**10. Natruretic peptydes**

Natruretic peptide system counteracts of some of the effects of neurohormonal activation causing vasodilatation, reduction of aldosterone production (by direct influence on the adrenal gland), increased diuresis and natriuresis, reduction of renin production, decreased vasopressin realize, decreased activation of the sympathethic nervous system. Direct influence of the naturetic peptydes on the myocardium includes prevention of hypertrophy and reduction of fibroblast proliferation. BNP is a natriuretic peptide released in response to ventricular volume expansion and pressure overload.

Cardiopulmonary by-pass in children induces renal and neurohormonal changes similar to those observed in congestive heart failure: upregulation of the RAA axis, increase of renin concentration, release of vasopressin. The endogenous biological activity of natriuretic hormone system is decreased after the bypass. This is caused by deficiency of biologically active neurohormons, presence of inactive neurohormons, resistance to natriuretic hormone activity, receptor down-regulation, abnormal signal transduction, increased phosphodiesterase activity.

It has been also shown that neurohormons can decrease ischemia-reperfusion injury in multiple tissue including heart by inhibition of angiotensin II and aldosterone, limitation of intracellular Ca++ overload, maintainance of ATP stores, preservation of myofibril, mitochondrial and nuclear structure of cardiomyocytes.

In the natural history of diseased cardiovascular system complex interactions between local, humoral, and neural factors lead to abnormalities in the circulatory control. These adaptive

responses are aimed at maintaining adequate vital organ perfusion but can lead to unfavorable and undesirable changes both in the heart and the vascular system. An impaired regulation of cardiac autonomic system and activation of many neurohormonal factors as well as the rennin-angiotensin-aldosterone system (RAAS). These changes may contribute to numerous early and late complications e.g. dysregulation of fluid homeostasis, effusions, detrimental remodeling, protein-losing enteropathy and limited exercise capacity. They can also serve as important indices for risk stratification, prediction of unfavorable events and adjustment of treatment (3).

Neuroendocrine Regulation of Stress Response in Clinical Models 11

VSELs find beneficial conditions to growth and become reserve cell line participating in tissue and organ regeneration. In the postnatal life they are inactive and flow in blood stream in small amount. Mobilization of VSEL's is considered as a part of stress response it can increase upon different impulses e.g. tissue damage, ischemia, hypoxia, myocardial infarction, open heart surgery, extracorporeal circulation. Cells mobilized from bone marrow penetrate to blood and are attracted to damaged tissues by chemotactic factors, e.g.

Researches who identified and described morphology of VSELs also showed the ability of those cells to proliferate and differentiate into all three primary germ layers in appropriate differentiating medium. It has been also proved that VSELs express many markers of primordial germ cells, e.g. fetal alkaline phosphatase, Oct-4, SSEA-l, CXCR4, Mvh, Stella, Fragilis, Nobox and Hdac6, indicating their similarity to germ cells through which genes are passed from generation to generation – the best reservoir of stem cells (7, 8). Most active translocation of stem cells takes place during early stage of human embryogenesis. In the beginning of gastrulation and organogenesis stem cells migrate to places of new tissues and organs formation. Subsequently, stem cells settle down in tissue specific spaces and constitute a cell line undergoing self-renewal process. These cells also replenish damaged or apoptotic cells during individual life. VSELs may accumulate in bone marrow under the influence of chemotactic factors (correlation between CXCR4 receptor and lymphokine SDF-1). After colonizing bone marrow VSELs find beneficial conditions to growth and become reserve cell line participating in tissue and organ regeneration. In normal conditions VSELs circulate in the peripheral blood in small number and can increase upon different stimuli e.g. tissue damage or severe stress (ischemia, hypoxia, myocardial infarction, open heart surgery, extracorporeal circulation) (9). Cells mobilized from bone marrow penetrate to blood and are attracted to damaged tissues by chemotactic factors, e.g. SDF-l, HGF/SF, or VSEGF. It has been proved that many clinical scenarios are associated with increase of stem cells in bloodstream. Increase of the number of bone marrow derived stem cells was observed in skeletal muscle injury, myocardial infarction, stroke, bones fractures, leasions of the liver and kidneys, ischaemia of the extremities and after lung or liver transplantation. These cells were described as endothelial progenitor cells (EPC), myocardial or muscle progenitor cells, neural progenitor cells, liver progenitor cells etc… These data indicate that during injury of the tissues and organs non-hematopoetic stem cells are mobilized from the marrow (10) and probably from other tissue niches to the blood where they circulate as a source of the stem cells supporting regeneration of the tissues (11, 12). This process is governed by injured tissue derived chemoattractants such as SDF-l, and other factors e.g.: VEGF, HGF/SF, UF and FGF-2. It is also known that transcriptional factor HIF-1 (hypoxia regulated/induced transcription factor) connected with the tissue ischemia takes important palce in regulation of expression of these factors. The promotor for sdf-l, vegf and hgf/sf gens have bounding places for HIF-1. Therefore hypoxia / cyanosis can induce expression of factors responsible for stem cells releasing and their migration to the injured tissues and organs. VSELs which are present in the marrow are quiescent and they need unknown factors for activation and stimulation of their activity. These incentives and modulators are

SDF-l, HGF/SF, or VSEGF.

unknown.

**Figure 1.** Natruretic factors interactions.
