br Introduction O Dowd et al identified a

Introduction O’Dowd et al. identified a gene very similar to angiotensin type-1 receptor in 1993 (O’Dowd et al., 1993). The specific selective ligand of this receptor called APJ receptor was determined by Tatemoto et al. in 1998 as apelin (Tatemoto et al., 1998). The high expression of apelin and APJ takes place in the central nervous system and peripheral tissues, which undertake significant functions in the cardiovascular system, such as decreasing blood pressure, regulating the cardiovascular tone., renal diseases and renin-angiotensin system (Chun et al., 2008; Ishida et al., 2004). It is increasingly evident that the 85 8 constitutes apelin’s major target. Apelin and APJR are provided at a high level by the vascular smooth muscle, cardiac myocytes, and endothelial cells (Kawamata et al., 2001). It has been demonstrated that the nitric oxide release from endothelial cells is caused by apelin and therefore cardiac contractility is increased, and vascular tone is decreased (Szokodi et al., 2002; Tatemoto et al., 2001). Apelin is found in the myocardium and left ventricle, and an increase in the apelin mRNA levels is observed in case of the chronic heart failure (Kleinz and Davenport, 2005). The relationship of apelin/APJ system with hypertension has been currently examined in a number of studies (Yu et al., 2014). At present, it is clearly demonstrated that hypertension represents a cardiovascular disease with a progressive course originating from complex and interdependent etiologies (Glasser et al., 2011). Since kidneys play a significant role in the blood pressure regulation in the long period of time, renal diseases constitute the major reasons for hypertension causing the damage of different organs, for example, heart failure (Badyal et al., 2003). Although renal and cardiovascular diseases are mutually related, fatal and highly epidemic pathologies, the renal apelinergic system and the role of apelin in the renal metabolism have not been investigated in detail. Malyszko et al. found the apelin-36 level in dialysis patients to be low (Małyszko et al., 2006). Although apelin levels were low in these patients, coronary artery disease was observed. Then, the same research team indicated that the apelin level decreased significantly in patients diagnosed with coronary artery disease and who underwent a renal transplant. It was anticipated that this decrease in the apelin level might be due to the presence of coronary artery disease, endothelial damage or inflammation (Malyszko et al., 2008). The studies conducted are mostly related to the apelin level in plasma. It is stated that the apelin level in plasma decreases in hypertensive cases (Sonmez et al., 2010). However, this is a general result for the organism, and there is very little specific information about the organs. Thus, in our study, we aimed to determine the apelin and apelin receptor expression with the immunohistochemical examination and Western Blot method specifically in the cardiac and renal tissue in hypertensive rats with L-NAME.
Material and methods
Results
Discussion In this study, it was aimed to determine the apelin and APJR expressions in the heart and kidney samples of rats, which were administered with L-NAME for the purpose of making them hypertensive for the period of 4 weeks. The hypotensive effect of apelin is caused by endothelium-derived nitric oxide. In addition, apelin cause the increase of the plasma levels of nitric oxide metabolites. In mouse endothelial cell cultures, apelin was found to enhance the phosphorylation of endothelial-derived nitric oxide synthase enzyme. However, while apelin cause nitric oxide dependent vasodilatation in undamaged endothelium, it cause vasoconstriction in damaged endothelium via smooth muscle cells. Apelin shows positive inotropic effect in the heart. It is effective in vasodilatation (on undamaged endothelium), vasoconstriction (damaged endothelium), nitric oxide release, and angiogenesis in the vessels. It is known that there is a relationship between the increase in peripheral arterial resistance and nitric oxide (NO) in the pathophysiology of hypertension (Dunbar, 1992; Fregly, 1984). It was identified that peripheral arterial resistance increased and thus systemic hypertension occurred with the chronic inhibition of nitric oxide synthetase (NOS) enzyme (Fregly, 1984; Tipton et al., 1977). For the first time in 1992, two different research groups reported that chronic NOS inhibition could be used as a new arterial hypertension model. This finding is consistent with the data that NO is necessary for the long-term regulation of blood pressure. In addition to the fact that NOS inhibitor administered to rats in different doses causes hypertension, high doses cause more severe hypertension and renal damage (Roberto and Baylis, 1998). The first NOS inhibitor used to induce hypertension in rats is L-NAME, which is an L-arginine analog. The fact that L-NAME dissolves in water and can be easily given to animals with drinking water has led to the widespread use of this model in recent years (Gardiner et al., 1992; Roberto and Baylis, 1998). We also added L-NAME concentration to drinking water to ensure that the subjects were hypertensive in our study. In various studies, it has been shown that apelin has an antihypertensive impact. Nevertheless, in the study recently performed by Nagano et al., a temporal increase in the BP has been observed as a reaction to apelin stimulation in NG-nitro-l-arginine methyl ester (LNAME)-induced peripheral vascular damaged hypertension mice, which demonstrates that differently from the normal conditions, apelin can operate as a vasopressor peptide under the vascular damaged circumstance (Nagano et al., 2013). Apelin and APJ represent a signaling pathway, and their wide expression is observed in different tissues, particularly in the cardiovascular system, such as the heart, vessels, and kidneys (Lv et al., 2013a, Lv et al., 2013b). Various proofs show that the apelin/APJ pathway represents a crucial regulator of the cardiovascular function and takes a significant part in the emergence and development of cardiovascular diseases, such as heart failure, coronary heart disease (CAD), atherosclerosis, hypertension, myocardial ischemia–reperfusion injury (MIRI), pulmonary arterial hypertension (PAH) and atrial fibrillation (Barnes et al., 2010; Galanth et al., 2012; Tycinska et al., 2012).