Angiotensin-(1-7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats

Abstract

Joyner J, Neves LAA, Stovall K, Ferrario CM, Brosnihan KB. Angiotensin-(1-7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats. Am J Physiol Regul Integr Comp Physiol 294: R1073-R1080, 2008. First published January 9, 2007 doi:10.1152/ajpregu.00572.2007.-We previously demonstrated that kidney and urine levels of angiotensin-(1-7) [ANG-(1-7)] were increased in pregnancy. To explore the role of ANG-(1-7) on fluid and electrolyte homeostasis during pregnancy, we evaluated the effect of the ANG-(1-7) antagonist D-alanine-[ANG-(1-7)] (A-779) on kidney function. Virgin and pregnant rats received infusion of vehicle or A-779 (48 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) for 8 days by osmotic minipumps. Metabolic studies were done on treatment day 7-8. Virgin and pregnant rats at day 15 and 19 were killed, and blood and kidneys were collected. Kidneys were prepared for Western blot analysis for aquaporin-1 (AQP1) and aquaporin-2. In virgin female rats, A-779 increased urine volume and decreased urinary osmolality and AQP1 with no change in water intake. In 19-day pregnant rats, A-779 significantly decreased water intake and urine volume and increased urinary osmolality and kidney AQP1 expression. Only in late gestation did A-779 treatment decrease the difference between intake and output (balance). A-779 treatment increased plasma vasopressin in late gestation but did not change vasopressin in virgins. In virgin and pregnant animals, A-779 administration had no effect on blood pressure, plasma volume, blood volume, or urinary electrolytes. These results suggest that ANG-(1-7) produces antidiuresis associated with upregulation of AQP1 in virgin rats, whereas ANG-(1-7) produces diuresis in late gestation with downregulation of AQP1. ANG-(1-7) contributes to the enhanced water intake during pregnancy, allowing maintenance of the normal volume-expanded state despite diuresis produced in part by decreased AVP and AQP1. renin-angiotensin system; pregnancy; angiotensin-(1-7); D-alanine-[angiotensin-(1-7)]; D-alanine; aquaporin; vasopressin NORMAL PREGNANCY IS A physiological condition characterized by hemodynamic change, including increased cardiac output and hypervolemia, decreased total peripheral resistance, and decreased or normal blood pressure (2). The renin angiotensin system (RAS), which is involved in blood pressure regulation and salt and fluid homeostasis, is markedly increased during pregnancy, as evidenced by increased circulating concentration of angiotensinogen, renin activity, and angiotensin II (ANG II; see Refs. 2,5,and 20). Also, increased during normal pregnancy is angiotensin-(1-7) [ANG-(1-7)], the active vasodilator of the RAS. Urinary excretion of ANG-(1-7) rises progressively during human pregnancy to levels that are 20-fold higher by the end of gestation compared with the normal menstrual cycle (35). Urinary ANG-(1-7) concentration is also increased with gestation in rats (22). ANG-(1-7), along with its forming enzyme angiotensin conver...

Administration of D-alanine-[Ang-(1-7)] (A-779) prior to pregnancy in Sprague Dawley rats produces antidiuresis in late gestation

“…The present study confirms our previous demonstration (14) of the effects of endogenous Ang-(1-7) by use of its antagonist A-779 on fluid regulation and electrolytes. Under the experimental design of pretreatment of animals prior to pregnancy with A-779, Ang-(1-7) elicits contrasting effects on urine volume depending upon the animal's physiological state producing diuresis in late gestation and antidiuresis in virgin females.…”

“…This study was unique in design as compared to our previous publication (14) by lowering the dose and increasing the duration of A-779 administration. The current study pretreated female rats prior to pregnancy with A-779 (24μg/kg/hr) such that 19 day pregnant animals received 27-40 days of continuous A-779 administration.…”

“…Until our recent publication (14), the actions of Ang-(1-7) on the female kidney and during pregnancy had been unknown. In males, Ang-(1-7) had previously been shown to have diuretic and natiuretic properties in male Sprague Dawley rats that were independent of renal blood flow and glomerular filtration rates (8) (7).…”

“…The dose was selected based on previous publications (12;13) which demonstrated that A-779 was a specific antagonist of Ang-(1-7), and we selected half the dose used to treat animals after the start of pregnancy in our previous study (14) based on consideration of the longer duration of treatment. Female virgin rats were placed in metabolic cages following pump implantation and 24 hour metabolic studies, including water and food consumption, were conducted on treatment day 6-7.…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…In addition, in normal and hypertensive rats [177] and in water-loaded [178] or virgin female rats [179], ANG-(1-7) had an antidiuretic effect that was mediated, at least in part, by the Mas receptor. Furthermore, in SpragueDawley rats, the administration of ANG-(1-7) resulted in antidiuresis that was associated with an upregulation in renal aquaporin-1 [180], and in isolated rat inner medullary collecting duct cell suspensions, ANG-(1-7) (10 −9 M) increased cAMP production [181], a response that was attenuated by Mas receptor antagonists and the pharmacological blockade of the AVP V2 receptor. ANG-(1-7) also caused afferent arteriolar vasodilation and antagonized the vasoconstrictor effects of ANG II [114].…”