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Journal of Hypertension:
doi: 10.1097/HJH.0000000000000156
Editorial Commentaries

Salusin and central regulation of blood pressure in hypertension

Matsumura, Kiyoshi

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Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Correspondence to Kiyoshi Matsumura, MD, PhD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Tel: +81 92 642 5256; fax: +81 92 642 5271; e-mail: matsumk@intmed2.med.kyushu-u.ac.jp

Blood pressure is regulated or determined by many factors, such as fluid volume, sympathetic nervous system, renin–angiotensin system, and vascular structure. Overactivity of sympathetic nervous system is one of the important causes of primary hypertension [1], and central neural regulation of blood pressure has been extensively investigated in animal models of hypertension [2]. To date, many neuropeptides have been shown to be involved in the central regulation of sympathetic nervous system and blood pressure [3].

Salusin-α and salusin-β are the peptides of 28 and 20-amino acid residues, respectively, which were originally predicted from a human full-length enriched cDNA library [4]. Salusin is expressed not only in peripheral tissues but also in the central nervous system including neuronal cells of the hypothalamo-pituitary tract [5]. Intravenous administration of salusin-α or salusin-β was shown to cause a rapid decrease in arterial pressure; however, the depressor response of salusin-β was greater than that of salusin-α [4]. Moreover, these depressor responses were concomitant with a decrease in heart rate [4]. These cardiovascular responses, which were completely inhibited by pretreatment with atropine, a muscarinic receptor antagonist, were likely to be attributable to cardiac negative inotropic and chronotropic actions [6]. However, another possibility is that the salusins act on the central nervous system to decrease sympathetic nerve activity and arterial pressure.

In this issue of the Journal of Hypertension, Zhang et al.[7] focused on the cardiovascular effects of salusin-β on the rostral ventrolateral medulla (RVLM) of hypertensive rats. The RVLM is a central vasomotor center, and stimulation of the neurons of this brain region causes an activation of sympathetic nervous system and an increase in blood pressure [8]. The authors have provided evidence that salusin-β is present in the RVLM and causes increases in renal sympathetic nerve activity and blood pressure in two-kidney, one-clip (2K1C) hypertensive rats [7], but that these responses are not found in normotensive sham rats. Zhang et al.'s results are apparently different from the depressor response determined by intravenous administration of salusins. These unexpected findings may be explained by the observation that salusin-β level and the number of salusin-β-like immunopositive neurons in the RVLM were greatly increased in 2K1C hypertensive rats compared to normotensive sham rats [7].

Chen et al.[9] previously investigated the cardiovascular and sympathetic responses to microinjection of salusin-β in paraventricular nucleus (PVN) of the hypothalamus. They found that salusin-β in the PVN increased blood pressure, heart rate, and renal sympathetic activity via both circulating arginine vasopressin (AVP) and AVP in the RVLM of 2K1C hypertensive rats [9], and superoxide anions were involved in these responses [10], thus raising the hypothesis that AVP is involved in the cardiovascular effects of salusin-β⋅ However, Zhang et al.[7] in the current study clearly demonstrate that AVP does not contribute to the cardiovascular action of salusin-β on the RVLM of hypertensive rats.

The understanding of the mechanisms related to central neural regulation of blood pressure has rapidly progressed in recent years [2]. Oxidative stress, which is increased in both PVN and RVLM in the brain of hypertensive rats, is one of the candidate mechanisms to mediate blood pressure elevation [11,12]. It has been suggested that part of the angiotensin II–angiotensin II type 1 (AT1) receptor signaling pathway in the RVLM requires activation and phosphorylation of the p38 mitogen-activated protein kinase (p38MAPK) and the extracellular signal-regulated protein kinase (EPK1/2) [13,14]. In addition, this process requires activation of the NAD(P)H oxidase enzyme complex and generation of superoxide anion [13,14]. This mechanism may account for the previous finding that the exaggerated pressor response to glutamate in the RVLM of spontaneously hypertensive rat (SHR) was attenuated by chronic treatment with olmesartan, an AT1 receptor antagonist [15].

In another study, 2K1C hypertensive rats showed increases in both oxidative stress and blood pressure, which were prevented by chronic oral treatment with an AT1 receptor antagonist [16,17]. In this issue of the Journal of Hypertension, Zhang et al.[7] show that activation of the sympathetic nervous system and an increase in blood pressure induced by administration of salusin-β into the RVLM was mediated by NAD(P)H oxidase-derived superoxide anions in 2K1C hypertensive rats. In their study, however, administration of salusin-β into the RVLM of normotensive sham rats failed to increase NAD(P)H oxidase-derived superoxide anions, blood pressure, and renal sympathetic nerve activity. Although the 2K1C hypertensive rats showed increases in salusin-β level and the number of salusin-β-like immunopositive neurons in the RVLM, the interactions among angiotensin II, salusin-β, and oxidative stress are difficult to understand. Unfortunately, the authors could not clarify the role of the renin–angiotensin system in the cardiovascular response to salusin-β in the RVLM of 2K1C hypertensive rats. The renin–angiotensin system may be involved in the pressor response to salusin-β in the RVLM, because brain renin–angiotensin system is known to be activated in this model of hypertension [8,16,18].

Zhang et al.'s study provides new and valuable information; however, some questions still remain unanswered. The first question is whether treatment with an AT1 receptor antagonist prevents the increases in salusin-β level and the number of salusin-β-like immunopositive neurons in the RVLM of 2K1C hypertensive rats. The second question is how to explain the ineffectiveness of salusin-β in normotensive rats. Salusin-β has also been shown to be present in human plasma and urine [19] and the role of circulating salusin-β remains to be determined in the future.

In conclusion, Zhang et al.[7] investigated the cardiovascular and sympathetic responses to administration of salusin-β into the RVLM in 2K1C hypertensive rats. They suggested that salusin-β in the RVLM activated the sympathetic nervous system to increase blood pressure via NAD(P)H oxidase-derived superoxide anions in this model of hypertension. Although NAD(P)H oxidase-derived superoxide anions is likely to mediate the cardiovascular action of salusin-β in the RVLM, the overall physiological role of salusin on the central neural regulation of blood pressure has not been fully investigated. Further studies will be needed to better understand the mechanisms of interactions between salusin-β, oxidative stress, and angiotensin II, especially in hypertension.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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