Effects of Alamandine on Sympathetic Outflow and Angiotensin Ii-Induced Hypertension in Rat

Objective: Alamandine, a recently identified component of the renin-angiotensin system (RAS), is an endogenous heptapeptide derived from angiotensin-(1-7) or angiotensin A. Synthesized primarily through the enzymatic actions of angiotensin-converting enzyme 2 and aspartate decarboxylase, alamandine exerts its effects by binding to the Mas-related G protein-coupled receptor (MrgD). In contrast to the well-studied angiotensin II (ANG II), alamandine exhibits vasodilatory, anti-inflammatory, and anti-fibrotic properties, thereby representing a novel player in the cardioprotective axis of RAS, countering the detrimental effects associated with classical RAS activation. However, the role of alamandine in regulating sympathetic outflow remains unclear. Design and method: The present study sought to examine the effects of systemic alamandine on hemodynamic and sympathetic responses in rats and determine whether alamandine counteracts ANG II-caused hypertension. Blood pressure (BP, mmHg), heart rate (HR, beats/min), and renal sympathetic nerve activity (RSNA, % change) were recorded in urethane-anesthetized male Sprague Dawley rats. Results: While intravenous (IV) vehicle (n=6) did not induce a significant change, IV injection of alamandine (n=6) elicited a substantial (p<0.05) reduction in BP (from 91.5 ± 3.4 to 77.6 ± 3.1∗), HR (from 313 ± 7 to 274 ± 6∗), and RSNA (25.1 ± 2.4% change∗), beginning within 10-15 mins after IV injection. The responses peaked at 45-60 min and returned to baseline within 120 min. Additionally, while a two-week subcutaneous infusion of ANG II significantly elevated BP, concurrent treatment with alamandine obviously attenuated ANG II-induced pressor response (from 115.9 ± 4.7 to 90.1 ± 3.2∗). Conclusions: These results indicate that systemic alamandine has inhibitory effects on sympathetic drive and ANG II-induced hypertension. The diminished impact of alamandine on sympathetic outflow may play a role in the attenuation of pressor responses. Further study to elucidate its molecular mechanisms and physiological implications holds significant potential for advancing our understanding of RAS regulation and identifying novel therapeutic targets in the treatment of cardiovascular disorders such as hypertension and heart failure.