 hybrids of cross 2 (with the WKY Y chromosome, Yw) at 8, 12, and 16 weeks of age are shown in Fig 2, bottom. Systolic pressures of 16-week-old F2 males from cross 1 were significantly higher than systolic pressures in F2 males from cross 2 (167.0±3.8 versus 151.6±2.8 mm Hg; P=.002; 95% confidence interval, 5.8 to 25.0). There was no statistically significant difference between F2 females of cross 1 and cross 2 at the same age.
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XYw denotes male
F2 rats of cross 2 (at 8 weeks, n=23; at 12 weeks, n=35; at
16 weeks, n=35); 
G-w denotes female F2
rats with a WKY grandfather (at 8 weeks, n=41; at 12 weeks, n=45; at 16
weeks, n=45);
Direct Blood Pressure, Heart Rate, and Motor Activity in
Parental Strains
Baseline aggregate measures computed over the time period for
which telemetry data were collected for each sex and strain category
are shown in Table 1. SHRSP males had significantly
higher systolic, diastolic, and mean arterial
pressures compared with SHRSP females (Table 1). There were no
significant differences for heart rate and motor activity between the
two strains for either males or females. However, WKY females had
significantly higher mean heart rate and activity than WKY males (Table 1). The coefficient of variation for heart rate over the time period
studied was lower in SHRSP males and females compared with that in WKY
males and females. There were no differences in the coefficient of
variation for heart rate between males and females within each strain
(Table 1). Coefficients of variation for blood pressure and activity
were independent of strain and sex. Of note is the result of the test
on the interaction term from the sexxstrain factor ANOVA (Tables 1 and 2). The significance of this term provides strong
evidence that the male SHRSP have significantly higher blood pressures
than the other rats studied. Also, as there were no activity
differences between the strains, within each sex category, we could not
attribute the observed greater blood pressure values among the SHRSP to
differences in activity. This is important to consider in the context
of the telemetry data discussed below.
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Graphic representation of baseline systolic pressures recorded as 60-minute averages over the 4-day period for the individual SHRSP and WKY males and females is shown in Fig 3. Diastolic and mean arterial pressures followed the same pattern (data not shown). Note that for some rats a "flat" curve appears between hours 30 and 60. This was due to a temporary malfunction of the telemetry equipment, during which no data were collected. The flat line merely connects the data collected at the times flanking the malfunction.
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Salt-loaded aggregate measures computed over the time period for each sex and strain category are shown in Table 2. Preliminary experiments showed a 100% mortality rate within 10 days for SHRSP males given salt; therefore, salt-loading experiments were discontinued in this group. WKY males had significantly higher blood pressure than WKY females. SHRSP females had higher heart rate than WKY females, and the coefficient of variation for heart rate was significantly higher in WKY females compared with SHRSP females (Table 2). In contrast to baseline aggregate measures, coefficients of variation for systolic, diastolic, and mean pressures were significantly greater in SHRSP females than in WKY females (Table 2).
Direct Blood Pressure, Heart Rate, and Motor Activity in
F2 Hybrids
Baseline aggregate measures computed over the time period for
which telemetry data were collected for each sex and male grandparent
strain category are shown in Table 3. Males with the
SHRSP grandfather (Ys) had significantly higher systolic,
diastolic, and mean arterial pressures compared
with males with the WKY grandfather (Yw) (Table 3). Females with the
SHRSP grandfather had blood pressures at baseline similar to those of
F2 females with the WKY grandfather. Analysis of
mean heart rate and motor activity showed that female F2
rats within each cross had higher heart rate and activity than
F2 males, but there were no differences dependent on the
strain of male grandparent (Table 3). The effect of the origin of the Y
chromosome on systolic pressure in the F2 hybrids is shown
in Fig 4, top. Corresponding systolic pressures in
female F2 hybrids are shown in Fig 4, bottom. The
diastolic and mean arterial pressures of
F2 males and females followed the same pattern as systolic
pressures (Table 3). Baseline heart rates for the F2 males
and females are shown in Fig 5.
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Salt-loaded aggregate measures computed over the time period for each sex and male grandparent strain are shown in Table 4. Similar to basal conditions, F2 males with an SHRSP grandfather had significantly higher systolic, diastolic, and mean arterial pressures compared with males with the WKY grandfather (Table 4). Graphic representation of the Y chromosome effect on salt-loaded systolic pressure is shown in Fig 6, top. Corresponding salt-loaded systolic pressure for the F2 females from each cross is shown in Fig 6, bottom. Female F2 rats with an SHRSP grandfather had higher systolic, diastolic, and mean arterial pressures compared with female F2 rats with a WKY grandfather. These differences are smaller than those observed in the male F2 hybrids but are statistically significant (Fig 6, Tables 4 and 5). Female F2 hybrids within each cross had higher heart rate than F2 males of the same cross. Mean activity values were significantly higher in female F2 hybrids with the SHRSP grandfather compared with male F2 hybrids of the same cross. Moreover, female F2 rats with an SHRSP grandfather were also more active than female F2 hybrids with a WKY grandfather.
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Because of the large number of data points and information used to contrast the figures displaying the telemetry data, test statistic information associated with each time point was not included. Table 5 records the number of time points over the data collection period that achieved Bonferroni-corrected two-sample test statistics significant at an overall level of .05. It can be seen from Table 5 that the nonparametric median tests were more conservative than the parametric Student's t tests, especially during the salt-loading phase of the study. This was likely due to the nonnormality and greater variation in the blood pressure values obtained during salt loading, especially among F2 hybrids with SHRSP progenitors (eg, contrast the standard errors associated with the blood pressure measures between Tables 3 and 4). The effect of the SHRSP Y chromosome during both baseline and salt loading is quite pronounced.
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Discussion |
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The major finding of this study is a highly significant difference in systolic, mean, and diastolic pressures at baseline and after salt loading between male F2 hybrids with the Ys chromosome and those hybrids with the Yw chromosome. This highly significant blood pressure difference is in keeping with the results of Ely and Turner and coworkers9 10 11 12 obtained in their SHRxWKY cross and congenic lines.
The SHRSP and WKY rat colonies have been maintained with brother-sister mating for more than 20 generations and are highly inbred and homozygous. This has been tested in Glasgow by genotyping these strains with 140 rat microsatellite markers,19 with no heterozygosity found in either strain for any of the markers tested. Reciprocal F2 males make ideal study subjects for the Y chromosome influence because half of them have an SHRSP X chromosome and half a WKY X chromosome. Thus, any effect of the X chromosome averages out, and only the Y influence on physiological measurements is detectable. Our data are therefore highly suggestive that a locus or loci on the Y chromosome affect blood pressure in the SHRSP. However, it has been pointed out previously that parental imprinting may mimic Y chromosome linkage.9 13 Parental imprinting is characterized by a phenotypic difference of the same gene depending on whether this gene was inherited from the male or female parent.20 For example, the c-myc transgene shows differential methylation patterns; only offspring that inherit the transgene from their father can express the gene.20 By analogy it is possible that an autosomal hypertensive allele is only active if inherited from the male parent. For this hypothesis to be correct one would expect a significant difference in blood pressure of the F2 females depending on the male progenitor of the cross. Analysis of tail-cuff blood pressures at 16 weeks of age and baseline systolic, mean, and diastolic telemetry pressures at 18 weeks of age showed no difference between females from the two reciprocal crosses. The same rats were then given 1% NaCl in their drinking water for 12 days, and direct blood pressures were analyzed over the last 4 days of salt loading. It is of interest that F2 females with the SHRSP grandfather had significantly higher salt-loaded pressures than the F2 females with the WKY grandfather. This difference was smaller than for the F2 males after salt loading. Physiological phenotypes at baseline and in the salt-loaded state have been measured in the same F2 hybrids. It is therefore unlikely that these sporadic blood pressure differences after salt between the F2 females of the two crosses represent parental imprinting that is only detectable in the salt-loaded state.
Previous studies demonstrated that high dietary salt exposure increased blood pressure in the SHR and SHRSP as well as in the F2 hybrids derived from SHRxWKY or SHRSPxWKY crosses.7 8 13 21 These effects are less apparent in the WKY, and it is possible that the differential effects of salt may be related to differences in volume handling and sympathetic nervous system activation.21
There are previous reports on the modifying influence of salt loading on the sex chromosome effect. Hilbert et al7 reported that male F2 hybrids with the Ys chromosome had significantly higher baseline systolic and diastolic pressures at 16 weeks of age. In that study the Y chromosome effect was no longer apparent after 12 days of 1% NaCl added to drinking water, whereas in the current study the Y chromosome effect was present and highly significant in the salt-loaded state. The same study7 reported a significant blood pressure effect of a locus on the X chromosome. The current study cannot confirm or refute these findings. Future studies using microsatellite markers on the autosomes and the X chromosome will be designed to map further blood pressure loci in the SHRSPGlasgowxWKY cross.
Very few genetic loci have been identified on the Y chromosome, and no appropriate rat markers have been developed.22 Ely et al12 proposed that the SHR Y chromosome causes an acceleration of testosterone release and earlier puberty, with a resulting cascade of molecular and neuroendocrine events that contribute to hypertension. One of the Y chromosome potential candidate loci is a Tty gene that affects the timing of testosterone in development. The identity of this gene, and any interaction with the testis determining locus (SRY), remains to be elucidated.12 22
The present study is the first in which radiotelemetry was used to measure blood pressure, heart rate, and motor activity in parental strains and their reciprocal genetic crosses. It appears that direct arterial pressures measured in parental strains with the radiotelemetry system are higher than tail-cuff pressures9 13 and direct femoral catheter pressures7 at a similar age. These differences are most likely due to nighttime blood pressures, which are higher than daytime pressures and which have not been routinely recorded in previous studies. These diurnal variation patterns have been clearly recorded in our study and also in other rat strains.23 We found that SHRSP and WKY strains had normal circadian rhythms of blood pressure and heart rate that followed their motor activity. The same was true for the F2 hybrids. These data were similar to those obtained in SHR, WKY, and Sprague-Dawley strains but at variance with transgenic TGR(mRen-2)27 rats, in which blood pressure values were maximal during the day around noon.23
Continuous measurements of motor activity in our study showed that females in parental strains and in the F2 cohorts were on average more active than males matched for age and strain, or in the case of F2 hybrids, matched for the strain of grandfather. These relationships allow us to conclude that observed blood pressure differences were not related to motor activity of parental and F2 rats. These data confirmed the contribution of a locus or loci on the Y chromosome to the pathogenesis of hypertension in the SHRSP. In contrast to blood pressure, heart rate in the F2 hybrids at baseline and after salt loading was similar in males with Ys and Yw chromosomes. Similar to motor activity, female F2 hybrids had higher heart rates than males within each cross. These results are comparable to heart rate data obtained by Turner et al in their congenic strains SHR/a and SHR/y using the tail-cuff technique (M.E. Turner, personal communication, 1995). The similar patterns of blood pressure and heart rate differences between our F2 hybrids and congenic substrains described by Ely and Turner (References 9 through 129 10 11 12 and personal communication, 1995) strengthen our observations linking the Y chromosome to hypertension of the SHRSP. In the F2 hybrids even most careful physiological measurements may be compromised because of hybrid vigor. Eleven generations of backcrossing in the SHR/y and SHR/a substrains11 12 would have eliminated any hybrid vigor that might have influenced our measurements.
In summary, analysis of 143 F2 hybrids obtained from reciprocal crosses of SHRSP and WKY showed very strong evidence for a locus or loci on the SHRSP Y chromosome that contribute to hypertension in this model. Physiological variables measured with radiotelemetry in the parental strains and F2 hybrids showed several similarities with human essential hypertension, including male/female blood pressure differences and analogies in the circadian rhythm pattern. Although previous studies in hypertension attempting a direct extrapolation from rat genetics to human and vice versa24 25 26 have met with little success, it may be of interest to examine the sex-specific region of the human Y chromosome22 for a potential candidate gene for human essential hypertension.
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Acknowledgments |
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This work was supported by British Heart Foundation grants Nr PG 92100 and FS 93025; A.F.D. is a British Heart Foundation Senior Research Fellow, and B.C.J. is a Wellcome Research Fellow. The authors thank Angela McKay for typing the manuscript.
Received February 22, 1995; first decision April 3, 1995; accepted May 30, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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 M. W. McBride, F. J. Charchar, D. Graham, W. H. Miller, P. Strahorn, F. J. Carr, and A. F. Dominiczak Functional genomics in rodent models of hypertension J. Physiol., January 1, 2004; 554(1): 56 - 63. [Abstract] [Full Text] [PDF]
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M. W. McBride, F. J. Carr, D. Graham, N. H. Anderson, J. S. Clark, W. K. Lee, F. J. Charchar, M. J. Brosnan, and A. F. Dominiczak Microarray Analysis of Rat Chromosome 2 Congenic Strains Hypertension, March 1, 2003; 41(3): 847 - 853. [Abstract] [Full Text] [PDF]
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 C. Yagil, N. Hubner, R. Kreutz, D. Ganten, and Y. Yagil Congenic strains confirm the presence of salt-sensitivity QTLs on chromosome 1 in the Sabra rat model of hypertension Physiol Genomics, January 15, 2003; 12(2): 85 - 95. [Abstract] [Full Text] [PDF]
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F. J. Charchar, M. Tomaszewski, S. Padmanabhan, B. Lacka, M. N. Upton, G. C. Inglis, N. H. Anderson, A. McConnachie, E. Zukowska-Szczechowska, W. Grzeszczak, et al. The Y Chromosome Effect on Blood Pressure in Two European Populations Hypertension, February 1, 2002; 39(2): 353 - 356. [Abstract] [Full Text] [PDF]
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L. Marks, H. V.O. Carswell, E. E. Peters, D. I. Graham, J. Patterson, A. F. Dominiczak, and I. M. Macrae Characterization of the Microglial Response to Cerebral Ischemia in the Stroke-Prone Spontaneously Hypertensive Rat Hypertension, July 1, 2001; 38(1): 116 - 122. [Abstract] [Full Text] [PDF]
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V. Kren, N. Qi, D. Krenova, V. Zidek, M. Sladka, M. Jachymova, B. Mikova, K. Horky, A. Bonne, H. A. Van Lith, et al. Y-Chromosome Transfer Induces Changes in Blood Pressure and Blood Lipids in SHR Hypertension, April 1, 2001; 37(4): 1147 - 1152. [Abstract] [Full Text] [PDF]
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C. D. Negrin, M. W. McBride, H. V. O. Carswell, D. Graham, F. J. Carr, J. S. Clark, B. Jeffs, N. H. Anderson, I. M. Macrae, and A. F. Dominiczak Reciprocal Consomic Strains to Evaluate Y Chromosome Effects Hypertension, February 1, 2001; 37(2): 391 - 397. [Abstract] [Full Text] [PDF]
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C. A. Hamilton, M. J. Brosnan, M. McIntyre, D. Graham, and A. F. Dominiczak Superoxide Excess in Hypertension and Aging : A Common Cause of Endothelial Dysfunction Hypertension, February 1, 2001; 37(2): 529 - 534. [Abstract] [Full Text] [PDF]
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J. A. Ellis, M. Stebbing, and S. B. Harrap Association of the Human Y Chromosome With High Blood Pressure in the General Population Hypertension, November 1, 2000; 36(5): 731 - 733. [Abstract] [Full Text] [PDF]
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 M.Y. Alexander, M.J. Brosnan, C. A. Hamilton, J. P. Fennell, E. C. Beattie, E. Jardine, D. D. Heistad, and A. F. Dominiczak Gene transfer of endothelial nitric oxide synthase but not Cu/Zn superoxide dismutase restores nitric oxide availability in the SHRSP Cardiovasc Res, August 18, 2000; 47(3): 609 - 617. [Abstract] [Full Text] [PDF]
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A. M. Devlin, J. S. Clark, J. L. Reid, and A. F. Dominiczak DNA Synthesis and Apoptosis in Smooth Muscle Cells From a Model of Genetic Hypertension Hypertension, July 1, 2000; 36(1): 110 - 115. [Abstract] [Full Text] [PDF]
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 J. Gutkowska, M. Jankowski, S. Mukaddam-Daher, and S. M. McCann Corticotropin-releasing hormone causes antidiuresis and antinatriuresis by stimulating vasopressin and inhibiting atrial natriuretic peptide release in male rats PNAS, January 4, 2000; 97(1): 483 - 488. [Abstract] [Full Text] [PDF]
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 J. P. Rapp Genetic Analysis of Inherited Hypertension in the Rat Physiol Rev, January 1, 2000; 80(1): 135 - 172. [Abstract] [Full Text] [PDF]
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B. Jeffs, C. D. Negrin, D. Graham, J. S. Clark, N. H. Anderson, D. Gauguier, and A. F. Dominiczak Applicability of a "Speed" Congenic Strategy to Dissect Blood Pressure Quantitative Trait Loci on Rat Chromosome 2 Hypertension, January 1, 2000; 35(1): 179 - 187. [Abstract] [Full Text] [PDF]
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M.Y. Alexander, M.J. Brosnan, C. A Hamilton, P. Downie, A. M Devlin, F. Dowell, W. Martin, H. M Prentice, T. O'Brien, and A. F Dominiczak Gene transfer of endothelial nitric oxide synthase improves nitric oxide-dependent endothelial function in a hypertensive rat model Cardiovasc Res, August 15, 1999; 43(3): 798 - 807. [Abstract] [Full Text] [PDF]
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S. Kerr, M. J. Brosnan, M. McIntyre, J. L. Reid, A. F. Dominiczak, and C. A. Hamilton Superoxide Anion Production Is Increased in a Model of Genetic Hypertension : Role of the Endothelium Hypertension, June 1, 1999; 33(6): 1353 - 1358. [Abstract] [Full Text] [PDF]
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H. V. O. Carswell, N. H. Anderson, J. S. Clark, D. Graham, B. Jeffs, A. F. Dominiczak, and I. M. Macrae Genetic and Gender Influences on Sensitivity to Focal Cerebral Ischemia in the Stroke-Prone Spontaneously Hypertensive Rat Hypertension, February 1, 1999; 33(2): 681 - 685. [Abstract] [Full Text] [PDF]
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N. H. Anderson, A. M. Devlin, D. Graham, J. J. Morton, C. A. Hamilton, J. L. Reid, N. J. Schork, and A. F. Dominiczak Telemetry for Cardiovascular Monitoring in a Pharmacological Study : New Approaches to Data Analysis Hypertension, January 1, 1999; 33(1): 248 - 255. [Abstract] [Full Text] [PDF]
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M. J. Brosnan, J. S. Clark, B. Jeffs, C. D. Negrin, P. Van Vooren, S. M. Arribas, H. Carswell, T. J. Aitman, C. Szpirer, I. M. Macrae, et al. Genes Encoding Atrial and Brain Natriuretic Peptides as Candidates for Sensitivity to Brain Ischemia in Stroke-Prone Hypertensive Rats Hypertension, January 1, 1999; 33(1): 290 - 297. [Abstract] [Full Text] [PDF]
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J. A. Gratton, A. Sauter, M. Rudin, K. R. Lees, J. McColl, J. L. Reid, A. F. Dominiczak, I. M. Macrae, and D. F. Bohr Susceptibility to Cerebral Infarction in the Stroke-Prone Spontaneously Hypertensive Rat Is Inherited as a Dominant Trait • Editorial Comment Stroke, March 1, 1998; 29(3): 690 - 694. [Abstract] [Full Text] [PDF]
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D. Ely, A. Caplea, G. Dunphy, H. Daneshvar, M. Turner, A. Milsted, and M. Takiyyuddin Spontaneously Hypertensive Rat Y Chromosome Increases Indexes of Sympathetic Nervous System Activity Hypertension, February 1, 1997; 29(2): 613 - 618. [Abstract] [Full Text]
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R. Kreutz, P. Stock, B. Struk, and K. Lindpaintner The Y Chromosome: Epistatic and Ecogenetic Interactions in Genetic Hypertension Hypertension, November 1, 1996; 28(5): 895 - 897. [Abstract] [Full Text]
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J. S. Clark, B. Jeffs, A. O. Davidson, W. K. Lee, N. H. Anderson, M.-T. Bihoreau, M. J. Brosnan, A. M. Devlin, A. W. Kelman, K. Lindpaintner, et al. Quantitative Trait Loci in Genetically Hypertensive Rats: Possible Sex Specificity Hypertension, November 1, 1996; 28(5): 898 - 906. [Abstract] [Full Text]
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A. F. Dominiczak, A. M. Devlin, W. K. Lee, N. H. Anderson, D. F. Bohr, and J. L. Reid Vascular Smooth Muscle Polyploidy and Cardiac Hypertrophy in Genetic Hypertension Hypertension, March 1, 1996; 27(3): 752 - 759. [Abstract] [Full Text]
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