scholarly journals The angiotensin antagonist Losartan shifts social reward motivation and punishment sensitivity via modulating midbrain-striato-frontal circuits

2021 ◽  
Author(s):  
Xinqi Zhou ◽  
Ting Xu ◽  
Yixu Zeng ◽  
Ran Zhang ◽  
Ziyu Qi ◽  
...  
Keyword(s):  
Computational Modelling ◽  
Reaction Times ◽  
Dorsal Striatum ◽  
Renin Angiotensin System ◽  
Social Reward ◽  
Prediction Errors ◽  
Social Feedback ◽  
Double Blind ◽  
Angiotensin System ◽  
Renin Angiotensin

Background Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that modulating interactions between the dopamine and renin-angiotensin system with the angiotensin receptor antagonist Losartan (LT) can modulate learning and reward-related processes. We have therefore determined the behavioral and neural effects of LT on social reward and punishment processing in humans. Methods A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of LT (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation, connectivity and social feedback prediction errors were modelled. Results Relative to placebo, LT switched reaction times and arousal away from prioritizing punishment towards social reward. On the neural level the LT-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation and attenuated activity in the ventral tegmental area (VTA) and associated connectivity with the bilateral insula in response to punishment during the outcome phase. Computational modelling further revealed an LT-enhanced social reward prediction error signal in VTA and dorsal striatum. Conclusions LT shifted motivational and emotional salience away from social punishment towards social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.

scholarly journals Losartan shifts social reward motivation and punishment feedback sensitivity via modulating midbrain-striato-frontal circuits

2021 ◽  
Author(s):  
Xinqi Zhou ◽  
Ting Xu ◽  
Yixu Zeng ◽  
Ran Zhang ◽  
Ziyu Qi ◽  
...  
Keyword(s):  
Computational Modelling ◽  
Reaction Times ◽  
Dorsal Striatum ◽  
Renin Angiotensin System ◽  
Social Reward ◽  
Prediction Errors ◽  
Social Feedback ◽  
Double Blind ◽  
Angiotensin System ◽  
Renin Angiotensin

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that modulating interactions between the dopamine and renin-angiotensin system with the angiotensin receptor antagonist Losartan (LT) can modulate learning and reward-related processes. We have therefore determined the behavioral and neural effects of LT on social reward and punishment processing in humans. A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of LT (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation, connectivity and social feedback prediction errors were modelled. Relative to placebo, LT switched reaction times and arousal away from prioritizing punishment towards social reward. On the neural level the LT-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation and attenuated activity in the ventral tegmental area (VTA) and associated connectivity with the bilateral insula in response to punishment during the outcome phase. Computational modelling further revealed an LT-enhanced social reward prediction error signal in VTA and dorsal striatum. LT shifted motivational and emotional salience away from social punishment towards social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.

scholarly journals Clinical importance of the renin-angiotensin system in chronic heart failure: double blind comparison of captopril and prazosin.

BMJ ◽  
1985 ◽  
Vol 290 (6485) ◽  
pp. 1861-1865 ◽  
Author(s):  
J Bayliss ◽  
M S Norell ◽  
R Canepa-Anson ◽  
C Reid ◽  
P Poole-Wilson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Clinical Importance ◽  
Renin Angiotensin System ◽  
Double Blind ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Blind Comparison

scholarly journals The intrarenal renin-angiotensin system in hypertension: Insights from mathematical modelling

2021 ◽  
Author(s):  
Delaney Smith ◽  
Anita Layton
Keyword(s):  
Computational Modelling ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Clinical Hypertension ◽  
Induced Hypertension ◽  
Intrarenal Ras

The renin-angiotensin system (RAS) plays a pivotal role in the maintenance of volume homeostasis and blood pressure. In addition to the well-studied systemic RAS, local RAS have been documented in various tissues, including the kidney. Given the role of the intrarenal RAS in the pathogenesis of hypertension, a role established via various pharmacologic and genetic studies, substantial efforts have been made to unravel the processes that govern intrarenal RAS activity. In particular, several mechanisms have been proposed to explain the rise in intrarenal angiotensin II (Ang II) that accompanies Ang II infusion, including increased angiotensin type 1 receptor (AT1R)-mediated uptake of Ang II and enhanced intrarenal Ang II production. However, experimentally isolating their contribution to the intrarenal accumulation of Ang II in Ang II--induced hypertension is challenging, given that they are fundamentally connected. Computational modelling is advantageous because the feedback underlying each mechanism can removed and the effect on intrarenal Ang II can be studied. In this work, the mechanisms governing the intrarenal accumulation of Ang II during Ang II infusion experiments are delineated and the role of the intrarenal RAS in Ang II-induced hypertension is studied. To accomplish this, a compartmental ODE model of the systemic and intrarenal RAS is developed and Ang II infusion experiments are simulated. Simulations indicate that AT1R-mediated uptake of Ang II is the primary mechanism by which Ang II accumulates in the kidney during Ang II infusion. Enhanced local Ang II production is unnecessary. The results demonstrate the role of the intrarenal RAS in the pathogenesis of Ang II-induced hypertension and consequently, clinical hypertension associated with an overactive RAS.

Endothelial function during stimulation of renin-angiotensin system by low-sodium diet in humans

2001 ◽  
Vol 280 (5) ◽  
pp. H2248-H2254 ◽  
Author(s):  
Torbjørn Omland ◽  
Wendy Johnson ◽  
Mary Beth Gordon ◽  
Mark A. Creager
Keyword(s):  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Concomitant Treatment ◽  
Double Blind ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Stimulation Of

We examined whether physiological stimulation of the endogenous renin-angiotensin system results in impaired endothelium-dependent vasodilatation in forearm resistance vessels of healthy subjects and whether this impairment can be prevented by angiotensin II type 1 receptor blockade. A low-sodium diet was administered to 27 volunteers who were randomized to concomitant treatment with losartan (100 mg once daily) or matched placebo in a double-blind fashion. Forearm blood flow was assessed by venous occlusion plethysmography at baseline and after 5 days. Endothelium-dependent and -independent vasodilation was assessed by intra-arterial infusion of methacholine and verapamil, respectively. The low-sodium diet resulted in significantly decreased urine sodium excretion (placebo: 146 ± 64 vs. 10 ± 9 meq/24 h, P < 0.001; losartan: 141 ± 56 vs. 14 ± 14 meq/24 h, P < 0.001) and increased plasma renin activity (placebo: 1.0 ± 0.5 vs. 5.0 ± 2.5 ng · ml−1 · h−1, P < 0.001; losartan: 3.8 ± 7.2 vs. 19.1 ± 11.2 ng · ml−1 · h−1, P = 0.006) in both the losartan and placebo groups. With the baseline study as the reference, the diet intervention was not associated with any significant change in endothelium-dependent vasodilation to methacholine in either the placebo ( P = 0.74) or losartan ( P = 0.40) group. We conclude that short-term physiological stimulation of the renin-angiotensin system does not cause clinically significant endothelial dysfunction. Losartan did not influence endothelium-dependent vasodilation in humans with a stimulated renin-angiotensin system.

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