The Renin-Angiotensin Pathway in Posttraumatic Stress Disorder

Abstract

Objective PTSD is a debilitating stress-related illness associated with trauma exposure. The peripheral and central mechanisms mediating stress response in PTSD are incompletely understood. Recent data suggest that the renin-angiotensin pathway, essential to cardiovascular regulation, is also involved in mediating stress and anxiety. In this study, the authors examined the relationship between active treatment with blood pressure medication, including angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), and PTSD symptom severity within a highly traumatized civilian medical population. Method Cross-sectional, observational data was analyzed from a larger study, recruiting patients from Grady Memorial Hospital's outpatient population from 2006 to November 2010. Multi-variable linear regression models were fit to statistically evaluate the independent association of being prescribed an ACE-I or ARB with PTSD symptoms, using a sub-set of patients for whom medical information was available (n=505). PTSD diagnosis was assessed using the modified PTSD Symptom Scale (PSS) based on DSM-IV criteria with PTSD symptoms based on PSS and Clinician Administered PTSD Scale (CAPS). Results A significant association was determined between presence of ACE-I / ARB medication and decreased PTSD symptoms (mean PSS score 11.4 vs 14.9 for individuals prescribed vs not prescribed ACE-I/ARBs, respectively (p = 0.014)). After adjustment for covariates, ACE-I/ARB treatment remained significantly associated with decreased PTSD symptoms (p = 0.044). Notably, other blood pressure medications, including beta-blockers, calcium channel blockers, and diuretics, were not significantly associated with reduced PTSD symptoms. Conclusions These data provide the first clinical evidence supporting a role for the reninangiotensin system in the regulation of stress response in patients diagnosed with PTSD. Further studies should examine whether available medications targeting this pathway should be considered for future treatment and potential protection against PTSD symptoms.

Angiotensin type 1a receptors on corticotropin‐releasing factor neurons contribute to the expression of conditioned fear1

“…These results contribute to a growing body of evidence implicating central AT 1 R activity in the expression of conditioned fear and anxiety (Khoury et al, 2012, Marvar et al, 2013, Marinzalda Mde et al, 2014, Shekhar, 2014, Shekhar et al, 2006, Johnson et al, 2013, Nylocks et al, 2015, Saavedra et al, 2006), and identify CRFergic cells as a population on which AT 1 R antagonists may act to create these effects. Further, they indicate that the fear expression-attenuating effects of AT 1 R inactivation may be caused by a decrease in fear memory consolidation (i.e., the transfer of a memory from a short-term to a long-term store in a transcription-dependent manner)—rather than an inability to acquire conditioning—as AT 1a R (+/+) and CRF-AT 1a R (−/−) mice showed similar levels of freezing during auditory fear conditioning, but 24 hours later, CRF-AT 1a R (−/−) mice displayed significantly less overall freezing than wild types.…”

“…However, previous studies by our lab (Khoury et al, 2012, Marvar et al, 2013, Nylocks et al, 2015) and others (Marinzalda Mde et al, 2014, Krause et al, 2011) suggest an important role for this receptor in fear-related pathologies such as PTSD. Our current data extend these findings by demonstrating for the first time that AT 1a Rs on CRF-expressing cells contribute to conditioned fear expression without affecting fear acquisition or baseline anxiety, locomotion, blood pressure, or heart rate.…”

“…However, recent studies in humans and mice have suggested roles for AT 1a R activation in post-traumatic stress disorder (PTSD) and auditory fear conditioning, respectively. For example, treatment of humans with angiotensin receptor blockers (ARBs) has been associated with a decrease in the hyperarousal and intrusive symptoms of PTSD (Khoury et al, 2012, Nylocks et al, 2015). Similarly, either acute or chronic administration of the ARB losartan in mice has been found to enhance the extinction of fear memory, but not fear acquisition or extinction training (Marvar et al, 2013).…”

Candesartan ameliorates impaired fear extinction induced by innate immune activation

“…Since ARBs also exhibit partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonistic effects and cognitive enhancement beyond blockade of AT 1 receptors (Kurtz and Klein, 2009; Min et al, 2012; Schupp et al, 2004; Tsukuda et al, 2009), candesartan could also enhance fear extinction through activation of the PPAR-γ pathway. Regardless of the mechanism, ARBs appear to be particularly useful for enhancing extinction of aversive memories and may explain why trauma-exposed patients taking ARBs had lower risk of PTSD symptoms (Khoury et al, 2012). …”

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors

“…Patients with anxiety have increased risk for developing cardiovascular disease (Johannessen et al, 2006; Thurston et al, 2013) and a recent epidemiological study found that symptoms of posttraumatic stress disorder (PTSD), a type of anxiety disorder, are less severe in patients taking anti-hypertensive medications that target the renin-angiotensin-system (RAS) (Khoury et al, 2012). The effector peptide of the RAS is synthesized through a series of proteolytic cleavage events whereby renin converts angiotensinogen into angiotensin-I, which is cleaved by angiotensin converting enzyme (ACE) into angiotensin-II (Ang-II), which in turn, activates the angiotensin type 1 a receptor (AT 1a R).…”