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

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

doi:10.3389/fcvm.2022.897244

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

Front Cardiovasc Med. 2022 Jun 1:9:897244. doi: 10.3389/fcvm.2022.897244. eCollection 2022.

Authors

Ignazio Verzicco¹, Stefano Tedeschi¹, Gallia Graiani², Alice Bongrani¹, Maria Luisa Carnevali¹, Simona Dancelli¹, Jessica Zappa¹, Silvia Mattei³, Achiropita Bovino⁴, Stefania Cavazzini⁵, Rossana Rocco¹, Anna Calvi¹, Barbara Palladini¹, Riccardo Volpi¹, Valentina Cannone¹, Pietro Coghi¹, Alberico Borghetti¹, Aderville Cabassi¹

Affiliations

¹ Cardiorenal and Hypertension Research Unit, Physiopathology Unit, Clinica Medica Generale e Terapia Medica, Department of Medicine and Surgery (DIMEC), University of Parma, Parma, Italy.
² Histology and Histopathology Unit and Molecular Biology Laboratory, Dental School Parma, University of Parma, Parma, Italy.
³ Nefrologia e Dialisi, Azienda USL - Istituto di Ricerca a Carattere Scientifico IRCCS Reggio Emilia, Reggio Emilia, Italy.
⁴ Internal Medicine Unit, Ospedale Fidenza, Azienda USL Parma, Parma, Italy.
⁵ Laboratory of Industrial Toxicology, DIMEC, University of Parma, Parma, Italy.

Abstract

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to 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 the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (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 the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. 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 an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 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. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

Keywords: aquaporin 2; experimental hypertension; pre-hypertensive phase; spontaneously hypertensive rat; vasopressin; vasopressin receptor 1 and 2 antagonism.