Centrally administered Ang‐(1‐7) via Mas receptors reverses psychosocial stress‐induced cardiovascular responses in mice with muscular dystrophy

Muscular dystrophy is a devastating disease of muscle weakness, atrophy and dilated cardiomyopathy (DCM). We have demonstrated that angiotensin II (Ang II)‐dependent autonomic dysfunction precedes and predicts development of DCM in sarcoglycan delta deficient (Sgcd−/−) mice, an established model of muscular dystrophy [Exp Physiol 2015] . More recently, we found that Sgcd−/− mice exhibit depression‐like behaviors and are susceptible to psychosocial stress‐induced bradycardia, hypotension and arrhythmias at older ages (>45 weeks of age) [FASEB J 2017] . Thus, we hypothesized that central administration of angiotensin‐(1‐7) in older Sgcd−/− mice protects against Ang II‐mediated cardiovascular abnormalities during acute psychosocial stress challenge. Mean blood pressure (MAP) and heart rate (HR) were measured by telemetry in control C57BL6 (n=3–5) and Sgcd−/− (n=3–8) mice during social defeat (~15 min exposure to intruder mouse). At 40±3 weeks of age, mice were randomly assigned to one of the four experimental groups – (i) vehicle (saline); (ii) losartan (Ang II‐type 1 receptor antagonist, 1 mcg/kg/hr); (iii) Ang‐(1‐7) (100 ng/kg/hr); and (iv) Ang‐(1‐7)+Mas antagonist A779 (100 ng/kg/hr and 0.5 mcg/kg/hr, respectively). Drugs were administered ICV (catheter connected to osmotic minipump) for 8 weeks. Stressed Sgcd−/− mice exhibit an increase in AT1R‐binding (receptor autoradiography) in subfornical organ, organum vasculosum laminae terminalis, and paraventricular nucleus of hypothalamus. Social defeat produced profound bradycardia and hypotension in Sgcd−/− mice (see Table). Interestingly, while these drastic effects on MAP and HR in Sgcd−/− mice were modestly attenuated by losartan, the effects were completely abolished by Ang‐(1‐7) (P<0.05 vs. vehicle) and remained unaltered by Ang‐(1‐7)+A779 (NS vs . vehicle). Moreover, the increased plasma corticosterone (+86%) and norepinephrine (+62%) in stressed Sgcd−/− mice were normalized by Ang‐(1‐7) (P<0.05 vs. control). We conclude that Ang‐(1‐7) acting centrally via Mas receptors abrogates cardiovascular response to psychosocial stress and is likely a more effective treatment strategy than Ang II‐type 1 receptor antagonists in muscular dystrophy. Support or Funding Information AHA GIA17GRNT33670004 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .