Our laboratory has been investigating a locus on the Y chromosome (Yc) of the spontaneously hypertensive rat (SHR) that elevates blood pressure (BP). We have shown that the SHR Yc increases several indices of sympathetic nervous system (SNS) activity and BP. We propose that a transcription factor, Sry, is the Yc gene that elevates BP throughincreased tyrosine hydroxylase (TH) expression and catecholamine release. To investigate the ability of exogenous Sry to raise SNS indiceswe delivered either the expression construct, Sry1/pcDNA 3.1 or control vector, into the left adrenal medulla of adult WKY males by electroporation. After 3 weeks there was a 71% increase inresting plasma NE and a 150% increase in epinephrine compared to vector controls. TH activity increased 33% in the adrenal compared to vector controls. Blood pressure was 30mmHghigher in Sry injected animals (160mmHg) compared to vector controls (130mmHg) after 3 weeks. In conclusion, the Sry transcription factor delivered to the adrenal medulla increases BP, plasma catecholamines and TH activity (supported by grants from the American Heart Association- Ohio Valley Affiliate and NIHLBI).

Territorial stress (TS) elevates blood pressure (BP) in several mammalian species. However, cardiovascular pathology following chronic stress has not been consistently shown in a non-genetic hypertension model. Therefore, the hypothesis tested was that social stress would directly increase: BP, collagen deposition in coronary and mesenteric arteries, and myocardial fibrosis. Wistar-Kyoto (WKY) male rats, four weeks of age, were divided into one of three groups: controls (n = 9), territorial stress (TS, n = 12), and social isolation followed by territorial stress (SITS, n = 11). Blood pressure was measured biweekly, and blood samples biweekly for serum testosterone, corticosterone, epinephrine and norepinephrine. Blood pressure significantly increased in the TS(130 mmHg,p < 0.05) and SITS (150 mmHg, p < 0.05) groups, compared to controls (120 mmHg, ANOVA, F = 6.7, p < 0.001). Coronary collagen was increased 47% in the TS group and 90% in the SITS group compared to controls (p < 0.05). The coronary wall/lumen ratio increased significantly (45%, p < 0.05) in the SITS group compared to the controls. Myocardial fibrosis was increased 27% in the TS group and 74% in the SITS group compared to controls (p < 0.05). In conclusion, stress treatments increased BP and cardiac pathology in a normotensive rat strain.

The objective of this study was to compare strain and gender differences in kidney and heart norepinephrine (NE) content and turnover rate in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR, SHR/a, and SHR/y). Our laboratory has shown that the Y chromosome has a significant effect on blood pressure in the SHR model of hypertension through the use of two new rat stains, SHR/a and SHR/y, to study the Y chromosome. SHR/a have a SHR autosomal genetic background with a WKY Y chromosome, whereas the SHR/y rats have a WKY autosomal genetic background with a SHR Y chromosome. Tissues were homogenized after alpha-methyl-DL-p-tyrosine injection and analyzed for NE. The male kidney NE content was significantly lower in the WKY compared with the SHR, SHR/y, and SHR/a. Kidney and heart NE content was significantly higher in females compared with males in all strains except the SHR/y. The WKY and SHR/y females had significantly lower kidney NE turnover rates, and the SHR and SHR/a females had significantly higher kidney NE turnover rates than strain-matched males. This study suggests both a strain and gender difference in sympathetic nervous system activity through noradrenergic neurotransmission.

The objective of this study was to examine whether or not estradiol (E2) alters sodium intake in hypertensive and normotensive female rats. It was hypothesized that higher doses of E2 would increase sodium consumption and that this response would be greater in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto (WKY) rats. The study involved female SHR and WKY (n = 12/group). All animals were ovariectomized. Six of twelve rats from each strain received three progressively larger doses of beta-estradiol propionate (each dose lasting 2 wk), whereas the other six rats from each strain received sham implants. Blood E2 levels were measured by radioimmunoassay after each 2-wk period, allowing a 10-day washout period before the next E2 dose. Rats had access to 0.0, 0.5, 1.0, and 1.5% NaCl solutions to drink throughout the experiment. There was a significant positive correlation between sodium intake and plasma E2 (r = 0.8, P < 0.001). Both strains avoided the 1.5% NaCl, and the increased sodium intake was achieved by an increase in consumption of the 0.5% NaCl. SHR females consumed more sodium than WKY females, which is similar to what has been observed in males of these strains. In conclusion, E2 was positively correlated with sodium intake in both strains of rat, with the hypertensive rats consuming more sodium than the normotensive rats.

The present study evaluated the association between a testosterone-induced elevation in blood pressure (BP) and renal tyrosine hydroxylase activity in SHR/y and Wistar-Kyoto male rats. The SHR/y rat is a consomic strain having the Y chromosome of the Spontaneously Hypertensive Rat and autosomes and the X chromosome from normotensive Wistar-Kyoto (WKY). Rats were castrated at 4-6 weeks and divided into control and sham groups (n = 6/group) with testosterone and blank sham implants respectively. BP and blood were taken every 2 weeks for estimation of serum testosterone and catecholamines. The animals were terminated at 16-18 weeks and kidneys were removed for the estimation of tyrosine hydroxylase activity. The testosterone treated rats had higher BP, plasma testosterone levels, kidney weights, but lower renal tyrosine hydroxylase activity than the sham treated controls. Hence, chronic testosterone treatment inhibits renal tyrosine hydroxylase activity in WKY and SHR/y rats.

Our objective was to test the hypothesis that 1) a high Na (HNa, 3%) diet would increase blood pressure (BP) in male Wistar-Kyoto (WKY) and spontaneously hypertensive Y chromosome (SHR/y) rat strains in a territorial colony; 2) sympathetic nervous system (SNS) blockade using clonidine would lower BP on a HNa diet; and 3) prepubertal androgen receptor blockade with flutamide would lower BP on a HNa diet. A 2 x 4 factorial design used rat strains (WKY, SHR/y) and treatment [0.3% normal Na (NNa), 3% HNa, HNa/clonidine, and HNa/flutamide]. BP increased in both strains on the HNa diet (P < 0.0001). There was no significant decrease in BP in either strain with clonidine treatment. Androgen receptor blockade with flutamide significantly decreased BP in both strains (P < 0.0001) and normalized BP in the SHR/y colony. Neither heart rate nor activity could explain these BP differences. In conclusion, a Na sensitivity was observed in both strains, which was reduced to normotensive values by androgen blockade but not by SNS blockade.

Cardiac decorin and Type I collagen expression and collagen fibrosis were examined in a chicken line exhibiting the low score normal (LSN) genetic muscle weakness and compared to normal cardiac muscle at 14 and 20 d of embryonic development and at 1 and 6 wk posthatch. These extracellular matrix proteins were selected due to their role in regulating tissue elasticity, which is critical for normal cardiac function. Beginning at 1 wk posthatch, relative levels of decorin were higher in the LSN cardiac muscle than in the control, indicating a time-dependent increase in decorin expression. Type I collagen levels appeared to be unaffected by the LSN condition. Morphologically, myocardial and coronary artery fibrosis did not differ between the control and LSN at all stages examined. These results are suggestive of extracellular matrix remodeling in LSN cardiac muscle that is mediated through a decorin-dependent pathway.

This study reports the concentration of collagen and its hydroxypyridinoline crosslinks, collagen fibril organization in the dorsal aortas, and systolic blood pressure during the progression of atherosclerosis in Japanese quail selected for cholesterol-induced atherosclerosis. The quail were placed on either a control or 0.5% cholesterol-added diet at approximately 16 weeks of age. The concentration of total collagen did not change in the control arteries during the course of the study, whereas at 5 and 10 weeks of cholesterol feeding, collagen levels decreased in the cholesterol-fed birds. Hydroxypyridinoline concentration increased during the duration of the study in the cholesterol-fed birds and by 15 and 20 weeks of cholesterol feeding, levels were significantly increased over those observed in the control arteries. Transmission electron microscopy showed changes in the organization of collagen fibrils. Increased systolic blood pressure was noted beginning at 10 weeks of cholesterol feeding, which is suggestive of other systemic changes induced by hypercholesterolemia. These results demonstrated remodeling of the collagen component of the dorsal aorta extracellular matrix during the progression of atherosclerosis and are suggestive of other systemic cardiovascular system changes.

—Stress is a critical contributor to cardiovascular diseases through its impact on blood pressure variability and cardiac function. Familial clustering of reactivity to stress has been demonstrated in human subjects, and some rodent models of hypertension are hyperresponsive to stress. Therefore, the present study was designed to uncover the genetic determinants of the stress response. We performed a total genome linkage search to identify the loci of the body temperature response to immobilization stress in a set of recombinant inbred strains (RIS) originating from reciprocal crosses of spontaneously hypertensive rats (SHR) with a normotensive Brown Norway Lx strain. Two quantitative trait loci (QTLs) were revealed on chromosomes (Chrs) 10 and 12 (logarithm of odds scores, 2.2 and 1.3, respectively). The effects of these QTLs were enhanced by a high sodium diet (logarithm of odds scores, 4.0 and 3.3 for Chrs 10 and 12, respectively), which is suggestive of a salt-sensitive component for the phenotype. Congenics for Chr 10 confirmed both the QTL and the salt effect in RIS. Negatively associated loci were also identified on Chrs 8 and 11. Interaction between the loci of Chrs 10 and 12 was demonstrated, with the rat strains bearing SHR alleles at both loci having the highest thermal response to stress. Furthermore, the Y Chr of SHR origin enhanced the response to immobilization stress, as demonstrated in 2 independent models, RIS and Y Chr consomics. However, its full effect requires autosomes of the SHR strain. These findings provide the first evidence for the genetic determination of reactivity to stress with interactions between autosomal loci and between the Y and autosomal Chrs that contribute to the explanation of the 46% of variance in the stress response.

The objectives were to determine 1) if female rats have higher Na intake than males and if social stress increases Na intake, 2) if the sympathetic nervous system (SNS) mediates the stress effects and the gender effect, and 3) if the Y chromosome (Yc) from a hypertensive father increases Na intake. Four rat strains (n = 10/group) of both sexes were used: 1) Wistar Kyoto normotensive (WKY), 2) an F(16) backcross with a Yc from a hypertensive father (SHR/y), 3) spontaneously hypertensive rat (SHR), and 4) an F(16) backcross with a Yc from a normotensive father (SHR/a). Females showed greater baseline Na intake than males (hypertensive strains), intruder stress increased Na intake, and clonidine decreased Na intake, but not in WKY or SHR females. SHR/y males had higher baseline Na intake compared with WKY males. In conclusion, the higher Na intake in females during baseline and stress was partially mediated through the SNS in hypertensive strains and the SHR Yc was partially responsible for the increased Na intake in SHR/y and SHR males compared with WKY.

The objective of this paper was to test the hypothesis that testosterone (T) raises blood pressure (BP), which is associated with increased coronary adventitial collagen, whereas the hemodynamic force of BP increases the coronary media:lumen ratio. Five treatment groups of spontaneously hypertensive rat (SHR) were established (n = 8-10 per group): controls; hydralazine (HYZ); castration; castration + HYZ; and castration + HYZ + T + captopril. At 12 weeks of age, the castrate + HYZ group was divided so that the mean BP was the same in both groups (162 mmHg). Both groups continued to receive HYZ treatment; however one group received T implants. Also, at 12 weeks of age the castrate + HYZ + T + captopril group received T implants. BP in the HYZ group was reduced compared with controls (192 mmHg vs 218 mmHg, p < 0.01). Castration lowered BP to 170 mmHg (p < 0.01) compared with controls. However, T implants increased BP by 15 mmHg (p < 0.02) in the castrate + HYZ group and by 44 mmHg in the castrate + HYZ + captopril group (p < 0.01). Captopril in combination with HYZ significantly reduced BP compared with controls but T replacement increased BP and coronary collagen deposition in spite of HYZ and captopril treatment.

Our objective was to test the hypothesis that nocturnal mean arterial pressure (MAP), heart rate (HR), and activity would be increased in 1) colony over individually caged rats and 2) the spontaneously hypertensive rat (SHR) Y chromosome strain (SHR/y colony) compared with Wistar-Kyoto (WKY) rats. MAP, HR, and activity were monitored using radiotelemetry. The nocturnal MAP rise expressed as the percentage change in MAP from light to dark was increased ( P < 0.05) in the SHR/y colony. The SHR Y chromosome increased MAP in both the colony and caged groups compared with WKY ( P < 0.001). The SHR/y colony animals spent 23% of a 24-h period at a MAP >120 mmHg, whereas the WKY colony animals spent 2% of a 24-h period in this range. The MAP of the SHR/y colony on clonidine was reduced ( P < 0.001) to WKY baseline values. Activity but not HR was increased ( P < 0.01) in the WKY and SHR/y colonies compared with caged animals. In conclusion, colony housing and the SHR Y chromosome increased MAP compared with individually caged housing.