Uloga vazopresinskog sistema paraventrikularnog jedra u razvoju hipertenzije

Vazopresin ili antidiuretički hormon je peptidni molekul koji na vrlo složen način utiče na kardivovaskularnu i osmotsku homeostazu. Glavni izvori vazopresina su supraoptičko i paraventrikularno jedro hipotalamusa. Paraventrikularno jedro je ključna centralna stuktura u neuralnoj i endokrinoj regulaciji krvnog pritiska. Sastoji se od dve funkcionalne celine – neuroendokrine (sekretorne) i autonomne, koje su integralno povezane u modulaciji kardiovaskularnog odgovora na različite fiziološke zahteve. Neuroendokrini magnocelularni neuroni sintetišu i oslobađaju vazopresin u cirkulaciju, gde vazopresin ispoljava svoje hormonsko dejstvo. Jedan deo sintetisanog vazopresina oslobađa se i lokalno, unutar samog jedra, delujući kao neurotrasmiter/neuromodulator i utičući na signalizaciju okolnih neurona. Manja grupacija parvocelularnih neurona učestvuje u sekretornom odgovoru paraventrikularnog jedra na različite stresore, menjajujući aktivnost hipotalamo-hipofizno-nadbubrežne osovine. Autonomni deo paraventrikularnog jedra dire-ktno ili indirektno reguliše simpatičku aktivnost usmerenu ka kardiorenalnom sistemu. Brojne studije na životinjama i ljudima ukazuju na važnu vezu između nivoa sinteze vazopresina i nastanka hipertenzije. Različiti molekularno-biološki pristupi korišćeni su za procenu i izučavanje uticaja promene ekspresije i strukture centralnih i perifernih vazopresinskih receptora na krvni pritisak. Budući da je hipertenzija oboljenje sa izraženom incidencom u humanoj populaciji i da povećava rizik od razvoja kardiovaskularnih komplikacija visokog mortaliteta, od presudnog je značaja pronaći uzrok njenog nastanka. Rasvetljivanje mehanizama kojima vazopresinski sistem doprinosi genezi hipertenzije imalo bi veliki biomedicinski značaj i omogućilo bi razvoj antihipertenzivnih lekova nove generacije veće efikasnosti.Vasopressin or antidiuretic hormone is a peptide molecule that regulates osmotic and cardiovascular homeostasis in a complex manner. The main sources of vasopressin are the supraoptic and paraventricular nucleus of the hypothalamus. Paraventricular nucleus is the pivotal central structure involved in neural and endocrine regulation of blood pressure. It is composed of two functionally separate compartments – neuroendocrine (secretory) and autonomic, which integratively modulate cardiovascular response according to various physiological demands. Neuroendocrine magnocellular neurons are responsible for vasopressin synthesis and its secretion into the bloodstream, where vasopressin exerts hormonal effects. Some portion of synthesized vasopressin is released locally within the nucleus itself, acting as neurotransmitter/ neuromodulator and altering signalization of the surrounding neurons. Small amount of parvocellular neurons is involved in secretory response of the paraventricular nucleus to various stressors, changing the activity of hypothalamo-hypophyseal-adrenal axis. Autonomic part of the paraventricular nucleus directly or indirectly regulates the sympathetic charge toward the cardiorenal system. Numerous animal and human experimental studies indicate the important connection between vasopressin levels and the development of hypertension. Various genetic approaches have been used to determine and study the influence of expressional and structural changes in central and peripheral vasopressin receptors on blood pressure. Since hypertension shows high incidence in the human population and increases a risk for high mortality cardiovascular complications, it is essential to understand what causes it. Elucidating the mechanism behind vasopressin contribution to generate hypertension would have a significant biomedical impact and it would ensure the development of new generation antihypertensive drugs with increased efficacy

Voronoi Decomposition of Cardiovascular Dependency Structures in Different Ambient Conditions: An Entropy Study

This paper proposes a method that maps the coupling strength of an arbitrary number of signals D, D >= 2, into a single time series. It is motivated by the inability of multiscale entropy to jointly analyze more than two signals. The coupling strength is determined using the copula density defined over a [0 1](D) copula domain. The copula domain is decomposed into the Voronoi regions, with volumes inversely proportional to the dependency level (coupling strength) of the observed joint signals. A stream of dependency levels, ordered in time, creates a new time series that shows the fluctuation of the signals' coupling strength along the time axis. The composite multiscale entropy (CMSE) is then applied to three signals, systolic blood pressure (SBP), pulse interval (PI), and body temperature (t(B)), simultaneously recorded from rats exposed to different ambient temperatures (t(A)). The obtained results are consistent with the results from the classical studies, and the method itself offers more levels of freedom than the classical analysis

Copula as a dynamic measure of cardiovascular signal interactions

Objectives: Copula is a tool for measuring linear and non-linear interactions between two or more time series. The aim of this paper is to prove that a copula approach can accurately capture and visualize the spatial and temporal fluctuations in dependency structures of cardiovascular signals, and to outline the application possibilities. Methods: The method for measuring the level of interaction between systolic blood pressure and the corresponding pulse interval is validated statistically and pharmacologically. The time series are recorded from the freely moving male Wistar rats equipped with radio-telemetry device for blood pressure recording, before and after administration of autonomic blockers scopolamine, atenolol, prazosin and hexamethonium. Implicit (Gaussian and t) and explicit (Clayton, Frank and Gumbel) copulas were calculated and compared to the conventional bivariate methods (Kendal, Pearson, Spearman and classical correlation). Further statistical validation was done using artificially generated surrogate data. A window sliding procedure for dynamic monitoring the signals' coupling strength is implemented. Results: Under the baseline physiological conditions, SBP-PI dependency is significant for time lags 0 s-4 s. Hexamethonium completely abolished the dependency, scopolamine abolished it for time lags 0 s-2 s, atenolol first slightly increased, than for lags greater than 2 s decreased the dependency and prazosin had no effect. Isospectral and isodistributional surrogate data tests confirm that copulas successfully notify the absence of dependency as well. Conclusion: Copula approach accurately captures the temporal fluctuations in dependency structures of SBP and PI, simultaneously enabling a visualization of dependency levels within the particular signal zones. An analysis showed that copulas are more sensitive than the conventional statistical measures, with Frank copula exhibiting the best characterization of SBP and PI dependency

Sudden death: Neurogenic causes, prediction and prevention

Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation

Overexpression of oxytocin receptors in the hypothalamic PVN increases baroreceptor reflex sensitivity and buffers BP variability in conscious rats

BACKGROUND AND PURPOSE: The paraventricular nucleus (PVN) of the hypothalamus is an important integrative site for neuroendocrine control of the circulation. We investigated the role of oxytocin receptors (OT receptors) in PVN in cardiovascular homeostasis. EXPERIMENTAL APPROACH: Experiments were performed in conscious male Wistar rats equipped with a radiotelemetric device. The PVN was unilaterally co-transfected with an adenoviral vector (Ad), engineered to overexpress OT receptors, and an enhanced green fluorescent protein (eGFP) tag. Control groups: PVN was transfected with an Ad expressing eGFP alone or untransfected, sham rats (Wt). Recordings were obtained without and with selective blockade of OT receptors (OTX), during both baseline and stressful conditions. Baroreceptor reflex sensitivity (BRS) and cardiovascular short-term variability were evaluated using the sequence method and spectral methodology respectively. KEY RESULTS: Under baseline conditions, rats overexpressing OT receptors (OTR) exhibited enhanced BRS and reduced BP variability compared to control groups. Exposure to stress increased BP, BP variability and HR in all rats. In control groups, but not in OTR rats, BRS decreased during stress. Pretreatment of OTR rats with OTX reduced BRS and enhanced BP and HR variability under baseline and stressful conditions. Pretreatment of Wt rats with OTX, reduced BRS and increased BP variability under baseline and stressful conditions, but only increased HR variability during stress. CONCLUSIONS AND IMPLICATIONS: OT receptors in PVN are involved in tonic neural control of BRS and cardiovascular short-term variability. The failure of this mechanism could critically contribute to the loss of autonomic control in cardiovascular disease

Autonomic mechanisms underpinning the stress response in borderline hypertensive rats

This study investigates blood pressure (BP) and heart rate (HR) short-term variability and spontaneous baroreflex functioning in adult borderline hypertensive rats and normotensive control animals kept on normal-salt diet. Arterial pulse pressure was recorded by radio telemetry. Systolic BP, diastolic BP and HR variabilities and baroreflex were assessed by spectral analysis and the sequence method, respectively. In all experimental conditions (baseline and stress), borderline hypertensive rats exhibited higher BP, increased baroreflex sensitivity and resetting, relative to control animals. Acute shaker stress (single exposure to 200 cycles min-1 shaking platform) increased BP in both strains, while chronic shaker stress (3-day exposure to shaking platform) increased systolic BP in borderline hypertensive rats alone. Low- and high-frequency HR variability increased only in control animals in response to acute and chronic shaker (single exposure to restrainer) stress. Acute restraint stress increased BP, HR, low- and high-frequency variability of BP and HR in both strains to a greater extent than acute shaker stress. Only normotensive rats exhibited a reduced ratio of low- to high-frequency HR variability, pointing to domination of vagal cardiac control. In borderline hypertensive rats, but not in control animals, chronic restraint stress (9-day exposure to restrainer) increased low- and high-frequency BP and HR variability and their ratio, indicating a shift towards sympathetic cardiovascular control. It is concluded that maintenance of BP in borderline hypertensive rats in basal conditions and during stress is associated with enhanced baroreflex sensitivity and resetting. Imbalance in sympathovagal control was evident only during exposure of borderline hypertensive rats to stressors

Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats

Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5mg/kg), HPMA-DOX (5mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs