Involvement of the metabolic sensor GPR81 in cardiovascular control
Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes
Kristina Wallenius, Pia Thalén, Jan-Arne Björkman, Petra Johannesson, John Wiseman, Gerhard Böttcher, Ola Fjellström, Nicholas D. Oakes
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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 7

The pressor effect of the GPR81 agonist, AZ2, is substantially prevented by antagonism of either α-adrenoceptors (α-ARs) or endothelin (ET) receptors.

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The pressor effect of the GPR81 agonist, AZ2, is substantially prevented...
Adult male Wistar rats were anesthetized and implanted with jugular and carotid catheters, then left to stabilize for 2 hours. Following a 10-minute baseline period (t = –10 to 0 minutes), AZ2 was given alone (red symbols), or on top of pretreatments (given before –10 minutes): either the dual ET-A/B receptor antagonist, bosentan, 15 mg/kg i.v. (purple symbols); or the nonselective α-AR antagonist, phentolamine, 10 mg/kg i.v. (green symbols). Changes in mean arterial pressure (MAP), heart rate (HR), and total peripheral resistance index (TPRi) are expressed relative to the average of the baseline period. (A) Minute-by-minute change in MAP. (B) Mean change in MAP averaged over 0–20 minutes. (C) Minute-by-minute change in HR. (D) Mean change in HR averaged over 0–20 minutes. (E) Minute-by-minute change in TPRi. (F) Mean change in TPRi averaged over 0–20 minutes. Results are the mean ± SEM (n = 3–4/group). *P < 0.05, **P < 0.01 versus vehicle; #P < 0.05, ##P < 0.01 versus AZ2. ANOVA, followed up by multiple comparison test with Holm-Sidak correction.