Diabetes mellitus causes hypertonicity, increased plasma arginine vasopressin (AVP), polydipsia, and polyuria. Downregulation of AVP V2 receptors may contribute to the polyuria through diminished V2 receptor-mediated free water retention. After 2 wk of streptozotocin-induced diabetes mellitus, the diabetic rats had raised plasma glucose, AVP, and osmolality levels (P < 0.001) compared with nondiabetic controls (Sham). Insulin treatment (4 U long-acting insulin sc, daily) partially lowered these values (P < 0.01). There was a reduction in the number of renal and hepatic V1 receptors in the diabetic and diabetic+insulin animals compared with the sham animals (P < 0.05). The receptor affinity remained unchanged. In parallel, there was a reduction in maximum AVP-activated total inositol phosphate production in the liver and kidney of the diabetic and diabetic+insulin animals compared with the sham animals (P < 0.05). The density and affinity of renal V2 receptors and AVP-stimulated adenosine 3',5'-cyclic monophosphate production in the diabetic and diabetic+insulin animals were unchanged compared with the sham. These results demonstrate differential regulation of AVP receptors and suggest that downregulation of renal V2 receptors does not contribute to the polyuria of diabetes. In contrast, downregulation of V1 receptors might contribute to diminished V1 receptor-mediated biological responses to AVP seen in diabetes mellitus.
We studied the contribution of vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the nonpeptide orally effective vasopressin VI receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasopressin VI receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140±4 mmHg (n=12) in DOCA-salt rats compared with 111±2 mm Hg in salt control rats (n=18). Acute oral OPC-21268 (30 mg/kg) significantly (P<.01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24±3 mm Hg occurring at 2.5±0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178±2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P<.01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal S everal lines of evidence support a role for arginine vasopressin (AVP) in the development and maintenance of high blood pressure (BP) in the deoxycorticosterone acetate (DOCA)-salt model of 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. 4-5 However, other investigators failed to demonstrate a reduction in BP with acute VI receptor blockade 68 or showed a reduction in BP with acute V2 or acute or chronic V1-V2 receptor antagonism 910 in DOCA-salt hypertension. Thus, the pressor roles of AVP and/or the VI and V2 AVP receptors in both the pathogenesis and maintenance of hypertension in DOCA-salt hypertension in the rat remain unclear.Received August 9,1993; accepted in revised form February 23, 1994.From the University of Melbourne (Australia), Austin Hospital. Correspondence to Dr Louise M. Burrell, University of Melbourne, Austin Hospital, Studley Rd, Heidelberg 3084, Victoria, Australia. decrease of 27±5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120±l mm Hg, n=20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7 days) hepatic VI receptor binding was significantly reduced for up to 10 hours (P<.05). The r...
Since arginine vasopressin may play a role in mlneralocorticoid hypertension, we examined the effects of deoxycorticosterone acetate (DOCA)-salt on vasopressin V, and V 2 receptor binding and their second messengers, inositol phosphate and adenylate cyclase, respectively, in liver and kidney to determine whether altered vasopressin receptor binding is pathogenetic in mineralocorticoid hypertension. The mean arterial blood pressure of mineralocorticoid (DOCA-salt)-treated rats (163±1 mm Hg) was increased compared with control salt-treated rats (salt) (122±1 mm Hg) and water-treated rats (120±l mm Hg;p<0.001). Mineralocorticoid treatment also increased plasma sodium, osmolality, and vasopressin concentration (p< 0.001). In the hypertensive animals, there was a reduction in hepatic V, (DOCA-salt, 91 ±12; salt, 132 ±13; and water, 145 ±13 fraol/mg protein; p<0.05) and renal V 2 receptor binding density (DOCA-salt, 53±5; salt, 93±9; and water, 95±9 fraol/mg protein; p<0.01), although receptor affinities remained unaltered. In contrast, the density of renal V, receptors was increased by mineralocorticoid treatment (DOCA-salt, 24±2; salt, 16±2; water, 18±1 fmol/mg protein; p<0.05), although the affinity was unchanged. Downregulation of V 2 receptors was associated with a decrease in maximum cyclic adenosine monophosphate levels (DOCA-salt, 19±4; salt, 49±6; water, 53±9 pmol • mg protein" 1 • 10 min~';p<0.05), whereas changes in V, receptor levels were not associated with changes in maximum inositol phosphate levels. Therefore, changes in plasma vasopressin levels rather than changes in vasopressin receptors and their maximum second messenger levels are more likely to play a role in the development of mineralocorticoid hypertension. 2 -4 Also the administration of an AVP antibody reduces blood pressure.1 -5 However, the strongest evidence is obtained from experiments using the Battleboro rat, which is unable to synthesize functional AVP and does not develop hypertension when treated with DOCA-salt. 56AVP mediates its physiological effects through two types of membrane-bound receptors that have been classified Vi and V 2 . The V! receptors are located in many tissues, including the vasculature, brain, liver, and kidney, are coupled to inositol phosphate turnover, and mediate the vasopressor and grycogenolytic effects of AVP. The V 2 receptors are found mainly in the kidney, are linked to adenylate cyclase and the production of cyclic adenosine monophosphate (cAMP), and are associated with antidiuresis.7 However, V 2 agonists also have extrarenal effects, including increased plasma factor VIII and von Willebrand factor levels 8 and vasodilatation. 9The importance of V] receptors in DOCA-salt hypertension is unclear. The reported effects of V, antagonists have been contradictory; studies suggest that these peptides produce moderate reductions 610 or no change 1112 in blood pressure in DOCA-salt-treated animals. However, V 2 receptors appear to be involved in the development of DOCA-salt hypertension since the use of a V 2 ...
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