(Hypertension. 1997;29:613-618.)
© 1997 American Heart Association, Inc.
Articles |
Spontaneously Hypertensive Rat Y Chromosome Increases Indexes of Sympathetic Nervous System Activity
the Department of Biology, The University of Akron (Ohio), and the Department of Medicine, University of California and Department of Veterans Affairs, San Diego (M. Takiyyuddin).
Correspondence to Daniel Ely, Department of Biology, The University of Akron, Akron, OH 44325-3908. E-mail r1dle@vm1.cc.uakron.edu
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Abstract |
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Previous studies from our laboratory have demonstrated that the Y chromosome from the spontaneously hypertensive rat (SHR) is responsible for a significant portion of the elevated blood pressure and also produces an earlier pubertal rise in plasma testosterone. We performed the following studies to determine whether the SHR Y chromosome raises blood pressure by sympathetic nervous system responses as measured by adrenal chromogranin A and plasma and tissue catecholamines. Male SHR from The University of Akron colony were studied from 5 to 20 weeks of age. Blood pressure was measured by tail-cuff, tail artery cannulation, and aortic telemetry (Data Sciences); acute (air stress) and chronic (territorial colony) social stressors were compared; blood was collected for determination of plasma catecholamines; and adrenal glands were analyzed at 15 weeks for catecholamines. Rats with the SHR Y chromosome had higher blood pressure and plasma norepinephrine than those with the normotensive Wistar-Kyoto (WKY) Y chromosome. However, the SHR Y chromosome did not significantly change responsiveness to acute or chronic stressors. Phentolamine and clonidine prevented the stress responses. Adrenal chromogranin A levels were elevated 37% and 40% and adrenal norepinephrine content 29% and 100% at 4 and 10 weeks of age, respectively, in rats with an SHR Y chromosome compared with WKY. Chemical sympathectomy normalized blood pressure in all strains and significantly reduced norepinephrine (36% to 41%) in all strains except in WKY, which already had a normal blood pressure. In conclusion, the SHR Y chromosome appears to increase the chronic sympathetic nervous system. A potential mechanism could be a Y locus that influences chronic sympathetic nervous system activity, which may reinforce neurohumoral factors and structural components of the vessel wall, accelerating the development of hypertension.
Key Words: Y chromosome • blood pressure • norepinephrine • sympathetic nervous system • stress, social • chromogranin A
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Introduction |
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Our laboratory has demonstrated that the Y chromosome of the SHR (SHR/Hsd from Harlan Sprague Dawley, Inc) has a locus that increases BP when transferred into a normotensive WKY/Hsd genetic background, even after 17 generations of backcrossing to WKY.1 2 An SHR Y chromosome effect is consistent with the data reported in the stroke-prone strain of SHR.3 4 5 One report failed to find a Y chromosome BP effect using SHR from Charles River Laboratories (SHR/Crl).6 We have repeated their experiment with our protocols and WKY from our colony and confirmed the lack of a Y chromosome BP effect in F1 SHR/Crl backcrosses.7 Therefore, these data suggest that a mutation has occurred either inactivating or removing the BP locus from the SHR/Crl Y chromosome. A second phenotype that we have demonstrated to be associated with the SHR Y chromosome is an early testosterone rise during puberty8 ; however, the mechanisms underlying this effect are not known.
The SHR model of hypertension is characterized by increased activity of the SNS, which is intimately involved in stress responses.9 10 11 12 13 Also, phenotypic sex, androgens, and androgen receptors influence both BP and the SNS in SHR strains.8 14 15 Our objective in the following studies was to determine whether indexes of SNS activity were involved in BP responses in rats with an SHR Y chromosome compared with those with a WKY Y chromosome.
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Methods |
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Animal Strains
SHR and WKY were originally obtained from Harlan Sprague Dawley (Indianapolis, Ind) in 1981, and colonies have been maintained in our laboratory for the last 15 years. In the following studies, we used consomic strains that we developed. The SHR/y strain has the SHR Y chromosome backcrossed into a WKY background for 17 generations, and the SHR/a strain has the WKY Y chromosome backcrossed into an SHR background for 17 generations.2 All rats were treated in a humane manner according to National Institutes of Health guidelines, and all experiments were approved by the University of Akron Institutional Animal Use and Care Committee.
Experiment 1: Acute Stressors
The objective of this experiment was to determine whether the SHR Y chromosome influences the SNS responsiveness to acute stress during a high sodium diet. Males of each strain (15 to 20 weeks; SHR, WKY, SHR/y, and SHR/a; n=6-10 per group) were implanted with aortic telemetry transmitters (Data Sciences) as previously described.8 Air stress procedures (30 seconds) were performed on rats fed a high sodium diet (3% sodium, ICN) from weeks 15 to 20 that were singly housed in standard rat cages (20x45x20 cm). The purpose of the high sodium diet was to potentiate BP under stress conditions as shown in our previous studies.12 16 17 Each strain was housed in a separate room. Lighting was maintained on a 12-hour cycle (dark from 6 PM to 6 AM; light from 6 AM to 6 PM), with controlled humidity (50% to 70%) and temperature (27°C to 29°C).
Two weeks after surgery (telemetry implantation), after BP had stabilized and exhibited a normal circadian rhythm, a baseline BP recording was taken (average for 2 hours before stress), followed by 30 seconds of air stress. The air stress consisted of a steady stream of air (8 L/min) blown toward the rat's face. BP was monitored at 10-second intervals during the stressor, and peak BP was recorded. One week later, the procedure was repeated, with 30 seconds of air stress after phentolamine administration (0.86 mg/kg IM) to block 
-adrenergic receptors. One week later, each rat was restrained for 2 hours in a hardware (0.064-cm squares) cloth restrainer that was the size of the rat and did not allow the rat to turn around. After the restraint stress, the rat was anesthetized with methohexital sodium (50 mg/kg IP), and a retro-orbital blood sample was taken for plasma norepinephrine analysis. Baseline BP (2-hour average) was determined before the restraint stress. All acute stress procedures were performed between 11 AM and 4 PM. Plasma norepinephrine was measured by high-performance liquid chromatography with electrochemical detection (Waters) using the technique of Foti et al18 as we previously described.19
Experiment 2: Adrenal CgA and Catecholamine Contents
The objective of this experiment was to determine whether the SHR Y chromosome increased a long-term index of SNS activity, that is, adrenal gland CgA and catecholamine contents. We used males of each of the four strains (SHR, WKY, SHR/a, and SHR/y; n=5 per group) at 4 and 10 weeks of age to examine the indexes of SNS activity before and during the developmental increase in BP. The rats were on a normal sodium (0.3%) diet and housed in standard cages, with two to three rats per cage.
The adrenal glands were removed and stored at -70°C until processed. Tissue homogenates were assayed for immunoreactive CgA as previously described.20 Immunoprecipitation and radioimmunoassay of radiolabeled N-terminal CgA peptide, CgA(1-16)-125I-[Tyr17], by rabbit polyclonal anti-peptide antisera was accomplished as previously outlined for immunoprecipitation of intact,125I-labeled CgA.21
The optimal (working) titer of the first antibody for radioimmunoassay was that which immunoprecipitated 30% to 40% of 10 000 cpm of the 125I-labeled antigen, and the final titer was 1:180 (vol/vol). Immunoreactive CgA was determined from parallel displacement of tracer by unlabeled antigen standard and unknown sample (tissue homogenate) from the antibody in the radioimmunoassay. Catecholamine tissue levels were determined radioenzymatically.22
Experiment 3: Chronic Stress and High Sodium
The objective of this experiment was to determine whether the SHR Y chromosome increased the long-term BP responses through an SNS mechanism of males socially interacting in a colony and competing for food, females, and territory. At 6 weeks of age, three treatment groups of WKY males (normal sodium colony, high sodium colony, and high sodium colony plus clonidine [120 µg/20 g food]) and the same three groups of SHR/y males (n=10 per group) were each placed in a large open-field population cage (colony stress treatment).12 The open field (120x120x20 cm) was connected on two sides by two large cages (40x45x20 cm) connected to the open field by polyvinyl chloride pipe. Water and either normal (0.3%) or high (3%) sodium food were provided ad libitum in each peripheral cage. High sodium food was used to potentiate the SNS, an effect we have previously reported.12 16 Strain- and age-matched females (n=10) were added to each colony. BP was measured weekly by a tail cuff12 (Narco BioSystems) from 6 to 15 weeks of age. The same protocol was followed for SHR and SHR/a treatment groups (normal sodium colony, high sodium colony, and high sodium colony plus clonidine). BP was measured weekly and blood samples were collected at 15 weeks for norepinephrine analysis as in experiment 1. At the end of the experiment, BP in randomly selected rats (three from each group, n=36) was verified by tail artery cannulation16 (Micro-Med system).
Experiment 4: Sympathectomy
The objective of this experiment was to use another technique, chemical sympathectomy, to reduce the developmental effect of the SNS on the BP control mechanisms in the four strains (SHR, WKY, SHR/a, and SHR/y; n=4-6 per group). Male neonates (day 2) were injected for 2 days with anti–nerve growth factor (1 µg/mLx104 in 0.1 mL, Sigma Chemical Co) and for 4 weeks (5 d/wk) with guanethidine sulfate (50 mg/kg SC in a volume of 10 µL/g body wt, Sigma). BP was measured by tail sphygmomanometry from 4 to 15 weeks, and a retro-orbital blood sample was taken at 15 weeks for plasma norepinephrine measured by high-performance liquid chromatography with electrochemical detection.18
Statistical Analysis
For multiple comparisons, a one-way ANOVA was calculated for BP differences among the four strains and a two-way ANOVA for strain and age effects and strain and treatment effects. Bonferroni t tests were used after ANOVA for pairwise comparisons, and in some cases, Pearson correlation coefficient and t tests were used.
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Results |
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Fig 1
shows the BP response to two acute stressors, air stress and restraint stress. Both stressors significantly increased BP (P<.001) in all strains. The absolute BP response to air stress in SHR/y was greater than that in WKY (195 versus 175 mm Hg, P<.05), whereas the air stress responses in SHR and SHR/a were similar (211 versus 208 mm Hg). Phentolamine significantly reduced the air stress response in all strains. Restraint stress also significantly increased BP more in SHR/y than in WKY (175 versus 154 mm Hg). The restraint stress increased BP in SHR and SHR/a to about the same extent (195 versus 194 mm Hg). The relative change in BP for each strain was similar for both types of stressors. However, the WKY and SHR/y groups were similar, with BP changes of 31 to 35 mm Hg in response to the stressors, whereas the SHR group showed changes of 23 to 24 mm Hg and the SHR/a group of 40 to 47 mm Hg.
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Adrenal glands of SHR/y males had 37% to 40% more CgA than glands of WKY males at both 4 and 10 weeks of age (P<.05, Fig 2). SHR/a had slightly higher CgA levels than SHR at 4 weeks (P<.05) but not at 10 weeks. Table 1 shows adrenal catecholamine content by strain and age and Table 2 the relevant statistics. SHR/y had higher norepinephrine than WKY at 10 weeks (P<.01) but not at 4 weeks. Two-way ANOVA showed an age effect for norepinephrine (F=12.5, P=.001), but there was no significant strain effect or interaction. Epinephrine analysis showed a strain effect (F=4.99, P=.005) and no age effect, but the interaction was significant (F=3.04, P=.04). Bonferroni t tests showed a significant epinephrine elevation in SHR/y compared with SHR and SHR/a at 4 weeks (P<.01). Dopamine levels did not differ significantly by strain or age.
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.05, SHR(a) vs SHR and SHR(y) vs WKY.
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BP analysis (two-way ANOVA) for experiment 3 (Fig 3) showed significant strain effect (F=93.8, P<.0001), treatment effect (F=121.8, P<.0001), and interaction (F=22.6, P<.0001). Follow-up t tests showed that in all strains except SHR/a, the high sodium treatment raised BP (P<.001) and clonidine treatment significantly lowered BP in all strains except WKY (P<.001). Between-strain (but same treatment) analysis showed that the absolute BP was significantly increased by high sodium because of the SHR Y chromosome (SHR/y) compared with WKY (P<.001). When the Y chromosome was removed from the SHR (SHR/a) under high sodium treatment, BP was significantly lowered (P<.001). Also, under normal sodium treatment in a colony, the SHR Y chromosome produced higher BP than in WKY (P<.001), and removal of the SHR Y chromosome likewise lowered BP compared with SHR (P<.001).
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Plasma norepinephrine levels mirrored the relationship of BP in strains during control and clonidine treatments (Fig 4). There were a significant strain effect (F=11.3, df=3, P<.001), treatment effect (F=333, df=1, P<.001), and interaction (F=7.2, df=3, P<.001) with regard to plasma norepinephrine levels (two-way ANOVA). Tail artery BP correlated satisfactorily with final indirect BP (r=.91, P<.01; data not shown). Fig 5 shows the consistent reduction in BP in all strains produced by chemical sympathectomy (two-way ANOVA: treatment and age treatment effect, WKY: F=128, df=1, P<.001; SHR/y: F=259, df=1, P<.001; SHR: F=282, df=1, P<.001; SHR/a: F=285, df=1, P<.001); age was also significant in each strain (P<.01), in that as expected, BP increased with age. There was also a corresponding significant reduction in plasma norepinephrine in the three hypertensive strains (SHR, SHR/a, SHR/y) ranging from 36% to 41% (Fig 6). The WKY group had the lowest control level of norepinephrine, and sympathectomy decreased this amount by only 7% (P=NS). Two-way ANOVA showed a significant strain effect (F=8.4, df=3, P<.001) and significant treatment effect (F=22.6, df=1, P<.001) but no significant interaction.
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Discussion |
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The Y chromosome from SHR when placed in a WKY normotensive genetic background under normal living conditions elevates BP by approximately 20 mm Hg, and removal of the SHR Y chromosome reduces BP by about 20 mm Hg. However, in the chronic high-stress condition of the colony and during a high sodium diet, the Y chromosome from the SHR and the autosomes interacted to raise BP to very high levels of 220 mm Hg, and removal of the Y chromosome lowered BP in the SHR/a by about 70 mm Hg. This suggests that the Y chromosome from SHR may interact with the SHR autosomes to further potentiate the BP rise. From the acute stress studies, it did not appear that the SHR Y chromosome conferred enhanced stress sensitivity; however, the chronic colony salt studies suggested a salt sensitivity because the two strains with the SHR Y chromosome showed significant BP elevations (SHR=30 mm Hg, SHR/y=16 mm Hg), and the two strains with the WKY Y chromosome showed very small BP changes (WKY=10 mm Hg, SHR/a=3 mm Hg). We postulate that one mechanism for this significant BP effect is altered SNS activity in animals with the SHR/Hsd Y chromosome. Support for this hypothesis is provided by several lines of data from the hypertensive strains: (1) increased adrenal CgA immunoreactivity; (2) elevated plasma norepinephrine during rest and chronic stress, blocked by phentolamine and clonidine, respectively; (3) elevated adrenal norepinephrine at 10 weeks; and (4) significant reductions of BP and plasma norepinephrine by chemical sympathectomy.
Our SHR strain does not have elevated BP in the presence of a chronic high sodium diet (3%, 4 to 15 weeks of age) without stress.16 However, when the rats were stressed chronically,12 BP was elevated significantly, with strain differences. Also, the type of chronic stress used in our laboratory is different from many laboratory stressors because it is an ethological type that the rats impose upon one other.12 We describe this as territorial stress because the males compete for food, females, and territory. SHR on a high sodium diet and exposed to this territorial stress show significantly elevated BP along with SNS indicators.12
The tissue chromogranin data reflect long-term SNS influences. The chromogranins are a family of acidic, soluble proteins initially described in adrenomedullary chromaffin granules but subsequently found in the core of most neuroendocrine secretory vesicles.23 Schober et al24 noted increased chromogranins in the stroke-prone SHR compared with the normotensive WKY strain. In addition, Takiyyuddin et al20 reported augmented synthesis and storage of adrenomedullary CgA and CgB, catecholamines, and catecholamine biosynthetic enzymes in the two-kidney, one clip Goldblatt model of renovascular hypertension. Because tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, is subject to transynaptic induction by efferent stimulation of chromaffin cells,25 26 the increase in adrenal CgA in hypertension appears to reflect increased SNS activity. Upregulation of CgA biosynthesis is most probably related to increased efferent splanchnic nerve traffic, a reproducible finding in Goldblatt hypertension.20 In rat adrenal glands, nervous activity leads to a significant increase of enkephalins and neuropeptides and their respective mRNAs, whereas CgA is not changed under these conditions.27 28 29 However, CgA is influenced by hormones, especially glucocorticoids.28 29 Hypophysectomy reduced CgA mRNA levels by 68%, and dexamethasone restored mRNA levels to 86% of normal.29 The mechanism for this is not known, but the increased CgA may be due to a greater release of catecholamines.17 24 30 31 Thus, increased adrenal CgA immunoreactivity in SHR/y is suggestive of increased SNS activation. This is in line with findings of other researchers who have demonstrated both central32 33 34 35 36 and peripheral3 14 37 38 39 40 SNS involvement in SHR by measuring catecholamine levels, synaptic transmission,41 or direct nerve recording.38 Actually, the CgA level was higher in SHR/y at 4 and 10 weeks than in SHR, although the adrenal norepinephrine level was not significantly different. The reason for this is not clear but could indicate differences in CgA metabolism influencing synthesis, degradation, and reuptake elements. Pertinent to our research was the actual adrenal norepinephrine tissue level, which showed similarity between SHR and SHR/y. The increased adrenal norepinephrine content in the SHR/y compared with WKY paralleled the CgA levels, providing further support for the idea that there is a chronic increase in the activity of the catecholamine biosynthetic pathway or an altered release or uptake pattern. This appears to be a developmental effect because there were no significant adrenal catecholamine differences among strains at 4 weeks. Also, the SHR/a had adrenal catecholamine and CgA levels more similar to those in SHR than WKY, suggesting that autosomal genes from a hypertensive background also contribute to adrenal catecholamine pathways. There probably is greater adrenal medullary influence on BP in the hypertensive genetic rat models. Recently, Vollmer et al42 showed that in mature male Sprague-Dawley rats, adrenal demedullation did not influence baseline or reflex manipulated BP. However, in a related genetic hypertensive model (stroke-prone), adrenal medullary secretory components (norepinephrine, epinephrine, dopamine, neuropeptide Y, and CgA and CgB) were higher in stroke-prone SHR than WKY at 4 and 12 months.24
The importance of the SNS in contributing to hypertension in the three hypertensive strains is further supported by the data showing that clonidine significantly lowered BP and plasma norepinephrine in the chronic studies. The baseline norepinephrine level was similar in the different studies for each strain, with minor variations. The restraint stress plasma norepinephrine values were slightly higher than the norepinephrine values of each strain in the colony treatment; however, values in the SHR group were about the same. Therefore, the chronic colony treatment was comparable in plasma norepinephrine stressor responsiveness to restraint stress. Both plasma norepinephrine and BP in the SHR/y group were higher than in WKY. This, together with the finding that sympathectomy and central SNS blockade prevented the BP rise in SHR/y, suggests that the Y chromosome has a locus that influences the SNS and consequently BP.
In conclusion, we have shown that in chronic studies, the SHR Y chromosome increases BP at rest and during stress compared with WKY. The Y chromosome–enhanced BP effect appears to be at least partially due to increased SNS activity as reflected in both plasma norepinephrine levels and adrenal medulla CgA and norepinephrine contents. The BP response is blocked by adrenergic antagonists, central noradrenergic agonists, and chemical sympathectomy at birth. Therefore, the Y chromosome effect may be due to a locus that influences the SNS directly or indirectly.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by grants from the National Institutes of Health (R01-HL-48072-01A1), Ohio Board of Regents (533983), and the American Heart Association (91010870). The technical support of Fieke Bryson, Sarah Francis, and Heather Lose is greatly appreciated.
Received September 20, 1995;
first decision November 10, 1995;
first decision September 13, 1996;
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References |
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 A. Caplea, D. Seachrist, H. Daneshvar, G. Dunphy, and D. Ely Noradrenergic content and turnover rate in kidney and heart shows gender and strain differences J Appl Physiol, February 1, 2002; 92(2): 567 - 571. [Abstract] [Full Text] [PDF]
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 A. Caplea, D. Seachrist, G. Dunphy, and D. Ely Sodium-induced rise in blood pressure is suppressed by androgen receptor blockade Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1793 - H1801. [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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A. Caplea, D. Seachrist, G. Dunphy, and D. Ely SHR Y chromosome enhances the nocturnal blood pressure in socially interacting rats Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H58 - H66. [Abstract] [Full Text] [PDF]
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 D. Ely, M. Herman, L. Ely, L. Barrett, and A. Milsted Sodium intake is increased by social stress and the Y chromosome and reduced by clonidine Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R407 - R412. [Abstract] [Full Text] [PDF]
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T. J. Jones, G. Dunphy, A. Milsted, and D. Ely Testosterone Effects on Renal Norepinephrine Content and Release in Rats With Different Y Chromosomes Hypertension, November 1, 1998; 32(5): 880 - 885. [Abstract] [Full Text] [PDF]
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V. Borovsky, M. Herman, G. Dunphy, A. Caplea, and D. Ely CO2 asphyxia increases plasma norepinephrine in rats via sympathetic nerves Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1998; 274(1): R19 - R22. [Abstract] [Full Text] [PDF]
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