Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats.

Oral administration of the peptide alamandine has antihypertensive and anti-fibrotic effects in rats. This work aimed to determine whether subcutaneous alamandine injection would attenuate hypertension and cardiac hypertrophy, and improve the function of a major target of hypertension-related damage, the left ventricle (LV), in spontaneously hypertensive rats (SHRs). This was examined in vivo in SHRs and normotensive rats subjected to 6-week subcutaneous infusion of alamandine or saline control, and in vitro in H9C2-derived and primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Tail artery blood pressure measurement and transthoracic echocardiography showed that hypertension and impaired LV function in SHRs were ameliorated upon alamandine infusion. Alamandine administration also decreased the mass gains of heart and lung in SHRs, suppressed cardiomyocyte cross-sectional area expansion, and inhibited the mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. The expression of alamandine receptor Mas-related G protein-coupled receptor, member D was increased in SHR hearts and in cardiomyocytes treated with Ang II. Alamandine inhibited the increases of protein kinase A (PKA) levels in the heart in SHRs and in cardiomyocytes treated with Ang II. In conclusion, the present study showed that alamandine administration attenuates hypertension, alleviates cardiac hypertrophy, and improves LV function. PKA signaling may be involved in the mechanisms underlying these effects.

Alamandine attenuates sepsis-associated cardiac dysfunction via inhibiting MAPKs signaling pathways.

Sepsis-induced myocardial dysfunction represents a major cause of death. Alamandine is an important biologically active peptide. The present study evaluated whether alamandine improves cardiac dysfunction, inflammation, and apoptosis, and affects the signaling pathways involved in these events. Experiments were carried out in mice treated with lipopolysaccharide (LPS) or alamandine, and in neonatal rat cardiomyocytes. Alamandine increased the ejection fraction and fractional shortening, both of which were decreased upon LPS infusion in mice. LPS and alamandine reduced blood pressure, and increased the expression of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) in the heart in mice. The LPS-induced decrease in α-myosin heavy chain (MHC) and ß-MHC, and increase in S100 calcium binding protein A8 (S100A8) and S100A9, were reversed by alamandine pre-treatment. Alamandine pre-treatment prevented LPS-induced myocardial inflammation, apoptosis and autophagy. LPS increased p-ERK, p-JNK, and p-p38 levels, which were inhibited by alamandine. Dibutyryl cyclic AMP (db-cAMP) increased p-ERK, p-JNK, and p-p38 levels, and reversed the inhibitory effects of alamandine on the LPS-induced increase in p-ERK, p-JNK, and p-p38. Moreover, db-cAMP reduced the expression of α-MHC and ß-MHC in cardiomyocytes, and reversed the almandine-induced attenuation of the LPS-induced decrease in α-MHC and ß-MHC. These results indicate that alamandine attenuates LPS-induced cardiac dysfunction, resulting in increased cardiac contractility, and reduced inflammation, autophagy, and apoptosis. Furthermore, alamandine attenuates sepsis induced by LPS via inhibiting the mitogen-activated protein kinases (MAPKs) signaling pathways.

Alamandine injected into the paraventricular nucleus increases blood pressure and sympathetic activation in spontaneously hypertensive rats.

Alamandine is a newly discovered new component of the renin-angiotensin (Ang) system (RAS) that has been shown to exert vasoactive effects in some areas of the nervous system. The present study investigated whether administration of alamandine to the hypothalamic paraventricular nucleus (PVN) modulates blood pressure and sympathetic activity. Mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were recorded in anaesthetized rats. PVN microinjection of alamandine increased MAP and RSNA both in Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHRs), but to a greater extent in SHRs. Moreover, these effects were blocked by pretreatment with alamandine receptor Mas-related G-protein-coupled receptor, member D (MrgD) antagonist D-Pro7-Ang-(1-7), adenylyl cyclase (AC) inhibitor SQ22536, and protein kinase A (PKA) inhibitor rp-adenosine-3',5'-cyclic monophosphorothionate (Rp-cAMP). Treatment with D-Pro7-Ang-(1-7), SQ22536, or Rp-cAMP alone in PVN decreased MAP and RSNA in the SHRs. Conversely cAMP alone increased MAP and RSNA, and pretreatment with cAMP enhanced alamandine's effects. These results indicate that microinjection of alamandine into the PVN increases blood pressure and sympathetic outflow via MrgD and the cAMP-PKA pathway.