Vicious Circle With Venous Hypertension, Irregular Flow, Pathological Venous Wall Remodeling, and Valve Destruction in Chronic Venous Disease: A Review.

Substantial advances occurred in phlebological practice in the last two decades. With the use of modern diagnostic equipment, the patients' venous hemodynamics can be examined in detail in everyday practice. Application of venous segments for arterial bypasses motivated studies on the effect of hemodynamic load on the venous wall. New animal models have been developed to study hemodynamic effects on the venous system. In vivo and in vitro studies revealed cellular phase transitions of venous endothelial, smooth muscle, and fibroblastic cells and changes in connective tissue composition, under hemodynamic load and at different locations of the chronically diseased venous system. This review is an attempt to integrate our knowledge from epidemiology, paleoanthropology and anthropology, clinical and experimental hemodynamic studies, histology, cell physiology, cell pathology, and molecular biology on the complex pathomechanism of this frequent disease. Our conclusion is that the disease is initiated by limited genetic adaptation of mankind not to bipedalism but to bipedalism in the unmoving standing or sitting position. In the course of the disease several pathologic vicious circles emerge, sustained venous hypertension inducing cellular phase transitions, chronic wall inflammation, apoptosis of cells, pathologic dilation, and valvular damage which, in turn, further aggravate the venous hypertension.

Treatment of type 2 diabetes mellitus in the elderly - Special considerations.

Type 2 diabetes is a frequent chronic disease. Given its strong positive association with older age, it is a significant public health issue in elderly populations. Furthermore, the aging of the population, driven by increasing life expectancy in high and middle-income countries leads to an increasing prevalence of diabetes.Although the same diagnostic criteria apply to the elderly and to younger people, there are unique aspects to the care for elderly type 2 diabetes patients. Both treatment goals and preferred medications, as well as non-pharmacological approaches should be adjusted in the elderly. For example, increasing the amount of physical activity may encounter difficulties, while introducing an appropriate diet may be more challenging. The patients' therapeutic adherence requires special attention due to cognitive and physical limitations. The most important treatment goal is to avoid hypoglycemia. Frailty, social and economic issues, comorbidities and the consequent polypharmacy frequently causing drug-drug interactions, as well as the increased danger of drug toxicity due to renal failure are only some of the problems that make the health care for old diabetes patients extremely difficult. Adequate care requires cooperation from a multidisciplinary team of health care professionals.Acute diabetes complications have a higher mortality in the elderly, thus close attention must be paid to avoid them. Family members should be involved in the care of elderly diabetes patients, and it is recommended to educate them on clinical signs of complications. Regular care for the patients including feedback on quality of life and early signs of health issues are essential.

The Semmelweis Study: a longitudinal occupational cohort study within the framework of the Semmelweis Caring University Model Program for supporting healthy aging.

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions.

Effects of Gender and Vitamin D on Vascular Reactivity of the Carotid Artery on a Testosterone-Induced PCOS Model.

The negative cardiovascular effects of polycystic ovary syndrome (PCOS) and vitamin D deficiency (VDD) have been discussed previously; however, the sex differences between PCOS females and males are not yet known. Our aim was to investigate the effect of PCOS and VDD in the carotid artery of male and female Wistar rats. Females were treated with transdermal testosterone (Androgel) for 8 weeks, which caused PCOS. VDD and vitamin D supplementation were accomplished via diet. The carotid arteries' contraction and relaxation were examined using myography. Receptor density was investigated using immunohistochemistry. In PCOS females, angiotensin receptor density, angiotensin II-induced contraction, androgen receptor optical density, and testosterone-induced relaxation increased. The increased contractile response may increase cardiovascular vulnerability in women with PCOS. As an effect of VDD, estrogen receptor density increased in all our groups, which probably compensated for the reduced relaxation caused by VDD. Testosterone-induced relaxation was decreased as a result of VDD in males and non-PCOS females, whereas this reduction was absent in PCOS females. Male sex is associated with increased contraction ability compared with non-PCOS and PCOS females. VDD and Androgel treatment show significant gender differences in their effects on carotid artery reactivity. Both VDD and PCOS result in a dysfunctional vascular response, which can contribute to cardiovascular diseases.

Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice.

Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-ß) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-ß density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.

Role of the Endocannabinoid System in Metabolic Control Processes and in the Pathogenesis of Metabolic Syndrome: An Update.

Metabolic syndrome is a complex disease state, which appears mostly as a consequence of an unhealthy, sedentary lifestyle. Metabolic complications include insulin resistance (IR), diabetes, dyslipidemia, hypertension, and atherosclerosis, impairing life standards and reducing life expectancy. The endocannabinoid system (ECS) has an important role in signalization processes, not only in the central nervous system, but also in the peripheral tissues. Several physiological functions are affected, and overexpression or downregulation contributes to several diseases. A better understanding of the functions of cannabinoid (CB) receptors may propose potential therapeutic effects by influencing receptor signaling and enzymes involved in downstream pathways. In this review, we summarize recent information regarding the roles of the ECS and the CB1 receptor signaling in the physiology and pathophysiology of energy and metabolic homeostasis, in the development of obesity by enhancing food intake, upregulating energy balance and fat accumulation, increasing lipogenesis and glucose production, and impairing insulin sensitivity and secretion. By analyzing the roles of the ECS in physiological and pathophysiological mechanisms, we introduce some recently identified signaling pathways in the mechanism of the pathogenesis of metabolic syndrome. Our review emphasizes that the presence of such recently identified ECS signaling steps raises new therapeutic potential in the treatment of complex metabolic diseases such as diabetes, insulin resistance, obesity, and hypertension.

Anemia of geriatric patients.

Anemia is a common finding in the elderly. Approximately 10 percent of the elderly suffers from anemia. Anemia per se is an independent factor of mortality in older patients regardless its cause. Frailty is also frequent in geriatric patients. That means that there is a decreased reserve capacity to react to different stress factors including anemia. The frequent presence of heart failure and also impaired cerebrovascular circulation makes more difficult to tolerate anemia in older age. Anemia is a symptom, finding and treating the underlying cause is also important. Treatment always depends on clinical findings: the more severe the symptoms, the more important to treat them. Severity of anemia depends not only the underlying cause, degree of anemia, co-morbidities and frailty of the patients, but also the speed of its development. Sudden blood loss due to an accident is less well tolerated than the same degree of anemia due to B12 deficiency. Main causes of anemia in the elderly include nutritional deficiencies, chronic diseases, tumors, and certain hematological malignancies such as chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome.

Functional and structural adaptations of the coronary macro- and microvasculature to regular aerobic exercise by activation of physiological, cellular, and molecular mechanisms: ESC Working Group on Coronary Pathophysiology and Microcirculation position paper.

Regular aerobic exercise (RAEX) elicits several positive adaptations in all organs and tissues of the body, culminating in improved health and well-being. Indeed, in over half a century, many studies have shown the benefit of RAEX on cardiovascular outcome in terms of morbidity and mortality. RAEX elicits a wide range of functional and structural adaptations in the heart and its coronary circulation, all of which are to maintain optimal myocardial oxygen and nutritional supply during increased demand. Although there is no evidence suggesting that oxidative metabolism is limited by coronary blood flow (CBF) rate in the normal heart even during maximal exercise, increased CBF and capillary exchange capacities have been reported. Adaptations of coronary macro- and microvessels include outward remodelling of epicardial coronary arteries, increased coronary arteriolar size and density, and increased capillary surface area. In addition, there are adjustments in the neural and endothelial regulation of coronary macrovascular tone. Similarly, there are several adaptations at the level of microcirculation, including enhanced (such as nitric oxide mediated) smooth muscle-dependent pressure-induced myogenic constriction and upregulated endothelium-dependent/shear-stress-induced dilation, increasing the range of diameter change. Alterations in the signalling interaction between coronary vessels and cardiac metabolism have also been described. At the molecular and cellular level, ion channels are key players in the local coronary vascular adaptations to RAEX, with enhanced activation of influx of Ca2+ contributing to the increased myogenic tone (via voltage-gated Ca2+ channels) as well as the enhanced endothelium-dependent dilation (via TRPV4 channels). Finally, RAEX elicits a number of beneficial effects on several haemorheological variables that may further improve CBF and myocardial oxygen delivery and nutrient exchange in the microcirculation by stabilizing and extending the range and further optimizing the regulation of myocardial blood flow during exercise. These adaptations also act to prevent and/or delay the development of coronary and cardiac diseases.

Semmelweis Caring University Model Program Based on the Development of a Center of Preventive Services: Health for All Employees at a University Occupational Setting.

The leadership of the Semmelweis University as a leading institution of higher education in Hungary and the Central Eastern European region within the area of medicine and health sciences has decided to reflect on the unfavorable public health situation in the country as well as the deteriorating health behavior and health status indicators in the Hungarian population by the development of an occupational setting-based personalized public health model program targeting its about 8500 employees. Based on its infrastructure and human resources the core element of the program is the establishment of the Center of Preventive Services (CPS) with units providing health risk assessment for each employee, and whenever necessary consultation with medical specialist in preventive medicine and public health, as well as counseling with dietician, physiotherapist and/or health psychologist. The service providers are the staff members of the relevant faculties in collaboration with partner primary and occupational care physicians. The units of the CPS can also serve as practical training sites for students at various levels of medical and health sciences training, and strongly contribute to the development and improvement of their skills to be able for working as a team in service provision. The employees are not only beneficiaries of health risk assessment and screening repeated on a regular basis and adequate interventions at the right time, but they also serve as a sample for a longitudinal cohort study and further ad hoc surveys for defining and implementing interventions to support health protection, disease prevention and healthy aging among them.

The aging venous system: from varicosities to vascular cognitive impairment.

Aging-induced pathological alterations of the circulatory system play a critical role in morbidity and mortality of older adults. While the importance of cellular and molecular mechanisms of arterial aging for increased cardiovascular risk in older adults is increasingly appreciated, aging processes of veins are much less studied and understood than those of arteries. In this review, age-related cellular and morphological alterations in the venous system are presented. Similarities and dissimilarities between arterial and venous aging are highlighted, and shared molecular mechanisms of arterial and venous aging are considered. The pathogenesis of venous diseases affecting older adults, including varicose veins, chronic venous insufficiency, and deep vein thrombosis, is discussed, and the potential contribution of venous pathologies to the onset of vascular cognitive impairment and neurodegenerative diseases is emphasized. It is our hope that a greater appreciation of the cellular and molecular processes of vascular aging will stimulate further investigation into strategies aimed at preventing or retarding age-related venous pathologies.

Modulation of Urate Transport by Drugs.

BACKGROUND: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. METHODS: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like Cmax/IC50 on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. RESULTS: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. CONCLUSIONS: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1.

Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation.

Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor-Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB1R) in these effects. Expression of CB1R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10-9-10-7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10-7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction.

On the role of bacterial metalloproteases in COVID-19 associated cytokine storm.

The cytokine release syndrome or cytokine storm, which is the hyper-induction of inflammatory responses has a central role in the mortality rate of COVID-19 and some other viral infections. Interleukin-6 (IL-6) is a key player in the development of cytokine storms. Shedding of interleukin-6 receptor (IL-6Rα) results in the accumulation of soluble interleukin-6 receptors (sIL-6R). Only relatively few cells express membrane-bound IL-6Rα. However, sIL-6R can act on potentially all cells and organs through the ubiquitously expressed gp130, the coreceptor of IL-6Rα. Through this, so-called trans-signaling, IL-6-sIL-6R is a powerful factor in the development of cytokine storms and multiorgan involvement. Some bacteria (e.g., Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes), commonly considered to cause co-infections during viral pneumonia, can directly induce the shedding of membrane receptors, including IL-6Rα, or enhance endogenous shedding mechanisms causing the increase of sIL-6R level. Here we hypothesise that bacteria promoting shedding and increase the sIL-6R level can be an important contributing factor for the development of cytokine storms. Therefore, inhibition of IL-6Rα shedding by drastically reducing the number of relevant bacteria may be a critical element in reducing the chance of a cytokine storm. Validation of this hypothesis can support the consideration of the prophylactic use of antibiotics more widely and at an earlier stage of infection to decrease the mortality rate of COVID-19. Video abstract.

Initiation of reticular and spider veins, incompetent perforantes and varicose veins in the saphenous vein network of the rat.

In an attempt to induce experimental varicosity, reverse perforant vein development was initiated in the rat leg by applying a chronic (14 and 32 weeks) partial stricture on the main branch of the deep femoral vein. At surfacing of the incompetent perforantes, typical reticular vein plaques and spider veins were identified by video-microscopy and quantitative histology. Deep vein blood was channeled by them into the saphenous vein system, the extra flow deforming these vessels, causing local dilations and broken course, even undulations of larger branches.

Coronary Microvascular and Cardiac Dysfunction Due to Homocysteine Pathometabolism; A Complex Therapeutic Design.

In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 µM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFκbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments.

Whole-body pulsed EMF stimulation improves cognitive and psychomotor activity in senescent rats.

During advanced aging passive exercise (PE) is becoming a valuable therapeutic intervention to improve physical and mental performances. In the present study chronic low frequency pulsed electromagnetic field (EMF) exposure was presented to senescent rats in order to clarify the behavioural effects related to cognitive and motility functions. Male Wistar rats of 30-32 months old were treated with EMF for six weeks, 3 times per week, 24 min per sessions prior to the age of 32 months. Stimulation intensities varied from 45 to 1250 µT. Psychomotility was estimated in an open field (OF), attention ability in novel object recognition (NOR), and spatial learning in the Morris water maze (MWM) tests. The results showed that EMF stimulation enhanced novelty-induced motility of vertical type, i.e. frequency of rearing activity was increased. In the cognitive tests EMF exposure increased attention-based discrimination in NOR and facilitated working memory type of spatial learning in the MWM tests. No undesirable type of side effects could be obtained even after the highest dose used. It is concluded that EMF stimulation in senescent age supports cognitive and psychomotor function in rats. The notion that PE may have complementary beneficial action on brain and motor functions in senescent age is strengthened by the present experimental results.

Remodeling of Wall Mechanics and the Myogenic Mechanism of Rat Intramural Coronary Arterioles in Response to a Short-Term Daily Exercise Program: Role of Endothelial Factors.

PURPOSE: Exercise elicits early adaptation of coronary vessels enabling the coronary circulation to respond adequately to higher flow demands. We hypothesized that short-term daily exercise induces biomechanical and functional remodeling of the coronary resistance arteries related to pressure. METHODS: Male rats were subjected to a progressively increasing 4-week treadmill exercise program (over 60 min/day, 1 mph in the final step). In vitro pressure-diameter measurements were performed on coronary segments (119 ± 5 µm in diameter at 50 mm Hg) with microarteriography. The magnitude of the myogenic response and contribution of endogenous nitric oxide and prostanoid production to the wall mechanics and pressure-diameter relationship were assessed. RESULTS: Arterioles isolated from exercised ani mals - compared to the sedentary group - had thicker walls, increased distensibility, and a decreased elastic modulus as a result of reduced wall stress in the low pressure range. The arterioles of exercised rats exhibited a more powerful myogenic response and less endogenous vasoconstrictor prostanoid modulation at higher pressures, while vasodilator nitric oxide modulation of diameter was augmented at low pressures (< 60 mm Hg). CONCLUSIONS: A short-term daily exercise program induces remodeling of rat intramural coronary arterioles, likely resulting in a greater range of coronary autoregulatory function (constrictor and dilator reserves) and more effective protection against great changes in intraluminal pressure, contributing thereby to the optimization of coronary blood flow during exercise.

High pressure-low flow remodeling of the rat saphenous vein wall.

Objective To better understand factors that may play a role in the development of varicosities. Methods We induced combined flow-pressure disturbance in the saphenous system of the rat by performing chronic partial clipping of the main branch. Biomechanical and quantitative histological testing was undertaken. Results A rich microvenous network developed. Bloodflow decreased to 0.65 ± 0.18 µl/s (control side, 3.5 ± 1.4 µl/s) and pressure elevated to 6.8 ± 0.7 mmHg (control side, 2.3 ± 0.2 mmHg, p < 0.05). Involution of the wall and lumen was observed (16.5%, 28.7% and 35.5% reduction in outer diameter, wall thickness and wall mass respectively, p < 0.05). Elevated macrophage (CD68) and cell division (Ki67) activity was observed. Elastic tissue and smooth muscle actin became less concentrated in the inner medial layers. Conclusions Low-flow induced morphological shrinking of the lumen in veins may override pressure-induced morphological distension. Loosening of the force-bearing elements during flow-induced wall remodeling may be an important pathological component in varicosity.

[Regulation of vasomotor tone of small skeletal muscle veins by intrinsic mechanisms]. / Vázizomkisvénák vazomotortónusának intrinszik szabályozómechanizmusai.

In many developed countries the prevalence of venous disorders and its consequences are higher than that of arterial diseases. Thus it is very important to understand the exact physiological and pathophysiological function of small veins and their control mechanisms. Small veins and venules have an important role in the regulation of capillary fluid exchange, as well as return of the venous blood into the heart. However, there is only limited knowledge available regarding the role of local mechanisms controlling the vasomotor tone and diameter of small veins. In the last decade the authors focused on the elucidation of these mechanisms in isolated skeletal muscle venules of rats. Their results suggest that the tone of small veins is controlled by the integration of several mechanisms, activated by the intraluminal pressure and flow/wall shear stress, in addition to numerous local mediators synthesized and released from the smooth muscle and endothelium. These mechanisms are involved - in a complex manner - in the control of postcapillary resistance, thus regulation of tissue blood supply, venous return and consequently in the modulation of the cardiac output, as well.