AUTHOR=Verzicco Ignazio , Tedeschi Stefano , Graiani Gallia , Bongrani Alice , Carnevali Maria Luisa , Dancelli Simona , Zappa Jessica , Mattei Silvia , Bovino Achiropita , Cavazzini Stefania , Rocco Rossana , Calvi Anna , Palladini Barbara , Volpi Riccardo , Cannone Valentina , Coghi Pietro , Borghetti Alberico , Cabassi Aderville 

TITLE=Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.897244

DOI=10.3389/fcvm.2022.897244

ISSN=2297-055X

ABSTRACT=In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development by an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (pre-hypertensive phase) to 28–30 weeks-old SHR (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in outer medulla vs age-matched WKY. ADH circulating levels did not differ between young prehypertensive SHR and WKY whereas increased was urine aquaporin2 (AQP2)/creatinine ratio and labelling of AQP2 in collecting duct. At 28–30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1 and alpha-1-Na-K ATPase as compared with WKY. These results suggest ADH increased sensitivity in pre-hypertensive female SHR. On these basis, a second series of experiments were set to study the role of ADH V1 and V2 receptor in the development of hypertension and a group of female prehypertensive SHRs was treated from the 25-to-49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptors antagonists to evalute BP time course. OPC 41061-treated SHRs had a delayed development of hypertension of 5 weeks without effect in OPC 21268-treated SHRs. 
In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Very early treatment with selective V2 antagonism delays future hypertension development in young SHRs.