PMID- 35119333
OWN - NLM
STAT- MEDLINE
DCOM- 20220504
LR  - 20220504
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 322
IP  - 4
DP  - 2022 Apr 1
TI  - SGLT2 inhibition potentiates the cardiovascular, renal, and metabolic effects of 
      sGC stimulation in hypertensive rats with prolonged exposure to high-fat diet.
PG  - H523-H536
LID - 10.1152/ajpheart.00386.2021 [doi]
AB  - Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and 
      metabolic dysfunction in hypertensive rats with altered renal development 
      (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose 
      cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and 
      metabolic function in settings of hypertension and obesity. This study examined 
      whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) 
      enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator 
      (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged 
      exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat 
      abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and 
      intrarenal infiltration of inflammatory cells were higher, but cardiac output and 
      creatinine clearance were lower in hypertensive rats (n = 15) than in 
      normotensive rats (n = 7). Praliciguat administration (n = 10) to hypertensive 
      rats reduced (P < 0.05) AP, FAV, plasma concentrations of leptin and 
      triglycerides, and increased (P < 0.05) cardiac output and creatinine clearance. 
      Empagliflozin administration (n = 8) only increased (P < 0.05) glucosuria and 
      creatinine clearance and decreased (P < 0.05) plasma leptin and triglycerides 
      concentrations in hypertensive rats. Simultaneous administration of praliciguat 
      and empagliflozin (n = 10) accelerated the decrease in AP, improved glucose 
      tolerance, reduced (P < 0.05) incremental body weight gain, and decreased (P < 
      0.05) insulin resistance index, RVR, and the infiltration of T-CD3 lymphocytes in 
      renal cortex and renal medulla. In summary, the combined administration of 
      praliciguat and empagliflozin leads to a greater improvement of the 
      cardiovascular, renal, and metabolic dysfunction secondary to prolonged exposure 
      to HFD in hypertensive rats with ARDev than the treatment with either praliciguat 
      or empagliflozin alone.NEW & NOTEWORTHY This is the first study, to our 
      knowledge, showing that SGLT2 inhibition potentiates the beneficial 
      cardiovascular, renal, and metabolic effects elicited by sGC stimulation in 
      hypertensive rats with prolonged high-fat diet. The effects of the simultaneous 
      administration of praliciguat and empagliflozin are greater than those elicited 
      by either one alone. The effects of the simultaneous treatment may be related to 
      a greater reduction in the inflammatory status.
FAU - Reverte, Virginia
AU  - Reverte V
AD  - Department of Physiology, School of Medicine, CEIR Mare Nostrum University of 
      Murcia, Murcia, Spain.
AD  - Biomedical Research Institute, Murcia, Spain.
FAU - Rodriguez, Francisca
AU  - Rodriguez F
AUID- ORCID: 0000-0002-8500-921X
AD  - Department of Physiology, School of Medicine, CEIR Mare Nostrum University of 
      Murcia, Murcia, Spain.
AD  - Biomedical Research Institute, Murcia, Spain.
FAU - Oltra, Lidia
AU  - Oltra L
AD  - Biomedical Research Institute, Murcia, Spain.
FAU - Moreno, Juan M
AU  - Moreno JM
AD  - Department of Physiology, School of Medicine, CEIR Mare Nostrum University of 
      Murcia, Murcia, Spain.
AD  - Biomedical Research Institute, Murcia, Spain.
FAU - Llinas, Maria T
AU  - Llinas MT
AUID- ORCID: 0000-0002-9857-9940
AD  - Department of Physiology, School of Medicine, CEIR Mare Nostrum University of 
      Murcia, Murcia, Spain.
AD  - Biomedical Research Institute, Murcia, Spain.
FAU - Shea, Courtney M
AU  - Shea CM
AD  - Cyclerion Therapeutics, Cambridge, Massachusetts.
FAU - Schwartzkopf, Chad D
AU  - Schwartzkopf CD
AD  - Cyclerion Therapeutics, Cambridge, Massachusetts.
FAU - Buys, Emmanuel S
AU  - Buys ES
AD  - Cyclerion Therapeutics, Cambridge, Massachusetts.
FAU - Masferrer, Jaime L
AU  - Masferrer JL
AD  - Cyclerion Therapeutics, Cambridge, Massachusetts.
FAU - Salazar, F Javier
AU  - Salazar FJ
AUID- ORCID: 0000-0003-4185-6692
AD  - Department of Physiology, School of Medicine, CEIR Mare Nostrum University of 
      Murcia, Murcia, Spain.
AD  - Biomedical Research Institute, Murcia, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220204
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Leptin)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - 0 (Triglycerides)
RN  - AYI8EX34EU (Creatinine)
RN  - EC 4.6.1.2 (Soluble Guanylyl Cyclase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Benzhydryl Compounds/pharmacology
MH  - Creatinine
MH  - Diet, High-Fat/adverse effects
MH  - Glucose
MH  - *Hypertension
MH  - *Insulin Resistance
MH  - Leptin
MH  - Rats
MH  - Sodium-Glucose Transporter 2
MH  - Soluble Guanylyl Cyclase
MH  - Triglycerides
PMC - PMC8917931
OTO - NOTNLM
OT  - SGLT2 inhibition
OT  - high-fat diet
OT  - hypertension
OT  - insulin resistance
OT  - sGC stimulation
COIS- C. Shea, C. Schwartzkopf, E.S. Buys, and J.L. Masferrer were full-time employees 
      of Cyclerion when the experiments of this study were performed and may own stock 
      options in Cyclerion Therapeutics. V. Reverte, F. Rodriguez, L. Oltra, J.M. 
      Moreno, M.T. Llinas, and F.J. Salazar do not have any financial or personal 
      association with Cyclerion Therapeutics other than the funding and collaboration 
      for this project and had full control over the design of the study, the decision 
      to publish, and the content of the manuscript. None of the other authors has any 
      conflicts of interest, financial or otherwise, to disclose.
EDAT- 2022/02/05 06:00
MHDA- 2022/05/06 06:00
PMCR- 2022/02/04
CRDT- 2022/02/04 12:11
PHST- 2022/02/05 06:00 [pubmed]
PHST- 2022/05/06 06:00 [medline]
PHST- 2022/02/04 12:11 [entrez]
PHST- 2022/02/04 00:00 [pmc-release]
AID - H-00386-2021 [pii]
AID - 10.1152/ajpheart.00386.2021 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2022 Apr 1;322(4):H523-H536. doi: 
      10.1152/ajpheart.00386.2021. Epub 2022 Feb 4.