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Professor Andrzej Trzebski

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In spite of significant progress in pharmacotherapy the incidence of newly diagnosed cases of cardiovascular diseases and cardiovascular morbidity is alarmingly high. Treatment of hypertension or heart failure still remains a serious challenge. Continuous attempts are made to identify the mechanisms that decide about susceptibility to pathogenic factors, and to determine effectiveness of a specific therapeutic approach. Coincidence of cardiovascular diseases with metabolic disorders and obesity has initiated intensive research for their common background. In the recent years increasing attention has been drawn to disproportionately greater number of depressive disorders and susceptibility to stress in patients with coronary artery disease. An opposite relationship, i.e. a greater number of sudden cardiovascular complications in patients with depression, has been also postulated. Progress in functional neuroanatomy and neurochemistry provided new information about the neural network responsible for regulation of cardiovascular functions, metabolism and emotionality in health and under pathological conditions. In this review we will focus on the role of neuromodulators and neurotransmitters engaged in regulation of the cardiovascular system, neuroendocrine and metabolic functions in health and in pathogenesis of cardiovascular diseases and obesity. Among them are classical neurotransmitters (epinephrine and norepinephrine, serotonin, GABA), classical (CRH, vasopressin, neuropeptide Y) and newly discovered (orexins, apelin, leptin IL-1ßeta, TNF-alpha, ghrelin) neuropeptides, gasotransmitters, eicozanoids, endocannabinoids, and some other compounds involved in regulation of neuroendocrine, sympatho-adrenal and parasympathetic nervous systems. Special attention is drawn to those factors which play a role in immunology and inflammatory processes. Interaction between various neurotransmitter/neuromodulatory systems which may be involved in integration of metabolic and cardiovascular functions is analyzed. The survey gives evidence for significant disturbances in release or action of the same mediators in hypertension heart failure, obesity, diabetes mellitus, metabolic syndrome, starvation, chronic stress, depression and other psychiatric disorders. With regard to the pathogenic background of the cardiovascular diseases especially valuable are the studies showing inappropriate function of angiotensin peptides, vasopressin, CRH, apelin, cytokines and orexins in chronic stress, cardiovascular and metabolic diseases. The studies surveyed in this review suggest that multiple brain mechanisms interact together sharing the same neural circuits responsible for adjustment of function of the cardiovascular system and metabolism to current needs.
Increasing evidence suggests that enhanced stimulation of the heart and kidney by mineralocorticoids plays significant role in development of the post-infarct cardiac failure. Because increased synthesis of mineralocorticoid receptors (MR) is one of the putative factors determining pathogenic effects of mineralocorticoids we decided to determine whether the myocardial infarct results in an enhanced expression of MR mRNA and MR protein. To this end male Sprague-Dawley rats were subjected either to ligation of the left coronary artery or to sham surgery. After four weeks expressions of MR mRNA and MR protein were evaluated in both groups of rats in the left (LV) and right (RV) ventricle walls, and in the renal cortex and renal medulla by means of semiquantitative PCR and Western blotting methods. Coronary ligation resulted in the myocardial infarction encompassing 30.2% ± 1.9% (range 23-40%) of the left ventricle wall. In the infarcted rats expression of MR mRNA was significantly greater than in the sham-operated rats, both in the LV (P<0.02) and in the RV (P<0.005). In the left but not in the right ventricle increased MR mRNA expression was associated with significant increase in expression of MR protein (P<0.001). In the renal cortex and renal medulla MR mRNA and MR protein expression in the infarcted and the sham-operated rats did not differ. The study reveals that during the post-infarct state expression of MR mRNA is elevated in both cardiac ventricles while expression of MR mRNA protein is increased only in the left ventricle. The results suggest that the enhanced expression of mineralocorticoid receptors may contribute to enhanced effects of mineralocorticoids in the heart during the post-infarct state.
The myocardial infarct causes prolonged activation of the renin-angiotensin system and profoundly influences cardiac performance and renal excretory capabilities. The aim of the present study was to determine whether the myocardial infarct is also associated with an altered expression of AT1a receptors (AT1aR) mRNA in the heart and the kidney. To this end male Sprague-Dawley rats were subjected either to the left coronary artery ligation or to the sham surgery. Four weeks after the surgery the animals were sacrificed. In 11 infarcted and 10 sham-operated rats expression of AT1aR mRNA in the walls of the left and right ventricle of the heart, and in the renal cortex and renal medulla was determined by semiquantitative PCR method. In another group of 10 infarcted and 14 sham-operated rats the diameter of cardiomyocytes in the left and right cardiac ventricle was determined. The size of the infarct in the rats used for mRNA determination and for morphometric measurements was equal to 29.4 ± 1.8% and to 31.0 ± 1.2 % of the left ventricular wall, respectively. Expression of AT1aR mRNA was significantly greater in the left (P< 0.01) and right ventricle (P<0.03) of the heart in the infarcted than in the sham operated rats. AT1aR mRNA expression was also significantly greater (P<0.02) in the renal medulla of the infarcted rats than in the renal medulla of the sham operated rats whereas no significant difference was found in the renal cortex. The myocardial infarct was associated with a significant increase of diameter of cardiomyocytes of the left ventricle of the heart (P < 0.0001), however there was no significant correlation between changes in AT1aR mRNA expression and diameter of cardiomyocytes. The results provide evidence that the myocardial infarct results in significant and prolonged upregulation of AT1a receptors mRNA expression in the heart and in the medullary region of the kidney.
The purpose of the study was to determine effect of high sodium intake on fluid and electrolyte turnover and heart remodeling in the cardiac failure elicited by myocardial infarction (MI). The experiments were performed on four groups of Sprague Dawley rats maintained on food containing 0.45% NaCl and drinking either water (groups 1, 2) or 1% NaCl (groups 3, 4). Groups 1 and 3 were sham-operated while in groups 2 and 4 MI was produced by the coronary artery ligation. In each group food and fluid as well as sodium intake, urine (Vu), sodium (UNaV), potassium (UKV) and solutes (UosmV) excretion were determined before and four weeks after the surgery. Size of the infarct, left ventricle (LV) weight and diameter of LV and right ventricle (RV) myocytes were determined during post-mortem examination. Before the surgery groups 3 and 4 ingested significantly more fluid and sodium, had higher Vu, UNaV, UKV and UosmV than the respective groups 1 and 2. In groups 2 and 4 MI resulted in significant decrease in Vu, UNaV and UosmV in comparison to the pre-surgical level. In Group 4 MI resulted also in a significant decrease of food and sodium intake. The MI size did not differ in groups 2 and 4 while diameter of LV myocytes was significantly greater in groups 2 and 4 than in groups 1 and 3, and in group 4 than in group 2. The study reveals that prolonged high sodium consumption increases fluid and electrolyte turnover both in the sham and in the MI rats and that the MI causes decrease in food and sodium intake in rats on high but not on regular sodium intake. In addition high sodium diet promotes development of greater post-MI hypertrophy of the LV myocytes.
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