Development of a new strain of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus.

Abstract

SUMMARY The aim of the present study was to investigate whether the presence of arginine vasopressin (AVP) is necessary for the establishment of high blood pressure in spontaneously hypertensive rats (SHR). For this purpose we crossbred SHR of the stroke-prone substrain (SHRSP) with rats homozygous for hypothalamic diabetes insipidus of the Brattleboro strain (DI) which are unable to synthetize AVP. The successful introduction of the DI gene into the SHRSP strain (SHRDI) was demonstrated by the following observations: In 10-month-old rats, water intake was similarly elevated in SHRDI as in DI rats (137 ± 6.5 vs 125 ± 10.5 ml per 24 hours). AVP was undetectable in the plasma, in the hypothalamus, and in the pituitary of SHRDI and DI rats. Urine osmolality and urinary concentration of sodium and potassium were markedly reduced. SHRDI and DI did not adequately concentrate their urine during an 8-hour period of water deprivation, but both strains of rats responded well with a fall in urine output and a rise in urine osmolality to subcutaneous administration of the non-pressor analog of AVP, DDAVP. Mean arterial blood pressure was markedly increased in SHRDI as well as in SHRSP (184 ± 9.7 vs 197 ± 5.2 mm Hg). Thus, we have developed a new line of spontaneously hypertensive rats homozygous for hypothalamic diabetes insipidus. From this finding it is concluded that AVP is not essential for the development and maintenance of spontaneous hypertension of rats. Authors' Note: The trivial name "Heidelberg Hypertensive Drinkers" (HHD) has been proposed for these rats.AVP-antiserum lowered blood pressure in these rats, it has been concluded that AVP plays a role in the maintenance of high blood pressure in SHRSP. 2In contrast to these results, we have recently found that plasma levels of AVP were below normal in SHRSP at 6, 9, and 12 weeks of age; they were higher than in age-matched Wistar-Kyoto rats (WKY) only in SHRSP older than 24 weeks of age.3 -4 Intravenous administration of specific vasopressor AVP antagonists 3 had no significant influence on mean arterial pressure'-4 and on cardiac output or total peripheral resistance. 4 Furthermore, reduced contents of AVP were found in the hypothalamus, in the brain stem, and in the amygdala of SHRSP.^ From these results we have concluded that circulating AVP does not contribute to the development and maintenance of high blood pressure. The question whether AVP is involved in the pathogenesis of spontaneous hypertension of rats'-2 or not 3 -4 is therefore unresolved.

Transgenic rats: new animal models in hypertension research. Invited lecture.

“…This procedure led to a stepwise accumulation of SHR genes and a reappearance of DI animals from the DI/+XDI/-intercrosses. 7 Results with these SHRSP-DI animals showed that blood pressure developed essentially the same way as in SHRSPs with respect to absolute levels and time course (Figure 3). The mortality of the resulting SHRSP-DI offspring was high.…”

“…This marks the important transition from classic breeding, the experiments of nature, to high-tech genetics, which offers previously impossible and unparalleled opportunities. 89 This review of our efforts to develop new animal models of experimental hypertension research is based on previously published reports on the gene analysis in SHRs, 3 -6 the introduction of mutated genes resulting in SHRs with hereditary hypothalamic DI (SHR-DI), 7 and the generation of hypertensive transgenic rats with an additional renin gene TGR(mRen-2 d ) 27.»-tension occurs frequently (95%). Animal models for primary hypertension therefore are needed, particularly ones with hereditary transmitted hypertension, to study the genetics of this disease.…”

“…A new strain of hypertensive rats with hypothalamic DI (SHRSP-DI) was obtained by crossbreeding SHRSPs with DI rats. 7 For this, SHRSPs, WKY rats, Brattleboro rats homozygous for DI, and Long-Evans (LE) control rats were used. The DI rats were identified by urine volume and a drinking test.…”

Evidence against a pressor role for vasopressin in spontaneous hypertension.

“…The development of a strain of SHR with diabetes insipidus 42 does not eliminate these possibilities, because the abnormalities in the VP system in the strokeprone strain of SHR used in the cross-breeding experiments are different from the abnormalities in the non-stroke-prone strain used in the present study. In the stroke-prone strain of SHR, VP does not contribute to the development of hypertension, but it may participate in maintaining pressure during the chronic phase.…”

Vasopressin, Urine Concentration, and Hypertension

“…Therefore, an imbalance between the intensity of vasoconstrictive V1a and nitric oxide-generating V2 effects could be ex-pected to alter BP regulation. Ganten et al (9) developed a strain of spontaneously hypertensive rats that also are homozygous for central diabetes insipidus (Brattleboro strain). The rats developed hypertension nonetheless, even though their vasopressin concentrations are zero, thereby showing that vasopressin actions are not a prerequisite in all forms of hypertension.…”