Vasopressin and vascular reactivity in the development of DOCA hypertension in rats with hereditary diabetes insipidus.

Abstract

SUMMARY To examine tbe role of rasopressin (VP) in DOCA-salt hypertension, arterial pressure and renal vascular reactirity were studied in control Long-Erans (LE) rats and in Brattleboro rats homozygous for diabetes insipidus (DI rats). Vascular reactirity to norepinephrine, VP and angiotensin II was assessed in isolated kidneys perfused at constant flow. LE rats snowed an increase in arterial pressure (AP) which was significant at 2 weeks post DOCA and averaged 180 mm Hg at 4 weeks. DI rats lacking VP showed no rise in AP after DOCA; however, DI rats given VP and DOCA developed hypertension with a course and magnitude similar to that observed in LE rats. At 6 to 10 weeks post DOCA, renal vascular reactivity to all agents was increased in LE rats and DI rats replaced with VP. Nonnotensive DI rats lacking VP snowed depressed reactivity. Assessment of changes in reactirity at 3 days post DOCA showed that changes preceded tbe rise in AP. These data suggest that VP may play a primary role in the patbogenesis of DOCA hypertension and that its mechanism may involve an induction of increased vascular reactirity. T HERE has been increasing evidence that vasopressin may play a role in the development of DOCA-salt hypertension. Elevations in plasma levels 1 and urinary excretion* of vasopressin (VP) have been reported in DOCA-salt hypertensive rats. Furthermore, administration to these rats of VP antagonists* or a VP antiserum 1 produces an acute reduction in arterial pressure suggesting that the hypertension is maintained, in part, by a VP mechanism. It is also notable that Brattleboro rats homozygous for diabetes insipidus (DI rats), which totally lack VP and the ability to synthesize the hormone, fail to develop hypertension when treated with DOCAsalt.'-' The mechanism by which VP might participate in DOCA-salt hypertension is not understood. In earlier experiments, however, it was observed that renal vascular reactivity to norepinephrine (NE), VP, and angiotensin II (All) was increased in DOCA hypertensive rats not only in the chronic stage but in the prehypertensive stage, 4 suggesting that changes in vascular reactivity, per se, participate in the development of DOCA hypertension.The purposes of the present studies were to determine: 1) whether VP replacement in DI rats restores the hypertensive properties of DOCA-salt; and 2) to define the nature of changes in vascular reactivity in these rats after DOCA to determine whether restoration by VP of hypertension in VP-deficient rats might be associated with an induction of increased vascular reactivity. Methods Experimental AnimalsStudies were carried out on 12-week-old male Brattleboro rats homozygous for diabetes insipidus (DI rats) and Long Evans rats (LE rats) obtained from Blue Spruce Farms. At this age the average weight of the DI rats was 255 ± 9 g while that of the LE rats was 346 ± 7 g. Rats were housed individually in metabolic cages and fed a standard laboratory rat chow (Purina,

Blood pressure-lowering effect of an orally active vasopressin V1 receptor antagonist in mineralocorticoid hypertension in the rat.

“…Studies in the Brattleboro rat, which is homozygous for hypothalamic diabetes insipidus and unable to synthesize functional AVP, provide indirect evidence for a role of AVP in the pathogenesis of DOCA-salt hypertension. These rats failed to develop hypertension when treated with DOCA and salt unless also treated with exogenous AVP 1 or desamino-D-arginine-8-vasopressin (dDAVP), a V2 agonist with minimal pressor and increased antidiuretic activity. 2 A direct vasopressor role for AVP in the maintenance of hypertension in the DOCA-salt hypertension model is suggested by the finding of elevated plasma AVP levels and a fall in BP with intravenous administration of AVP antiserum 3 or VI receptor antagonist.…”

Sympathetic nervous system in high sodium one-kidney, figure-8 renal hypertension.

“…As previously demonstrated, the infusion of [ 3 H]NE has no effect on the resting plasma total norepinephrine concentration using the infusion protocol outlined in this study. 24 Total radioactivity of [ 3 H]NE in the plasma of the hypertensive animals, however, was significantly greater than that in the normotensive rats (8,764±912 versus 5,733±445 dpm). The relative distributions of the radioactive tracer (Table 2) in the normotensive and hypertensive rats revealed that there was less radioactivity in the norepinephrine fraction and more in the COMT metabolite fraction in the renalwrapped rats compared with the sham-operated animals.…”

“…20 - 21 In addition, vasopressin-deficient Brattleboro rats are also protected against the development of DOC-saline hypertension. 22 " 24 Recent findings in our laboratory have indicated that one-kidney, figure-8 renal wrap hypertension is also a model of sodium-dependent hypertension. This form of hypertension is prevented when rats are maintained on a low sodium intake, while the hypertension is exacerbated when the rats are fed a high sodium diet.…”

The Brattleboro rat and salt-induced hypertension.

“…2 This has led to the hypothesis that inappropriate vasopressin secretion may be a causative factor in some forms of hypertension, despite direct evidence that antipressor analogs of vasopressin do not lower blood pressure in forms of experimental hypertension in which elevated levels of this hormone have been reported. 3 Workers in this field are apparently unaware that Brattleboro rats are extremely susceptible to salt-induced hypertension under the appropriate conditions.…”

“…Applying the latter stimulus in young rats, followed by a high salt diet as adults, did not induce hypertension. With these facts in mind, it is pertinent to note that both Crofton et al ' and Berecek et al 2 used adult Brattleboro rats in their experiments. These comments are not meant to denigrate the potential importance of altered vasopressin secretion as an etiological feature of some forms of hypertension, but to point out that salt intake and age are the pivotal factors in a Brattleboro rat's proclivity toward hypertension, and not the lack of vasopressin.…”