Elevated heart rate is a risk factor for cardiovascular and all‐cause mortalities in the general population and various cardiovascular pathologies. Insufficient heart rate decline during the night, that is, nondipping heart rate, also increases cardiovascular risk. Abnormal heart rate reflects an autonomic nervous system imbalance in terms of relative dominance of sympathetic tone. There are only a few prospective studies concerning the effect of heart rate reduction in coronary heart disease and heart failure. In hypertensive patients, retrospective analyses show no additional benefit of slowing down the heart rate by beta‐blockade to blood pressure reduction. Melatonin, a secretory product of the pineal gland, has several attributes, which predict melatonin to be a promising candidate in the struggle against elevated heart rate and its consequences in the hypertensive population. First, melatonin production depends on the sympathetic stimulation of the pineal gland. On the other hand, melatonin inhibits the sympathetic system in several ways representing potentially the counter‐regulatory mechanism to normalize excessive sympathetic drive. Second, administration of melatonin reduces heart rate in animals and humans. Third, the chronobiological action of melatonin may normalize the insufficient nocturnal decline of heart rate. Moreover, melatonin reduces the development of endothelial dysfunction and atherosclerosis, which are considered a crucial pathophysiological disorder of increased heart rate and pulsatile blood flow. The antihypertensive and antiremodeling action of melatonin along with its beneficial effects on lipid profile and insulin resistance may be of additional benefit. A clinical trial investigating melatonin actions in hypertensive patients with increased heart rate is warranted.

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.

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 (n = 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 L-NAME-induced hypertension and to interfere with the RAAS. Four groups (n = 10/group) of adult male Wistar rats were treated as follows for four weeks: control, ivabradine (10 mg/kg/day), L-NAME (40 mg/kg/day), and L-NAME plus ivabradine. L-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 L-NAME group and ivabradine did not modify them. The serum concentration of aldosterone and the aldosterone/Ang II ratio were enhanced by L-NAME and ivabradine reduced these changes. We conclude that ivabradine improved the LV function of the hypertensive heart in L-NAME-induced hypertension. The protective effect of ivabradine might have been associated with the reduction of the aldosterone level.

Background: Current heart failure therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (ie, calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents—myotropes—activates the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine. Methods: We determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine and ATP concentrations, and ATP production were assessed by ³¹ P nuclear magnetic resonance spectroscopy on isolated perfused rat hearts. Results: TA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased the rate-pressure product. Dobutamine increased both developed pressure and heart rate accompanied by decreased phosphocreatine-to-ATP ratio and decreased free energy of ATP hydrolysis (ΔG _~ATP ) and elevated left ventricular end diastolic pressure. In contrast, the TA1 increased developed pressure without any effect on heart rate, left ventricular end diastolic pressure, phosphocreatine/ATP ratio, or ΔG _~ATP . Conclusions: Novel myotrope TA1 increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long-term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.