Nina Japundžić-Žigon

Blockade of central vasopressin receptors reduces the cardiovascular response to acute stress in freely moving rats

To investigate the contribution of central vasopressin receptors to blood pressure (BP) and heart rate (HR) response to stress we injected non-peptide selective V(1a) (SR49059), V(1b) (SSR149415), V(2) (SR121463) receptor antagonists, diazepam or vehicle in the lateral cerebral ventricle of conscious freely moving rats stressed by blowing air on their heads for 2 min. Cardiovascular effects of stress were evaluated by analyzing maximum increase of BP and HR (MAX), latency of maximum response (LAT), integral under BP and HR curve (integral), duration of their recovery and spectral parameters of BP and HR indicative of increased sympathetic outflow (LF(BP) and LF/HF(HR)). Moreover, the increase of serum corticosterone was measured. Exposure to air-jet stress induced simultaneous increase in BP and HR followed by gradual decline during recovery while LF(BP) oscillation remained increased as well as serum corticosterone level. Rats pre-treated with vasopressin receptor antagonists were not sedated while diazepam induced sedation that persisted during exposure to stress. V(1a), V(1b) and V(2) receptor antagonists applied separately did not modify basal values of cardiovascular parameters but prevented the increase in integral(BP). In addition, V(1b) and V(2) receptor antagonists reduced BP(MAX) whereas V(1a), V(1b) antagonist and diazepam reduced HR(MAX) induced by exposure to air-jet stress. All drugs shortened the recovery period, prevented the increase of LF(BP) without affecting the increase in serum corticosterone levels. Results indicate that vasopressin receptors located within the central nervous system mediate, in part, the cardiovascular response to air-jet stress without affecting either the neuroendocrine component or inducing sedation. They support the view that the V(1b) receptor antagonist may be of potential therapeutic value in reducing arterial pressure induced by stress-related disorders.

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.

Central cholinergic modulation of blood pressure short-term variability.

The role of neurally born acetylcholine in the central modulation of cardiovascular short-term variability was assessed using a pharmacological probe physostigmine, a cholinesterase inhibitor that can act centrally also. Experiments were performed in instrumented conscious rats. Equidistant sampling at 20 Hz of systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR) allowed direct spectral analysis. Spectra were analysed in the whole, very-low frequency (VLF), low-frequency (LF) and high-frequency (HF) domains. Physostigmine, but not neostigmine, increased SAP, LF SAP and HF SAP variability while neostigmine, but not physostigmine, decreased HR without affecting HR variability. Atropine methyl nitrate prevented neostigmine-induced bradycardia and potentiated the effects of physostigmine on DAP, LF DAP and HF DAP variability. Atropine sulphate, hexamethonium, phentolamine and metoprolol inhibited physostigmine-induced increase of SAP and LF SAP. Pre-treatment of rats by quinapril prevented physostigmine-induced increase of SAP, but not of LF SAP, while the V(1a) antagonist prevented the increase of HF SAP. The results suggest that central cholinergic neurons facilitate but do not create LF SAP and HF SAP variability. The effect of physostigmine on LF SAP seems to be mediated via central muscarinic sites and the peripheral sympathetic system, while non-muscarinic central sites and vasopressin pathways subserve the increase of HF SAP.

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

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.

Central vasopressin V(1a) and V(1b) receptors modulate the cardiovascular response to air-jet stress in conscious rats.

Abstract This study investigates the contribution of central vasopressin receptors in the modulation of systolic arterial pressure (SAP) and heart rate (HR) response to air-jet stress in conscious Wistar rats equipped with a femoral arterial catheter and intracerebroventricular cannula using novel non-peptide and selective vasopressin V1a (SR49059) and V1b (SSR149415) antagonists. The effects of stress on SAP and HR were evaluated by measuring the maximal response to stress, the latency of the maximal response, the duration of the recovery period, and the increase in the low frequency (LF) short-term variability component. Stress induced a parallel and almost immediate increase in both SAP and HR, followed by enhanced LF SAP variability in the recovery period. Pretreatment of rats with V1a antagonist did not affect the maximal increase or the latency of SAP and HR response to acute stress, but shortened the recovery period of SAP and HR and prevented the increase in LF SAP. The V1b antagonist reduced the maximal increase in SAP without affecting HR and their latencies, shortened the recovery period of SAP and inhibited the increase in LF SAP variability. These results indicate that both central V1a and V1b receptors mediate cardiovascular changes induced by air-jet stress in conscious rats.

Evidence for involvement of central vasopressin V1b and V2 receptors in stress-induced baroreflex desensitization

It is well recognized that vasopressin modulates the neurogenic control of the circulation. Here, we report the central mechanisms by which vasopressin modulates cardiovascular response to stress induced by immobilization.

Vasopressin, Central Autonomic Control and Blood Pressure Regulation

Purpose of ReviewWe present recent advances in understanding of the role of vasopressin as a neurotransmitter in autonomic nervous system control of the circulation, emphasizing hypothalamic mechanisms in the paraventricular nucleus (PVN) involved in controlling sympathetic outflow toward the cardiovascular system.Recent FindingsSuggest that somato-dendritically released vasopressin modulates the activity of magnocellular neurons in the PVN and SON, their discharge pattern and systemic release. Advances have been made in uncovering autocrine and paracrine mechanisms controlling presympathetic neuron activity, involving intranuclear receptors, co-released neuroactive substances and glia.SummaryIt is now obvious that intranuclear release of vasopressin and the co-release of neuroactive substances in the PVN, as well as the level of expression of vasopressin receptors, modulate sympathetic outflow to the cardiovascular system and determine vulnerability to stress. Further research involving patho-physiological models is needed to validate these targets and foster the development of more efficient treatment.

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

Abstract 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 (5 mg/kg), HPMA–DOX (5 mg 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.

Over-expression of V1A receptors in PVN modulates autonomic cardiovascular control.

The hypothalamic paraventricular nucleus (PVN) is a key integrative site for the neuroendocrine control of the circulation and of the stress response. It is also a major source of the neuropeptide hormone vasopressin (VP), and co-expresses V1a receptors (V1aR). We thus sought to investigate the role of V1aR in PVN in cardiovascular control in response to stress. Experiments were performed in male Wistar rats equipped with radiotelemetric device. The right PVN was transfected with adenoviral vectors (Ads) engineered to over-express V1aR along with an enhanced green fluorescent protein (eGFP) tag. Control groups were PVN transfected with Ads expressing eGFP alone, or wild-type rats (Wt). Rats were recorded with and without selective blockade of V1aR (V1aRX) in PVN under both baseline and stressed conditions. Blood pressure (BP), heart rate (HR), their short-term variabilities, and baroreflex sensitivity (BRS) were evaluated using spectral analysis and the sequence method, respectively. Under baseline physiological conditions,V1aR rats exhibited reduced BRS and a marked increase of BP and HR variability during exposure to stress. These effects were all prevented by V1aRX pretreatment. In Wt rats, V1aRX did not modify cardiovascular parameters under baseline conditions, and prevented BP variability increase by stress. However, V1aRX pretreatment did not modify baroreflex desensitization by stress in either rat strain. It follows that increased expression of V1aR in PVN influences autonomic cardiovascular regulation and demarcates vulnerability to stress. We thus suggest a possible role of hypothalamic V1aR in cardiovascular pathology.

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.