Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of somatic diseases. The ...pathophysiology of anxiety development is complex and involves alterations in stress hormone production, neurosignaling pathways or free radical production. The various manifestations of anxiety, its complex pathophysiological background and the side effects of available treatments underlie the quest for constantly seeking therapies for these conditions. Melatonin, an indolamine produced in the pineal gland and released into the blood on a nightly basis, has been demonstrated to exert anxiolytic action in animal experiments and different clinical conditions. This hormone influences a number of physiological actions either via specific melatonin receptors or by receptor-independent pleiotropic effects. The underlying pathomechanism of melatonin's benefit in anxiety may reside in its sympatholytic action, interaction with the renin-angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature. Of importance, the concentration of this indolamine is significantly higher in cerebrospinal fluid than in the blood. Thus, ensuring sufficient melatonin production by reducing light pollution, which suppresses melatonin levels, may represent an endogenous neuroprotective and anxiolytic treatment. Since melatonin is freely available, economically undemanding and has limited side effects, it may be considered an additional or alternative treatment for various conditions associated with anxiety.
This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced ...by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1–5, Ang 1–7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1–7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.
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•Both continuous light exposure and lactacystin treatment induced pre-hypertension.•Both models are normal to low serum renin-angiotensin models of pre-hypertension.•In lactacystin induced pre-hypertension aldosterone level was increased.•Sacubitril/valsartan or valsartan protected against heart remodeling and dysfunction.•Protection by both drugs were related to angiotensin II blockade and angiotensin 1–7.
The renin-angiotensin-aldosterone system (RAAS) is a dominant player in several cardiovascular pathologies. This study investigated whether alterations induced by l-NAME, (NLG)-nitro-l-arginine ...methyl ester, a nitric oxide synthase inhibitor, and the protective effect of melatonin are associated with changes in the RAAS. Four groups of 3-month-old male Wistar rats (
= 10) were treated as follows for four weeks: untreated controls, rats treated with melatonin (10 mg/kg/day), rats treated with l-NAME (40 mg/kg/day), and rats treated with l-NAME + melatonin. l-NAME administration led to hypertension and left ventricular (LV) fibrosis in terms of enhancement of soluble, insoluble and total collagen concentration and content. Melatonin reduced systolic blood pressure enhancement and lowered the concentration and content of insoluble and total collagen in the LV. The serum concentration of angiotensin (Ang) 1-8 (Ang II) and its downstream metabolites were reduced in the l-NAME group and remained unaltered by melatonin. The serum aldosterone level and its ratio to Ang II (AA2-ratio) were increased in the l-NAME group without being modified by melatonin. We conclude that l-NAME-hypertension is associated with reduced level of Ang II and its downstream metabolites and increased aldosterone concentration and AA2-ratio. Melatonin exerts its protective effect in l-NAME-induced hypertension without affecting RAAS.
Ivabradine, the selective inhibitor of the If current in the sinoatrial node, exerts cardiovascular protection by its bradycardic effect and potentially pleiotropic actions. However, there is a ...shortage of data regarding ivabradine's interaction with the renin-angiotensin-aldosterone system (RAAS). This study investigated whether ivabradine is able to protect a hypertensive heart in the model of
-NAME-induced hypertension and to interfere with the RAAS. Four groups (
= 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day),
-NAME (40 mg/kg/day), and
-NAME plus ivabradine.
-NAME administration increased systolic blood pressure (SBP) and left ventricular (LV) weight, enhanced hydroxyproline concentration in the LV, and deteriorated the systolic and diastolic LV function. Ivabradine reduced heart rate (HR) and SBP, and improved the LV function. The serum concentrations of angiotensin Ang 1⁻8 (Ang II), Ang 1⁻5, Ang 1⁻7, Ang 1⁻10, Ang 2⁻8, and Ang 3⁻8 were decreased in the
-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by
-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in
-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.
Chronic kidney disease (CKD) is a serious public health problem. Current therapies are designed to slow down progression of the disease and avoid the necessity of dialysis or kidney transplantation. ...CKD is characterized by chronic inflammation and progressive cell death resulting in fibrotic rebuilding of renal tissue. Melatonin, the primary product of the pineal gland, has been shown to have pluripotent protective effects in many organs and tissues. It exerts anti-hypertensive, anti-inflammatory, anti-apoptotic, and antiremodelling actions. A principal mechanism of these numerous melatonin benefits resides in its extraordinary high efficacy as an antioxidant and scavenger protecting cells both extracellularly and in all subcellular structures. In addition to these receptor-independent actions, the effects of melatonin via specific MT-receptors may be beneficial. In several animal models of CKD, involving experimental hypertension, diabetes mellitus and various models of nephrotoxicity, melatonin reduced the oxidative burden, attenuated the chronic inflammation and limited apoptosis. These effects were associated with the reduction of proteinuria, damage of parenchymal cells and fibrosis. In humans, melatonin's chronobiological action attenuates sleep disturbances in hemodialyzed patients suffering from a relative melatonin deficiency. Moreover, melatonin reduces the oxidative burden and improves iron metabolism in hemodialyzed patients. In conclusion, the pleiotropic physiological actions of melatonin induce beneficial effects at numerous pathophysiological levels related to CKD both under experimental and clinical conditions. It is hoped that this review will prompt a large clinical trial to determine the efficacy of this nontoxic indoleamine as a potential treatment for this debilitating disease.
Lactacystin is a specific proteasome inhibitor that blocks the hydrolysis of intracellular proteins by ubiquitin/proteasome system inhibition. The administration of lactacystin to rats induced ...hypertension and remodeling of the left ventricle and aorta. This study tested whether lactacystin induces structural and fibrotic rebuilding of the kidneys and whether melatonin and captopril can prevent these potential changes. Six weeks of lactacystin administration to rats increased their average systolic blood pressure (SBP). In the kidneys, lactacystin reduced glomerular density, increased the glomerular tuft area, and enhanced hydroxyproline concentrations. It also elevated the intraglomerular proportion including the amounts of collagen (Col) I and Col III. Lactacystin also raised the tubulointerstitial amounts of Col I and the sum of Col I and Col III with no effect on vascular/perivascular collagen. Six weeks of captopril treatment reduced SBP, while melatonin had no effect. Both melatonin and captopril increased glomerular density, reduced the glomerular tuft area, and lowered the hydroxyproline concentration in the kidneys. Both drugs reduced the proportion and total amounts of intraglomerular and tubulointerstitial Col I and Col III. We conclude that chronic lactacystin treatment stimulated structural and fibrotic remodeling of the kidneys, and melatonin and captopril partly prevented these alterations. Considering the effect of lactacystin on both the heart and kidneys, chronic treatment with this drug may be a prospective model of cardiorenal damage suitable for testing pharmacological drugs as protective agents.
Lactacystin is a proteasome inhibitor that interferes with several factors involved in heart remodelling. The aim of this study was to investigate whether the chronic administration of lactacystin ...induces hypertension and heart remodelling and whether these changes can be modified by captopril or melatonin. In addition, the lactacystin-model was compared with N
-nitro-l-arginine-methyl ester (L-NAME)- and continuous light-induced hypertension. Six groups of three-month-old male Wistar rats (11 per group) were treated for six weeks as follows: control (vehicle), L-NAME (40 mg/kg/day), continuous light (24 h/day), lactacystin (5 mg/kg/day) alone, and lactacystin with captopril (100 mg/kg/day), or melatonin (10 mg/kg/day). Lactacystin treatment increased systolic blood pressure (SBP) and induced fibrosis of the left ventricle (LV), as observed in L-NAME-hypertension and continuous light-hypertension. LV weight and the cross-sectional area of the aorta were increased only in L-NAME-induced hypertension. The level of oxidative load was preserved or reduced in all three models of hypertension. Nitric oxide synthase (NOS) activity in the LV and kidney was unchanged in the lactacystin group. Nuclear factor-kappa B (NF-κB) protein expression in the LV was increased in all treated groups in the cytoplasm, however, in neither group in the nucleus. Although melatonin had no effect on SBP, only this indolamine (but not captopril) reduced the concentration of insoluble and total collagen in the LV and stimulated the NO-pathway in the lactacystin group. We conclude that chronic administration of lactacystin represents a novel model of hypertension with collagenous rebuilding of the LV, convenient for testing antihypertensive drugs or agents exerting a cardiovascular benefit beyond blood pressure reduction.
There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart ...disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male
were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease.
This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous ...hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.
Hypertension-induced renal injury is characterized by structural kidney alterations and function deterioration. Therapeutics for kidney protection are limited, thus novel renoprotectives in ...hypertension are being continuously sought out. Ivabradine, an inhibitor of the I
f
current in the sinoatrial node reducing heart rate (HR), was shown to be of benefit in various cardiovascular pathologies. Yet, data regarding potential renoprotection by ivabradine in hypertension are sparse. Thirty-six adult male Wistar rats were divided into non-diseased controls and rats with N
G
-nitro-L-arginine methyl ester (L-NAME)-induced hypertension to assess ivabradine's site-specific effect on kidney fibrosis. After 4 weeks of treatment, L-NAME increased the average systolic blood pressure (SBP) (by 27%), decreased glomerular density (by 28%) and increased glomerular tuft area (by 44%). Moreover, L-NAME induced glomerular, tubulointerstitial, and vascular/perivascular fibrosis by enhancing type I collagen volume (16-, 19- and 25-fold, respectively). L-NAME also increased the glomerular type IV collagen volume and the tubular injury score (3- and 8-fold, respectively). Ivabradine decreased average SBP and HR (by 8 and 12%, respectively), increased glomerular density (by 57%) and reduced glomerular tuft area (by 30%). Importantly, ivabradine decreased type I collagen volume at all three of the investigated sites (by 33, 38, and 72%, respectively) and enhanced vascular/perivascular type III collagen volume (by 67%). Furthermore, ivabradine decreased the glomerular type IV collagen volume and the tubular injury score (by 63 and 34%, respectively). We conclude that ivabradine attenuated the alterations of glomerular density and tuft area and modified renal fibrosis in a site-specific manner in L-NAME-hypertension. It is suggested that ivabradine may be renoprotective in hypertensive kidney disease.
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