Cardiovascular therapeutics: A new potential for anxiety treatment?

Figures

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  Figure 1. The potential link between anxiety and cardiovascular pathologies. Anxiety disorder activates stress, neurohumoral cascade, serotonergic and gamma‐aminobutyric acid (GABA) pathways and increases free radical burden. 6 , 7 The activation of neural and humoral mechanisms supports the development of endothelial dysfunction, hypertension, diabetes mellitus, and target organ damage. Conversely, the cardiovascular pathologies associated with neurohumoral imbalance result in the formation of various anxiety disorders. 8 , 9 , 10 [Color figure can be viewed at wileyonlinelibrary.com]

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  Figure 2. The role of brain angiotensin II. Angiotensin II in the brain modifies stress hormonal pathways, hemodynamic status in systemic and brain circulation, and structural and functional characteristics in the central nervous system. 44 , 45 All of these issues, individually or in concert, modulate the emotional and behavioral manifestation. 42 ADH, antidiuretic hormone; HPA axis, hypothalamic‐pituitary‐adrenal axis; SNS, sympathetic nervous system [Color figure can be viewed at wileyonlinelibrary.com]

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  Figure 3. Modification of the renin‐angiotensin‐aldosterone system and its effect on anxiety. The inhibition of the renin‐angiotensin system in the brain by angiotensin II type 1 receptor blockers (ARBs) or attenuating angiotensin II (Ang II) formation via angiotensin‐converting enzyme inhibitors (ACEi) exhibits neuroprotective effects and reduces the level of the stress response and anxiety. 103 , 104 , 109 , 192 The possible mechanisms underlying the anxiolytic effect of ARBs and ACEi include the upregulation of the Ang II type 2 receptor (AT2R) in the brain, and the enhancement of angiotensin (1–7) production acting on Mas receptors (MasR). 193 The stimulation of both AT2R by Ang II and MasR by angiotensin (1–7) is considered to protect the cardiovascular system via vasodilation and antiproliferative effects 194 , 195 while exerting anxiolytic effects. Similarly, aldosterone antagonists reduce hemodynamic burden, potassium losses, profibrotic effects, 196 , 197 and anxiety level. 132 , 133 ACE, angiotensin‐converting enzyme; AT1R, angiotensin II type 1 receptor; HPA, hypothalamic‐pituitary‐adrenal axis; NEP, neutral‐endopeptidase; SNS, sympathetic nervous system [Color figure can be…

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  Figure 4. The role of statins on mood and behavior. Statins competitively inhibit 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase, the key enzyme in cholesterol biosynthesis in the liver. 252 Reducing the cholesterol level is considered protective for the vasculature, 254 while the simultaneous reduction of the synthesis of coenzyme Q‐10 (CoQ‐10) could result in undesirable myopathy. 258 However, a reduction of membrane cholesterol in the brain neurons decreased serotonin reuptake transporter (SERT) activity and attenuated the level of ligand binding to the serotonin1A (5‐HT1A) receptor 259 that resulted in anxiety, aggressive and impulsive behavior. 260 On the other hand, enhanced antioxidant capacity in the brain after statin use mitigates anxiety. 139 , 140 CoA, coenzyme A; CV, cardiovascular; Farnesyl‐PP, farnesyl pyrophosphate [Color figure can be viewed at wileyonlinelibrary.com]