Daniel Ely

Neuroendocrine response patterns in dominant and subordinate mice

Abstract The sequence and type of neuroendocrine and behavioral patterns resulting from the development of a social hierarchy in colonies of mice were studied. It was found that dominant males were more active and responded to social interaction with predominantly a sympathetic adrenal-medullary pattern. Subordinate males were less active and predominantly responded with a pituitary adrenal-cortical pattern. The neuroendocrine patterns were reversed when the social position of the animal was reversed. Also the subordinate males demonstrated greater plasma corticosterone responsiveness to ACTH administration and immobilization stress as compared to dominant males.

Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome.

The objective of our study was to determine the genetic influence on blood pressure in spontaneously hypertensive rats (SHR), and normotensive Wistar-Kyoto (WKY) rats using genetic crosses. Blood pressure was measured by tail sphygmomanometry from 8 to 20 weeks of age. Blood pressure was significantly higher from 12 to 20 weeks in the male offspring derived from WKY mothers x SHR fathers as compared with male offspring derived from SHR mothers X WKY fathers (180 +/- 4 versus 160 +/- 5 mm Hg, p less than 0.01). There was no significant difference between the blood pressure of the F1 females, further supporting Y chromosome linkage and not parental imprinting. The blood pressure data from F2 males derived from reciprocal crosses of parental strains were consistent with the presence of a Y-linked locus, but not with an X-linked locus controlling blood pressure. The data strongly suggest that hypertension in the SHR has two primary components of equal magnitude, one consisting of a small number of autosomal loci with a second Y-linked component.

Genetic divergence between the Wistar-Kyoto rat and the spontaneously hypertensive rat.

A method of restriction fragment length polymorphism (RFLP) analysis was used to estimate the amount of genetic divergence between the spontaneously hypertensive rat (SHR) strain and the Wistar-Kyoto (WKY) strain. DNA from each strain was digested with eight restriction endonucleases and hybridized with six single copy gene sequences. The number of hybridization bands in each digestion was used to estimate the total number of bases analyzed and RFLPs were scored as single mutations. Divergence was then estimated by dividing the number of mutations by the number of bases analyzed. In a total of 808 bases analyzed in WKY rats, a minimum of 13 mutations were scored in SHR, which yields a nucleotide divergence of 1 change per 62 bp. This is an extremely high amount of divergence given the known origin of these two strains and is comparable to the maximum divergence possible between unrelated humans.

Spontaneously Hypertensive Rat Y Chromosome Increases Indexes of Sympathetic Nervous System Activity

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.

The hypertensive Y chromosome elevates blood pressure in F11 normotensive rats.

Our laboratory has shown that the Y chromosome has a significant effect on blood pressure in the spontaneously hypertensive rat (SHR) model of hypertension and that the testes and androgen receptor contribute to the blood pressure rise. As an extension of our research, we have developed two new rat strains, SHR/a and SHR/y (F11) to study the Y chromosome. The objectives of the following research were 1) to study the blood pressure of rats with an SHR Y chromosome in a normotensive genetic background (SHR/y) or a normotensive Y chromosome in an SHR genetic background (SHR/a), 2) to determine the effect of male sex phenotype on the blood pressure of these rats, 3) to determine if testosterone replacement in castrated rats would restore blood pressure, and 4) to determine whether the Y chromosome from the SHR/y strain when crossed with a normotensive female can induce hypertension in androgen receptor-deficient male offspring. Blood pressure of male SHR/y rats was significantly higher than that of normotensive Wistar-Kyoto males (p < 0.01), and SHR/a males had significantly lower blood pressure compared with that of the parent SHR strain (p = 0.05). Testosterone replacement in castrated rats of both strains (SHR/a and SHR/y) restored blood pressure to control levels. Normotensive female King-Holtzman rats heterozygous for the testicular feminization gene were crossed with F11 SHR/a and SHR/y males.(ABSTRACT TRUNCATED AT 250 WORDS)

Separate Sex-Influenced and Genetic Components in Spontaneously Hypertensive Rat Hypertension

Previous results from our laboratory indicated two major genetic components of spontaneously hypertensive rat (SHR) hypertension, an autosomal component and a Y chromosome component Two new substrains, SHR/a and SHR/y, were developed using a series of backcrosses to isolate each of these components. The SHR/a substrain has the autosomal loci and X chromosome from the SHR strain and the Y chromosome from the Wistar-Kyoto (WKY) rat strain. The SHR/y substrain has only the Y chromosome from the SHR and autosomal loci and X chromosome from the WKY strain. Throughout these breeding programs parents were chosen at random without selection for blood pressure. Males of both substrains maintained blood pressures over 180 mm Hg. Comparisons of blood pressure in these new substrains with the original parental strains can be used to determine the relative proportions of each genetic component in hypertension. The Y chromosome component contributes 34 mm Hg, which is the difference between SHR/y male and WKY male blood pressure. The total autosomal component contributes 46 mm Hg, which is the difference between SHR/a male and WKY male blood pressure. The autosomal component is a sex-influenced trait; males in the SHR/a strain have significantly higher pressures than SHR/a females. Of the 46 mm Hg estimated for the autosomal component, 41 mm Hg is the result of these loci interacting with male phenotypic sex. This sex-influenced component is separate and distinct from the Y chromosome component

Hypertension, social rank, and aortic arteriosclerosis in CBA/J mice

Abstract A significant rise in systolic blood pressure and increased aortic arteriosclerosis was observed over a period of four months in dominant male mice as compared to subordinate and control animals. Subordinate animals assuming the dominant position also developed a significant rise in blood pressure and dominant animals removed from social interaction showed a significant decrease in blood pressure. Males that were castrated failed to develop a social hierarchy and exhibited normotensive blood pressure. Also dominant animals exhibited higher plasma testosterone levels and more aortic arteriosclerosis than subordinates.

Androgen receptor and the testes influence hypertension in a hybrid rat model.

The objective of this study was to determine if males with a deficient androgen receptor would develop hypertension when crossed with a hypertensive parent Female King-Holtzman rats (n=15), heterozygous for the testicular feminization (Tfm) gene, were crossed with male spontaneously hypertensive rats (SHR), and blood pressure was measured weekly from 5–14 weeks in the F1 hybrid males. Approximately 50% of the F1 hybrid males were Tfm males and androgen receptor-deficient, and 50% were normal. Blood pressure in the parent King- Holtzman males, Tfms, and female rats was also followed for the same time period. The F1 normal male hybrids had a significantly higher (p<0.05) systolic blood pressure than the Tfm hybrid males after 12 weeks (195±8 versus 170±8 mm Hg, respectively). Blood pressure in the male and Tfm Holtzman rats was 120±5 mm Hg and 110±6 mm Hg, respectively. Castration lowered blood pressure by 38 mm Hg in the hybrid males and 27 mm Hg in the Tfm hybrids. Female F1 hybrids also showed a pressure rise above that of female Holtzman controls (155±6 mm Hg versus 110±6 mm Hg, p<0.01) but lower than the F1 males and Tfm hybrids. Ovariectomized females with testosterone implants did not show an elevation in blood pressure. Plasma electrolytes, norepinephrine, and cholesterol were not significantly different between normal and Tfm hybrid males. The results suggest that the presence of an androgen receptor and a testis-derived factor mediate the blood pressure rise in the hybrid males. A Y chromosome effect or sex-influenced locus may be involved since both the normal and Tfm males had significantly higher blood pressures than their female siblings.

STRESS AND HIGH SODIUM EFFECTS ON BLOOD PRESSURE AND BRAIN CATECHOLAMINES IN SPONTANEOUSLY HYPERTENSIVE RATS

The following experiments were designed to determine if territorial stress, dietary sodium (Na), or the combination of stress and Na effect the rate of development of hypertension in the spontaneously hypertensive rat (SHR 4-18 wks) and if central catecholamines (C) were altered by these treatments. BP was significantly elevated from 2-8 weeks of stress treatment as compared to SHR controls. Norepinephrine (NE) levels in the nucleus tractus solitarius and amygdala (A), and dopamine (D) levels in the hippocampus and A showed significant elevations in the stressed group. High Na (3%) treatment combined with stress treatment produced an even further BP increase and elevated D levels in the amygdala, and elevated NE levels in the area postrema as compared to control SHRs. Selected brain C variables were able to correctly classify animals into high and low BP groups with 90-100% accuracy. Our data support the concept that there are important stress and Na effects upon brain neurochemistry which influence the development of hypertension in the SHR.

Review of the Y chromosome and hypertension

The Y chromosome from spontaneously hypertensive rats (SHR) has a locus that raises blood pressure 20-25 mmHg. Associated with the SHR Y chromosome effect is a 4-week earlier pubertal rise of testosterone and dependence upon the androgen receptor for the full blood pressure effect. Several indices of enhanced sympathetic nervous system (SNS) activity are also associated with the SHR Y chromosome. Blockade of SNS outflow reduced the blood pressure effect. Salt sensitivity was increased by the Y chromosome as was salt appetite which was SNS dependent. A strong correlation (r = 0. 57, P<0.001) was demonstrable between plasma testosterone and angiotensin II. Coronary collagen increased with blood pressure and the presence of the SHR Y chromosome. A promising candidate gene for the Y effect is the Sry locus (testis determining factor), a transcription factor which may also have other functions.