Long-term stimulation of myocardial beta-receptors by isoproterenol is a well-established model of heart damage and failure. This study investigated the potential interactions of isoproterenol administration with the renin-angiotensin-aldosterone system (RAAS) and whether sacubitril/valsartan (ARNI) protection against left ventricular (LV) remodeling and dysfunction was associated with the modulation of the RAAS. Four groups of three-month-old male Wistar rats were treated for six weeks as follows: controls, sacubitril/valsartan (ARNI, 68 mg/kg/day orally), isoproterenol (5 mg/kg the first day and 1 mg for next six days + four weeks recovery), isoproterenol (as above) + ARNI (one week pre-treatment followed by 5 weeks treatment during ISO-treatment and recovery period). Systolic blood pressure (SBP) was markedly reduced only in the first week of both ISO-treated groups. Isoproterenol induced pathological remodeling of the LV, as well as deterioration of its function as determined by echocardiography. Yet, no changes in serum renin-angiotensin-aldosterone levels were observed. ARNI lowered SBP, alleviated LV remodeling, improved LV systolic and diastolic dysfunction and also raised the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 and aldosterone. We conclude that isoproterenol treatment for one week followed by a four-week recovery induced a normal-to-low serum renin-angiotensin-aldosterone model of left ventricular damage. Protection by ARNI against pathological remodeling and LV dysfunction was related to Ang II blockade and upregulation of the alternative pathway of the renin-angiotensin-aldosterone system.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), developed for the treatment of diabetes mellitus, exert remarkable cardiovascular benefits beyond glycaemic control. The underlying mechanism of this pluripotent protection is heterogeneous and involves interactions with a number of haemodynamic, metabolic and cellular signalling pathways. Emerging findings demonstrate that a natural gaseous product of arterial wall, H2S, participates in a number of physiological reactions, and its deficiency is associated with cardiovascular pathologies, such as arterial hypertension, heart failure and chronic kidney disease. Recent experimental observations have suggested the possibility of a functional link between SGLT2i and H2S signalling in the context of cardiovascular protection. Emerging data suggest that SGLT2i- and H2S-dependent pathways may overlap or complement each other in protective mechanisms. Several plausible areas of interaction between SGLT2i and H2S have recently emerged. Both agents stimulate PI3K/Akt/eNOS signalling, thereby increasing the bioavailability of NO with beneficial vasodilatory and antiproliferative effects. SGLT2i and H2S also favourably regulate the redox state through inhibition of NADPH oxidase, thus protecting subcellular structures. Moreover, both SGLT2i and H2S appear to affect autophagy and improve mitochondrial function through AMPK and sirtuin signalling, thus contributing to the restoration of physiological substrate processing pathways and cellular energy balance. In addition, both SGLT2i and H2S supposedly downregulate the Na+/H+ exchanger, normalize the Fe2+ cytosolic level in cardiomyocytes and promote erythropoietin release, actions that could improve the metabolism and function of cardiovascular organs. Elucidating the nature of possible crosstalk between H2S, delivered by endogenous stimulation or exogenous supplementation, and SGLT2i may desirably modify the approach to the treatment of cardiovascular diseases and represents a challenging research topic.

Cardiovascular disorders and the medications used to treat them can affect physiological patterns of behavior. The aim of the present study was to determine whether the dual inhibition of neprilysin and angiotensin II—sacubitril/valsartan (ARNI) can modify anxiety-like behavior in male spontaneously hypertensive rats (SHR). We compared ARNI with two other drugs in the portfolio of heart failure treatment, captopril and ivabradine. Six groups (n = 13) of 12-week-old rats were treated for six weeks: control (Wistar rats), control + ARNI, SHR, SHR + ARNI, SHR + captopril, and SHR + ivabradine. The elevated plus maze test, the open field test, and the light–dark box test were used to determine anxiety-like behavior. SHRs exhibited higher systolic blood pressure (SBP), heart rate (HR), left ventricular weight (LVW), and hydroxyproline concentration (LVHP) but displayed a reduced level of anxiety-like behavior in comparison to controls. ARNI reduced SBP, HR, and LVW but had no significant effect on the level of anxiety in SHR, and similar results were achieved by captopril and ivabradine. Additionally, correlation analysis indicated that anxiety-like behavior in Wistar rats or SHR, either with or without cardiovascular therapy, was independent of SBP, HR, LVW, or LVHP. The level of anxiety-like behavior can, therefore, be considered part of the inherent neurobehavioral traits unrelated to fundamental hemodynamic or structural cardiovascular parameters.

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 Wistar rats 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.

Atherosclerosis is the underlying factor in the premature death of millions of humans annually. The cause of death is often a result of the rupture of an atherosclerotic plaque followed by the discharge of the associated molecular debris into the vessel lumen which occludes the artery leading to ischemia of downstream tissue and to morbidity or mortality of the individual. This is most serious when it occurs in the heart (heart attack) or brain (stroke). Atherosclerotic plaques are classified as either soft, rupture-prone, or hard, rupture resistant. Melatonin, the production of which diminishes with age, has major actions in converting soft to hard plaques. Experimentally, melatonin reduces the ingrowth of capillaries from the tunica media into the plaque relieving pressure on the plaque, reducing intraplaque hemorrhage and limiting the size of the necrotic core. Moreover, melatonin promotes the formation of collagen by invading vascular smooth muscle cells which strengthen the plaque crown making it resistant to rupture. Melatonin is also a powerful antioxidant and anti-inflammatory agent such that is reduces oxidative damage to tissues associated with the plaque and limits inflammation both of which contribute to plaque cap weakness. Additional benefits of melatonin relative to atherosclerosis is inhibition of adhesion molecules on the endothelial cell surface, limiting the invasion of monocytes into the arterial intima, and reducing the conversion of anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages. Given the high physiological and financial cost of cardiac and neural ischemic events, this information should be given high priority in the clinical setting.

Cardiovascular disease is the cause of physical infirmity and thousands of deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms of energy production and metabolic processing. Additionally, inflammation and the accumulation of non-contractile fibrous tissue contribute to cardiac malfunction. Melatonin, an endogenously produced molecule, experimentally reduces the initiation and progression of atherosclerotic lesions, which are often the basis of coronary artery disease. The current review critically analyzes published data related to the experimental use of melatonin to forestall coronary artery pathologies. Collectively, these studies document melatonin's anti-atherosclerotic actions in reducing LDL oxidation and triglyceride levels, lowering endothelial malfunction, limiting adhesion molecule formation, preventing macrophage polarization to the M1 pro-inflammatory phenotype, changing cellular metabolism, scavenging destructive reactive oxygen species, preventing the proliferation and invasion of arterial smooth muscle cells into the lesioned area, restricting the ingrowth of blood vessels from the vasa vasorum, and solidifying the plaque cap to reduce the chance of its rupture. Diabetic hyperglycemia, which aggravates atherosclerotic plaque formation, is also inhibited by melatonin supplementation in experimental animals. The potential value of non-toxic melatonin as a possible inhibitor of cardiac pathology in humans should be seriously considered by performing clinical trials using this multifunctional molecule.

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.

Background Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN).Results Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect.Conclusions Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

This study investigated whether chronic isoproterenol administration could induce kidney alterations and whether ivabradine, a heart rate (HR)-reducing substance exerting cardiovascular protection, is able to attenuate potential kidney damage. Twenty-eight Wistar rats were divided into non-diseased controls, rats treated with ivabradine, rats treated with isoproterenol, and rats treated with isoproterenol plus ivabradine. Six weeks of isoproterenol administration was associated with decreased systolic blood pressure (SBP) (by 25%) and glomerular, tubulointerstitial and vascular/perivascular fibrosis due to enhanced type I collagen volume (7-, 8-, and 4-fold, respectively). Ivabradine reduced HR (by 15%), partly prevented SBP decline (by 10%) and site-specifically mitigated kidney fibrosis by decreasing type I collagen volume in all three sites investigated (by 69, 58, and 67%, respectively) and the ratio of type I collagen-to-type III collagen in glomerular and vascular/perivascular sites (by 79 and 73%, respectively). We conclude that ivabradine exerts protection against kidney remodelling in isoproterenol-induced kidney damage.

Besides acute respiratory distress syndrome, acute cardiac injury is a major complication in severe coronavirus disease 2019 (COVID-19) and is associated with a poor clinical outcome. Acute cardiac injury with COVID-19 can be of various etiologies, including myocardial ischemia or infarction and myocarditis, and may compromise cardiac function, resulting in acute heart failure or cardiogenic shock. Systemic inflammatory response increases heart rate (HR), which disrupts the myocardial oxygen supply/demand balance and worsens cardiac energy efficiency, thus further deteriorating the cardiac performance of the injured myocardium. In fact, the combination of elevated resting HR and markers of inflammation synergistically predicts adverse cardiovascular prognosis. Thus, targeted HR reduction may potentially be of benefit in cardiovascular pathologies associated with COVID-19. Ivabradine is a drug that selectively reduces HR via I-f current inhibition in the sinoatrial node without a negative effect on inotropy. Besides selective HR reduction, ivabradine was found to exert various beneficial pleiotropic effects, either HR-dependent or HR-independent, including anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative actions and the attenuation of endothelial dysfunction and neurohumoral activation. Cardioprotection by ivabradine has already been indicated in cardiovascular pathologies that are prevalent with COVID-19, including myocarditis, acute coronary syndrome, cardiogenic shock or cardiac dysautonomia. Here, we suggest that ivabradine may be beneficial in the management of COVID-19-related cardiovascular complications.

Besides the well-recognized risk factors, novel conditions increasing cardiovascular morbidity and mortality are emerging. Undesirable emotions and behavior such as anxiety and depression, appear to participate in worsening cardiovascular pathologies. On the other hand, deteriorating conditions of the heart and vasculature result in disturbed mental and emotional health. The pathophysiological background of this bidirectional interplay could reside in an inappropriate activation of vegetative neurohormonal and other humoral systems in both cardiovascular and psychological disturbances. This results in circulus vitiosus potentiating mental and circulatory disorders. Thus, it appears to be of utmost importance to examine the alteration of emotions, cognition, and behavior in cardiovascular patients. In terms of this consideration, recognizing the potential of principal cardiovascular drugs to interact with the mental state in patients with heart or vasculature disturbances is unavoidable, to optimize their therapeutic benefit. In general, beta-blockers, central sympatholytics, ACE inhibitors, ARBs, aldosterone receptor blockers, sacubitril/valsartan, and fibrates are considered to exert anxiolytic effect in animal experiments and clinical settings. Statins and some beta-blockers appear to have an equivocal impact on mood and anxiety and ivabradine expressed neutral psychological impact. It seems reasonable to suppose that the knowledge of a patient's mood, cognition, and behavior, along with applying careful consideration of the choice of the particular cardiovascular drug and respecting its potential psychological benefit or harm might improve the individualized approach to the treatment of cardiovascular disorders.

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.

GENERAL COMMENTARY article Front. Pharmacol., 28 January 2022Sec. Translational Pharmacology Volume 13 - 2022 | https://doi.org/10.3389/fphar.2022.842512

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We were pleased to read the publication by Lan and colleagues [1] which included a meta-analysis of the Randomized Controlled Trials (RTCs) in which melatonin was used as a treatment for COVID-19.This article is protected by copyright. All rights reserved.

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.