Establishment of the Inbred Strain of the Spontaneously Hypertensive Rat and Genetic Factors Involved in Hypertension

Okamoto, Kozo; Yamori, Yukio; Ooshima, Akira; Park, C.; Haebara, Hideyuki; Matsumoto, Masao; Tanaka, Toshinari; Okuda, Tomohiko; Hazama, Fumitada; Kyogoku, Miyako

doi:10.1007/978-3-642-65441-1_1

Cited by 43 publications

(29 citation statements)

References 11 publications

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“…Results SHR typically develop hypertension after 6-7 weeks of age. 21 Consequently, SHR were studied at 3-4 weeks (before the onset of hypertension) and 8-9 weeks (after development of hypertension) of age along with normotensive WKY controls. To confirm that hypertension occurred at the predicted time, tail arterial systolic pressure was measured.…”

Section: Methodsmentioning

confidence: 99%

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

1992

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Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR. and causes a natriuresis and diuresis. 4 These renal actions of ET-1, however, clearly do not cause the same biological responses. For instance, ET-1-induced vasoconstriction reduces glomerular filtration rate, thereby reducing sodium and water excretion, 2 and ET-1 directly inhibits sodium and water reabsorption by the collecting duct. 5 -6 The reasons for this apparent lack of coordinate effects of ET-1 are unknown; however, it probably reflects the independent actions of locally produced ET-1. At least two such locally acting systems exist for ET-1 in the kidney. The first, that of endothelial cell-derived ET-1 modulation of vascular smooth muscle tone, may play a role in the pathogenesis

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Section: Methodsmentioning

confidence: 99%

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

1992

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“…This inbred strain was developed by selective breeding of the Wistar-Kyoto (WKY) stock for higher blood pressure. 1 The response to this selection was rapid, with almost 100% hypertension by generation three. 2 This quick selective response indicates that only a few genetic loci were involved.…”

Section: Daniel L Ely and Monte E Turnermentioning

confidence: 99%

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

1990

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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 mothersxWKY fathers (180±4 versus 160±5 well-studied animal model of human essential hypertension. This inbred strain was developed by selective breeding of the Wistar-Kyoto (WKY) stock for higher blood pressure.1 The response to this selection was rapid, with almost 100% hypertension by generation three.2 This quick selective response indicates that only a few genetic loci were involved. This genetically selected SHR strain spontaneously and consistently develops moderate-to-severe hypertension between 7 and 15 weeks of age and has served as one model of genetic hypertension in humans. 34 Several studies have shown that, although the SHR is stress responsive, it is actually quite resistant to elevated dietary sodium unless coupled with high stress.5 -7 However, the genetic mechanism of hypertension in the SHR model is not yet understood, and comparative studies of various genetic hypertensive rat strains suggest several different pathogenic mechanisms.8 A few studies have used crosses of closely related strains and subsequent backcrosses that further support the idea that very few loci (from one to four) appear to be Received October 2,1989; accepted in revised form April 19,1990. involved in the development of SHR hypertension. -12Also, a few studies have examined genetic markers of hypertension using different animal models. 13-19 However, no consistent trends have emerged across rat models and specifically in the SHR as to the specific genes responsible for hypertension.One of the more studied rat models with regard to the genetics of hypertension is the Dahl salt-sensitive (DS) and salt-resistant (DR) rat. In the DS rat there is no reported evidence for sex-linked loci controlling blood pressure.20 Sex steroids do, however, exert effects as female DS rats show slower sodiuminduced rises in blood pressure than males and castration of females altered their blood pressure to respond like that of males to salt. 21 Endocrine studies have shown that the adrenals are necessary for the development of hypertension in DS rats, 22 and genetic studies have shown that the characteristic steroid patterns of DS and DR rats are controlled by a single genetic locus (HYP-1) with two codominant alleles.14 However, there are other loci involved as the HYP-1 locus accounted for a 16 mm Hg blood pressure difference between DS and DR rats and the remaining difference was due to other unidentified genetic loci (see Reference 23 for a comprehensive review on DS and DR rats).Also, in the psychosocial stress hypertension mouse model, 24 the rat model, 2 -25 and in human hypertension, there is highe...

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“…In these rats, the hypertensive state develops without provocation and is readily apparent soon after weaning age (2). The pathophysiology underlying the development and the maintenance of hypertension in the spontaneously hypertensive rat has not been elucidated.…”

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Neurogenic and Humoral Factors Controlling Vascular Resistance in the Spontaneously Hypertensive Rat

Lais

Shaffer

Brody

1974

Circulation Research

105

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The mechanism of sustained hypertension in spontaneously hypertensive rats has not been elucidated. In the present investigation, vasoconstrictor responses to a variety of neurogenic and humoral interventions were studied in the perfused hindquarters of Okamoto spontaneously hypertensive rats and normotensive Wistar rats. In addition, central sympathetic electrical discharge was measured. Vasoconstrictor responses in the hindquarters to lumbar sympathetic nerve stimulation were unchanged or reduced in the spontaneously hypertensive rats, but the responses to intra-arterially administered norepinephrine and epinephrine were enhanced. Vascular responses to intra-arterially administered tyramine, angiotensin, and barium chloride were also greater in the spontaneously hypertensive rats. Vascular resistance was significantly higher in the spontaneously hypertensive rats, and this difference remained following bilateral lumbar sympathectomy. Despite elevated systemic blood pressure, integrated nerve activity at rest was not different in the spontaneously hypertensive rats. The inverse relationship between arterial blood pressure and sympathetic nerve discharge was not different between spontaneously hypertensive and control rats when pressure was either raised or lowered. Changes in efferent sympathetic discharge produced by activation of chemoreceptors (asphyxia) were somewhat less in the spontaneously hypertensive rats. The contribution of low-pressure baroreceptors (45° tilt) to activation of sympathetic vasomotor tone was not different in the spontaneously hypertensive rats despite a greater decline in systemic blood pressure during the procedure. These data demonstrate that established hypertension in the spontaneously hypertensive rat does not derive from either enhanced central adrenergic discharge or altered central integration of afferent information from peripheral sensory receptors but may result from humoral (e.g., increased reactivity to vasoconstrictors) or structural factors. KEY WORDSvascular reactivity adrenergic vasomotor tone catecholamines central vasomotor control baroreceptors sympathetic nervous system chemoreceptors sympathectomy• The spontaneously hypertensive rat was isolated as a pure inbred strain by Okamoto and Aoki (1). In these rats, the hypertensive state develops without provocation and is readily apparent soon after weaning age (2). The pathophysiology underlying the development and the maintenance of hypertension in the spontaneously hypertensive rat has not been elucidated. Of the many factors that could contribute to the maintenance of hypertensive state, only the renin-angiotensin pressor system seems to be excluded from participation (3, 4). Some investigators (5-7) have suggested that the hypertensive state is maintained by an increase in neurogenic vasoconstrictor influences which should theoretically be associated with 764an increase in the turnover of catecholamines (8). However, a growing body of reports indicates a decrease in catecholamine turnover in peripheral t...

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Establishment of the Inbred Strain of the Spontaneously Hypertensive Rat and Genetic Factors Involved in Hypertension

Cited by 43 publications

References 11 publications

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.

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

Neurogenic and Humoral Factors Controlling Vascular Resistance in the Spontaneously Hypertensive Rat

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