**5. Endotheline**

6 Neuroendocrinology and Behavior

Heart

Kidney

caused mainly by abnormal autonomic nervous system activity, lower non-pulsatile pulmonary flow, neurohormonal disturbances and dysfunction of the endothelium. The primary mechanism restricting exercise capacity is the lack of ability to increase and maintain the cardiac output and pulmonary flow in response to exercise. This is complementary with delayed chronotropic reaction, decreased heart rate acceleration and abnormal reflex from ergoreceptors. Exercise studies with external pacemaker heart stimulation to increase heart rate despite of slowing it reflex did not cause increase of exercise tolerance (3). In our model heart rate was significantly lower at anaerobic threshold indicating delayed chronotropic response or adaptation to the demand of increased output generation (the slower the heart rate, the better preload). This was accompanied by significant respiratory tidal volume lowering, diminished carbon dioxide production, and respiratory equivalent of carbon dioxide compared to control group. These differences disappeared at peak exercise suggesting maintenance of optimal

Increased cardiomyocyte calcium entry

metabolism gens

Myocardial hypertrophy / remodeling β1 - receptors down-regulation

Increased expression of fetal gens Decreased expression of calcium

Myocardial hypertrophy

Gene expression:

Apoptosis Necrosis Fibrosis

Significant positive correlation of VE/VCO2 (respiratory equivalent of carbon dioxide) at peak exercise with proBNP and endothelin-1 were found. The parameter VE/VCO2 reflects relationship between minute ventilation and carbon dioxide clearance and is considered as a more sensitive prognostic factor than oxygen consumption in diagnosis of circulatory insufficiency. In patients with chronic heart failure VE/VCO2 is increased and negatively correlated with cardiac output at peak exercise and is independent of subject effort and peripheral function (3, 4). In our study VE/VCO2 peak is significantly higher in investigated group, compared to age matched controls. The correlation with endothelin-1 and proBNP indicates the possibility of identification of such patients by neurohormonal screening tests

hemodynamic and respiratory parameters for maximal physiological effect.

Effects of sympathetic stimulation Cellular effects

Increased contractility (inotropy)

Decreased myocardial relaxation

Increased heart rate Increased wall stress

Increased oxygen demand

(lusitropy)

Constriction Increased afterload

Vasoconstriction Sodium retention Water retention

Sodium retention Water retention

**Table 2.** Sympathetic nervous system activation

Peripheral vessels

RAAS activation

Endothelins (ET -1,-2,-3) are a molecules produced by endothelium acting as a vasoconstrictors and mitogenic factors. In patients with heart failure their plasma concentrations are increased their concentration is proportional to the severity of the disease. Endothelins promote vasoconstriction, inflammation, fibrosis, and hypertrophy in the pulmonary and systemic vasculature.

Plasma ET-1 levels are elevated in patients who have cardiomyopathy or chronic heart failure, and correlate with severity and prognosis. In particular, the degree of plasma elevation of endothelin correlates with the magnitude of alterations in cardiac hemodynamics and functional class.

In our material, higher pulmonary artery resistance was related to higher endothelin concentration in patients with single ventricle, therefore endothelin receptor antagonist could result in reduction of pulmonary resistance.
