Fedor Simko

Melatonin as a potential antihypertensive treatment.

Abstract:  The number of patients with well‐controlled hypertension is alarmingly low worldwide and new approaches to treatment of increased blood pressure (BP) are being sought. Melatonin has a role in blood pressure regulation. The nighttime production of melatonin is found to be reduced in hypertensive individuals. Administration of melatonin decreased BP in several animal models of hypertension, in healthy men and women, and in patients with arterial hypertension. Most promising results were achieved in patients with non‐dipping nighttime pressure, in which the circadian rhythm of BP variation is disturbed. Several potential mechanisms of BP reduction are considered. Melatonin can, via its scavenging and antioxidant nature, improve endothelial function with increased availability of nitric oxide exerting vasodilatory and hypotensive effects. Melatonin seems to interfere with peripheral and central autonomic system, with a subsequent decrease in the tone of the adrenergic system and an increase of the cholinergic system. Melatonin may act on BP also via specific melatonin receptors localized in peripheral vessels or in parts of central nervous system participating in BP control. With a large clinical trial using melatonin in hypertension treatment, many important questions could be answered, such as the dose of melatonin and regimen of its application, the choice of patients with greatest possible benefit from melatonin treatment, the potential of anti‐remodeling effect of melatonin and the interaction of melatonin with other antihypertensive drugs.

Regression of L-NAME-Induced Hypertension : The Role of Nitric Oxide and Endothelium-Derived Constricting Factor

NG-Nitro-L-arginine-methyl ester (L-NAME)–induced hypertension is a well established model of experimental hypertension. Although regression experiments are effective at approximating a clinical setting the reversal of already established L-NAME hypertension has not been intensively researched. We investigated whether spontaneous regression of L-NAME hypertension after discontinuing the drug administration was associated with recovery of endothelial dysfunction. Special attention was devoted to NO signaling and endothelium-derived constricting factor (EDCF) formation in various parts of the vascular tree. Male adult Wistar rats were divided into 4 groups: an L-NAME (5 weeks), a spontaneous recovery (5 weeks L-NAME + 3 weeks of recovery) and two age-matched control groups (a 5- and 8-week control group). The NO-mediated and EDCF-mediated components of acetylcholine-induced responses were evaluated in preconstricted small mesenteric and femoral arteries. The activity, mRNA and protein expression of NO synthase together with the mRNA expression of cyclooxygenase were determined in the aorta. L-NAME administration caused hypertension, impaired NO signaling (as indicated by the reduced NO component of acetylcholine-induced relaxation and decreased NO synthase activity) in all arteries investigated and reduced the inner diameter of the femoral artery. Moreover, we observed enhanced cyclooxygenase-dependent EDCF formation in the femoral arteries and enhanced cyclooxygenase-2 expression in the aortas of L-NAME–treated rats. During spontaneous recovery a functional restoration of NO signaling took place in all parts of the vascular tree. However, the increases in systolic blood pressure, EDCF formation, and cyclooxygenase expression and the reduction in femoral artery diameter were not completely restored. We conclude that impaired NO signaling was improved after the cessation of L-NAME administration. However, persisting arterial structural alterations and enhanced EDCF formation may decelerate blood pressure reduction even after the restoration of NO synthase activity.

Potential roles of melatonin and chronotherapy among the new trends in hypertension treatment

Abstract:  The number of well‐controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti‐remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate‐binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high‐risk hypertensives, for hypertensives with LVH, and possibly for high‐risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin–angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events.

EFFECT OF CAPTOPRIL IN L-NAME-INDUCED HYPERTENSION ON THE RAT MYOCARDIUM, AORTA, BRAIN AND KIDNEY

Long‐term administration of NG‐nitro‐L‐arginine methyl ester (L‐NAME) induces development of hypertension and hypertrophy of the left ventricle in rats. The aim of the present study was to demonstrate the effect of chronic L‐NAME treatment on DNA and RNA concentration, and protein synthesis in the rat heart, aorta, brain and kidney and to determine the effect of angiotensin converting enzyme (ACE) inhibitor captopril on these potential alterations. Four groups of rats were investigated: control, L‐NAME (40 mg kg−1 day−1), captopril (100 mg kg−1 day−1), and L‐NAME (40 mg kg−1 day−1) + captopril (100 mg kg−1 day−1). NO synthase activity in the heart, aorta, brain and kidney was found to be decreased in the L‐NAME group. In the group of rats treated with L‐NAME + captopril, captopril did not affect NO synthase inhibition. Captopril, however, completely prevented development of hypertension and left ventricular hypertrophy in this group. In the L‐NAME group, DNA and RNA concentrations, as well as [14C]leucine incorporation, were significantly increased in all the tissues investigated. In the L‐NAME + captopril group, captopril completely prevented the enhancement of DNA and RNA concentrations and [14C]leucine incorporation in all tissues compared to the L‐NAME group. Moreover, a significant decrease in RNA concentration and [14C]leucine incorporation below control values was found in the captopril group as well as the L‐NAME + captopril group in all the tissues investigated. We conclude that captopril prevented the development of hypertension and increase in nucleic acid concentration and protein synthesis in the heart, aorta, brain and kidney in rats treated with L‐NAME + captopril. However, this protective effect of captopril was not associated with increased NO synthase activity in this model of hypertension.

Effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodelling in spontaneously hypertensive rats.

Objective Melatonin was shown to reduce blood pressure, oxidative load and to increase nitric oxide bioavailability predisposing melatonin to have antiremodelling potential. Design The aim of this study was to show whether melatonin can reverse left ventricular remodelling in spontaneously hypertensive rats (SHR) and to compare this potential protective effect with captopril, spironolactone, or simvastatin. Methods Six groups of 3-month old rats (eight per group) were treated for 5 weeks: control untreated Wistar rats, control SHR, SHR plus melatonin (10 mg/kg per 24 h), SHR plus captopril (100 mg/kg per 24 h), SHR plus spironolactone (200 mg/kg per 24 h) and SHR plus simvastatin (10 mg/kg per 24 h). Their systolic blood pressure (SBP) was measured by the tail-cuff method. The relative weights of the left ventricle, nitric oxide synthase (NOS) activity, endothelial NOS and nuclear factor kappa B (NF-κB) protein expression, conjugated dienes concentration, level of collagenous proteins and hydroxyproline were measured. Results SBP was reduced by all drugs investigated but most prominently by captopril in SHR. The activity of NOS and endothelial NOS expression increased in the left ventricles of SHR compared with controls. Melatonin and spironolactone further increased NOS expression. Left ventricular oxidative load, estimated by NF-κB expression and conjugated dienes concentration, increased in SHR. Only melatonin reduced NF-κB expression and decreased conjugated diens concentration. Only captopril reduced left ventricular hypertrophy in SHR, whereas melatonin reduced collagenous protein concentration and hydroxyproline content in the left ventricle. Conclusion It is concluded that although melatonin, in comparison with captopril, did not reverse left ventricle hypertrophy, it reversed left ventricular fibrosis. This protection by melatonin may be caused by its prominent antioxidative effect.

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

The pineal hormone, melatonin (N-acetyl-5-methoxytryptamine), shows potent receptor-dependent and -independent actions, which participate in blood pressure regulation. The antihypertensive effect of melatonin was demonstrated in experimental and clinical hypertension. Receptor-dependent effects are mediated predominantly through MT1 and MT2 G-protein coupled receptors. The pleiotropic receptor-independent effects of melatonin with a possible impact on blood pressure involve the reactive oxygen species (ROS) scavenging nature, activation and over-expression of several antioxidant enzymes or their protection from oxidative damage and the ability to increase the efficiency of the mitochondrial electron transport chain. Besides the interaction with the vascular system, this indolamine may exert part of its antihypertensive action through its interaction with the central nervous system (CNS). The imbalance between the sympathetic and parasympathetic vegetative system is an important pathophysiological disorder and therapeutic target in hypertension. Melatonin is protective in CNS on several different levels: It reduces free radical burden, improves endothelial dysfunction, reduces inflammation and shifts the balance between the sympathetic and parasympathetic system in favor of the parasympathetic system. The increased level of serum melatonin observed in some types of hypertension may be a counter-regulatory adaptive mechanism against the sympathetic overstimulation. Since melatonin acts favorably on different levels of hypertension, including organ protection and with minimal side effects, it could become regularly involved in the struggle against this widespread cardiovascular pathology.

Cardiovascular effects of melatonin receptor agonists.

Introduction: Melatonin synchronizes circadian rhythms with light/dark period and it was demonstrated to correct chronodisruption. Several melatonin receptor agonists with improved pharmacokinetics or increased receptor affinity are being developed, three of them are already in clinical use. However, the actions of melatonin extend beyond chronobiology to cardiovascular and metabolic systems as well. Given the high prevalence of cardiovascular disease and their common occurrence with chronodisruption, it is of utmost importance to classify the cardiometabolic effects of the newly approved and putative melatoninergic drugs. Areas covered: In the present review, the available (although very sparse) data on such effects, in particular by the approved (circadin, ramelteon, agomelatine) or clinically advanced (tasimelteon, piromelatine = Neu-P11, TIK-301) compounds are summarized. The authors have searched for an association with blood pressure, vascular reactivity, ischemia, myocardial and vascular remodeling and metabolic syndrome. Expert opinion: The data suggest that cardiovascular effects of melatonin are at least partly mediated via MT1/MT2 receptors and associated with its chronobiotic action. Therefore, despite the sparse direct evidence, it is believed that these effects will be shared by melatonin analogs as well. With the expected approval of novel melatoninergic compounds, it is suggested that the investigation of their cardiovascular effects should no longer be neglected.

Chronic antioxidant therapy fails to ameliorate hypertension: potential mechanisms behind.

Hypertension in association with oxidative stress belongs to the most discussed topics within the literature on cardiovascular diseases. It is generally believed that elevated production of reactive oxygen species (ROS) plays an important role in hypertension, but clinical studies on chronic antioxidant therapy of hypertension fail to confirm this hypothesis. This discrepancy may be partly determined by the different effects of short and long-lasting treatment with antioxidants or scavengers. Elevated ROS production in hypertension need not be only harmful. It may also stimulate the activity of the antioxidant defence system and improve the nitric oxide (NO)/cyclic 3′, 5′-guanosine monophosphate pathway, resulting in the establishment of a new equilibrium between enhanced oxidative load and the stimulated NO pathway, thus maintaining sufficient NO bioavailability. It has been suggested that antioxidant treatment might be beneficial for a short time, until increased NO generation predominates over ROS production. Further weakening of ROS formation by antioxidants may attenuate nuclear factor kappa B activation resulting in decreased endothelial NO synthase expression and activity. Prolonged antioxidant therapy may thus attenuate the beneficial regulatory effect of ROS, leading to decreased NO generation and the re-establishment of the undesirable disproportion between deleterious and protective forces. As a consequence prolonged antioxidant treatment in human hypertension may fail to provide the expected clinical profit.

Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol‐induced heart failure

Melatonin was previously shown to reduce blood pressure and left ventricular (LV) remodeling in several models of experimental heart damage. This study investigated whether melatonin prevents LV remodeling and improves survival in isoproterenol‐induced heart failure. In the first experiment, four groups of 3‐month‐old male Wistar rats (12 per group) were treated for 2 wk as follows: controls, rats treated with melatonin (10 mg/kg/day) (M), rats treated with isoproterenol (5 mg/kg/day intraperitoneally the second week) (Iso), and rats treated with melatonin (2 wk) and isoproterenol (the second week) in corresponding doses (IsoM). In the second experiment, 30 rats were treated with isoproterenol and 30 rats with isoproterenol plus melatonin for a period of 28 days and their mortality was investigated. Isoproterenol‐induced heart failure with hypertrophy of the left and right ventricles (LV, RV), lowered systolic blood pressure (SBP) and elevated pulmonary congestion. Fibrotic rebuilding was accompanied by alterations of tubulin level in the LV and oxidative stress development. Melatonin failed to reduce the weight of the LV or RV; however, it curtailed the weight of the lungs and attenuated the decline in SBP. Moreover, melatonin decreased the level of oxidative stress and of insoluble and total collagen and partly prevented the beta‐tubulin alteration in the LV. Most importantly, melatonin reduced mortality and prolonged the average survival time. In conclusion, melatonin exerts cardioprotective effects and improves outcome in a model of isoproterenol‐induced heart damage. The antiremodeling effect of melatonin may be of potential benefit in patients with heart failure.

Experimental models of melatonin-deficient hypertension

Melatonin secreted by the pineal gland plays an important role in the regulation of blood pressure (BP) and its administration reduces hypertension both in animals and humans. There are two experimental models of melatonin-deficient hypertension: one induced by pinealectomy and another by continuous 24 hour exposure to light. Both models cause melatonin deficiency and prevent darkness-mediated nocturnal melatonin secretion and are associated with increased BP and myocardial, vascular and renal dysfunction. These models also lead to neurohumoral activation of the renin-angiotensin system, sympathetic nervous system, adrenocorticotrophin-glucocorticoid axis and cause insulin resistance. Together, these alterations contribute to rise in blood pressure by vasoconstrictive or circulatory fluid volume overload. The light induced hypertension model mimics the melatonin deficiency in patients with insufficient nocturnal BP decline, in those who have night shift or who are exposed to environmental light pollution. For this reason, this model is useful in development of anti-hypertensive drugs.