Involvement of the metabolic sensor GPR81 in cardiovascular control
Kristina Wallenius, … , Ola Fjellström, Nicholas D. Oakes
Kristina Wallenius, … , Ola Fjellström, Nicholas D. Oakes
Published October 5, 2017
Citation Information: JCI Insight. 2017;2(19):e92564. https://doi.org/10.1172/jci.insight.92564.
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Research Article Cardiology Metabolism

Involvement of the metabolic sensor GPR81 in cardiovascular control

Abstract

GPR81 is a receptor for the metabolic intermediate lactate with an established role in regulating adipocyte lipolysis. Potentially novel GPR81 agonists were identified that suppressed fasting plasma free fatty acid levels in rodents and in addition improved insulin sensitivity in mouse models of insulin resistance and diabetes. Unexpectedly, the agonists simultaneously induced hypertension in rodents, including wild-type, but not GPR81-deficient mice. Detailed cardiovascular studies in anesthetized dogs showed that the pressor effect was associated with heterogenous effects on vascular resistance among the measured tissues: increasing in the kidney while remaining unchanged in hindlimb and heart. Studies in rats revealed that the pressor effect could be blocked, and the renal resistance effect at least partially blocked, with pharmacological antagonism of endothelin receptors. In situ hybridization localized GPR81 to the microcirculation, notably afferent arterioles of the kidney. In conclusion, these results provide evidence for a potentially novel role of GPR81 agonism in blood pressure control and regulation of renal vascular resistance including modulation of a known vasoeffector mechanism, the endothelin system. In addition, support is provided for the concept of fatty acid lowering as a means of improving insulin sensitivity.

Authors

Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes

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Figure 5

Structurally diverse GPR81 agonists increase blood pressure at doses needed for plasma free fatty acid (FFA) suppression.

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Structurally diverse GPR81 agonists increase blood pressure at doses nee...
Adult male Wistar rats were anesthetized in the fasting state and implanted with jugular and carotid catheters and left to stabilize for 2 hours. Following a 15-minute baseline period (t = –15 to 0 minutes), AZ2 or 3-chloro-5-hydroxybenzoic acid (CHBA) were infused i.v. at 0.9 μmol/kg/min or 10 μmol/kg/min, respectively, for 15 minutes starting at t = 0. Panels to the left show results for AZ2. Right panels show CHBA results. (A and D) Plasma FFA (mM), (B and E) mean arterial pressure (MAP) (percentage baseline period mean), and (C and F) heart rate (HR) (percentage baseline period mean). Results are the mean ± SEM. (A) P is treatment × time interaction (repeated-measures ANOVA). ***P < 0.001 AZ2 versus vehicle (Veh) at the corresponding time period (Bonferroni corrected, Veh n = 4, AZ2 n = 3). (B) **P < 0.01 AZ2 versus Veh average MAP (0–15 minutes) (Student’s t test, Veh n = 4, AZ2 n = 3). (C) **P < 0.01 AZ2 versus Veh average HR (0–15 minutes) (Student’s t test, Veh n = 4, AZ2 n = 3). (D) P is treatment × time interaction (repeated-measures ANOVA). ***P < 0.001 CHBA versus Veh at the corresponding time period (Bonferroni corrected, Veh n = 5, CHBA n = 3). (E) **P < 0.01 AZ2 versus Veh average MAP (0–15 minutes) (Student’s t test, Veh n = 5, CHBA n = 3). (F) *P < 0.01 AZ2 versus Veh average HR (0–15 minutes) (Student’s t test, Veh n = 5, CHBA n = 3).