Cardiovascular Function In Rats Research Articles

Acute Intermittent Hypoxia Induces Chemoreflex-Independent Sympathetic Plasticity and Improves Cardiovascular Function in a Rodent Model of Spinal Cord Injury

Background: Cardiovascular complications are one of the leading causes of morbidity and mortality in people with spinal cord injury (SCI). Activation of spinal sympathetic circuitry is critical to offset cardiovascular dysregulation and disease in those with high-level SCI. Acute intermittent hypoxia (AIH) elicits plasticity (i.e., a gradual increase in nerve activity post-AIH exposure) in phrenic and non-phrenic spinal motor circuitry and improves motor function — yet the cardiovascular benefits of AIH after SCI are largely unexplored. Aims: Determine mechanisms (Aim 1) and potential benefits (Aim 2) of AIH-induced sympathetic plasticity post-SCI. Hypothesis: We hypothesized that AIH elicits chemoreflex-dependent sympathetic plasticity and improves cardiovascular function in rats with SCI. Methods: For Aim 1, 40 adult (10-12 weeks) male Wistar rats were subjected to a spinal cord contusion injury (T3, 300 kdyn) and randomly assigned to 5 groups of 8 each: AIH alone, AIH after carotid body denervation (CBX, no peripheral chemoreflex), time control with no intervention (TC), simulated hemorrhage (to mimic AIH-induced hypotension), and AIH plus phenylephrine (to prevent hypotension during hypoxic episodes). Two weeks post-SCI recovery, rats were anesthetized with urethane (~2.1g.kg−1 i.v.) and underwent femoral venous and arterial catheterizations to monitor blood pressure (BP), sample arterial blood gases, and enable intravenous fluid and drug delivery. Additionally, splanchnic sympathetic nerve activity (sSNA) was recorded using a suction electrode at baseline and for up to 90-min following each experimental paradigm. AIH consisted of 10 x 1 min episodes of FiO2 = 0.1 (balanced N2) interspersed with 2 min of FiO2 = 1. Hexamethonium bromide (30 mg.kg−1) was infused to subtract noise levels from each recording, after which rats were euthanized with chloral hydrate. For Aim 2, 19 additional rats were subjected to the same injury model and time post-injury and allocated to 2 groups: AIH ( n = 11) and TC ( n = 8). These rats were instrumented with left-ventricular (LV) and arterial catheters and assessed simultaneously for cardiac and peripheral hemodynamic function at baseline and 90-min post-AIH/TC. Results: Aim 1) When expressed as % change from baseline, sSNA increased at 90-min post-treatment in AIH (93±67%, P = 0.02) and CBX (193±182%, P < 0.001), but not TC rats (50±45%, P = 0.40). Preventing BP reduction during hypoxic episodes with i.v. phenylephrine blocked the increase in sSNA 90-min post-AIH (12±66%, P > 0.99). Mimicking the AIH-induced BP reduction with simulated hemorrhage (10 x 1-min BP reductions of ~20-25 mmHg equal to those during AIH, interspersed by 2-min of euvolemia), increased sSNA 90-min post-intervention (106±86%, P = 0.01). Aim 2) The changes in maximal LV pressure (AIH = 11±8 mmHg vs. TC = 2±5 mmHg, P = 0.05) and mean arterial pressure (AIH = 8±7 mmHg vs. TC = 0±4 mmHg, P = 0.05) were greater at 90-min post-AIH treatment. Conclusions: We conclude that AIH elicits sympathetic plasticity and improves cardiovascular function post-SCI. Since AIH-induced sympathetic plasticity remains in the presence of a bilateral CBX, is replicated by episodic simulated hemorrhage, and is blocked by phenylephrine, AIH-induced sympathetic plasticity is independent of carotid (peripheral) chemoreflex activation, and is closely linked to episodic hypotension. We suggest that AIH-induced sympathetic plasticity arises from episodic reductions in spinal/medullary cardiovascular centers blood flow (and oxygen delivery) post-SCI. International Spinal Research Trust and Natural Sciences, Engineering Research Council of Canada, International Collaboration on Repair Discoveries. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant to treat partial seizures and neuropathic pain. While a majority of the side effects are associated with the nervous system, emerging evidence suggests a high risk for heart disease in the patients taking GBP. Given GBP can bind with high affnity to the α2δ subunits of voltage-gated Ca2+ channels (VGCCs) to block Ca2+ influx of cardiomyocytes, we hypothesize GBP suppresses cardiac function by evoking calcium signaling dysfunction. By using a preclinical rat model treated with GBP, we investigated (1) the acute cardiovascular responses to GBP (bolus i.v. injection; 50 mg/kg, 100 mg/ml x 0.1 ml in 3 min) and (2) the effects of chronic GBP treatment (i.p. 100 mg/kg/day x 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane-anesthesia, blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics of the rats were measured using two Millar pressure transducers; one was implanted in abdominal aorta via right femoral artery, and the another was implanted in the LV chamber via right carotid artery. The LV myocardium was analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction, with the brain cortex used as a control tissue. In experiment (1), we found that i.v. GBP treatment significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (*p < 0.05 and **p < 0.01 vs baseline; n = 4/group). This cardiovascular inhibition started at the injection time point and lasted at least 60 min, with a maximal effect appearing at 30 min post injection. In experiment (2), we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium of these rats, we used mass spectra to identify 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Particularly, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain, suggesting a myocardium-specific dysregulation of calcium signaling pathway, which may play a critical role in GBP-induced cardiac inhibition. Subsequent bioinformatics assays revealed a reduced Ca2+ release of sarcoplasmic reticulum (SR) and increased electrophoretic Ca2+ uptake into the matrix of mitochondria in the hearts of GBP-treated rats. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes where GBP binds to VGCCs to reduce extracellular Ca2+ influx and cytosolic Ca2+ release from SR, resulting in blockage of excitation-contraction coupling. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function. This project is funded by NIH R01 HL 160820. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats.

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant for the treatment of partial seizures and neuropathic pain. Whereas a majority of the side effects are associated with the nervous system, emerging evidence suggests there is a high risk of heart diseases in patients taking GBP. In the present study, we first used a preclinical model of rats to investigate, firstly, the acute cardiovascular responses to GBP (bolus i.v. injection, 50 mg/kg) and secondly the effects of chronic GBP treatment (i.p. 100 mg/kg/day × 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane anesthesia, rat blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics were measured using Millar pressure transducers. The LV myocardium and brain cortex were analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction. In the first experiment, we found that i.v. GBP significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (* p < 0.05 and ** p < 0.01 vs. baseline; n = 4). In the second experiment, we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium, we identified 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Notably, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.

Abstract 13324: Impact of Chronic Electronic Cigarette Vapor Exposure on the Recovery of Cardiovascular Function in Experimental Rat Myocardial Ischemia/Reperfusion Model

Background: The impact of long-term electronic cigarettes (E-cig) vaping on cardiovascular function in rats were investigated. Methods: Sprague Dawley rats (both sex, 6 weeks old) were randomly exposed to filtered air (n=32), E-cig with nicotine (E-cig Nic + , n=26), E-cig without nicotine (E-cig Nic - , n=26), or standard cigarette smoke (n=31). After exposure to inhalation exposure for 8 weeks, the rats were subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Cardiovascular function was measured with intracavitary Millar catheters and echocardiography during the surgical procedure. Results: As the data shown in the Table, at 2.5 hours after coronary artery reperfusion, heart rate, cardiac output and positive/negative LV dp/dt were lower in the E-cig Nic + group compared to the air and/or cigarette group. LVFS in the cigarette group was higher than compared to E-cig Nic + or air group. There was a significantly higher systemic arterial resistance in the E-cig Nic + group compared to the cigarette group. Conclusions: Chronic E-cig Nic + exposure impairs the cardiovascular function recovery during the phase of coronary artery reperfusion after heart attack, indicated by reductions of heart rate, cardiac output, LV positive and negative dp/dt (suggesting a reduction in contractility and relaxation); and increase in systemic arterial resistance in the setting of experimental acute myocardial infarction compared to air and/or standard cigarette smoke.

Intrauterine Growth Restriction Induces Adulthood Chronic Metabolic Disorder in Cardiac and Skeletal Muscles

ObjectiveAlthough population-based studies of intrauterine growth restriction (IUGR) demonstrated a series of postnatal complications, several studies identified that IUGR could definitely cause dysfunction of metabolism of cardiac and skeletal muscles in the perinatal period and early life. However, it is still unknown if such metabolic alternation would remain for long term or not, and whether normal protein diet administration postnatally would protect the IUGR offsprings from a “catch-up growth” and be able to reverse the premature metabolic remodeling.Materials and MethodsWe established an IUGR rat model with pregnant rats and a low-protein diet, and the developmental phenotypes had been carefully recorded. The cardiac and skeletal muscles had been collected to undergo RNA-seq.ResultsAccording to a series of comparisons of transcriptomes among various developmental processes, programmed metabolic dysfunction and chronic inflammation activity had been identified by transcriptome sequencing in IUGR offsprings, even such rats presented a normal developmental curve or body weight after normal postnatal diet feeding.ConclusionThe data revealed that IUGR had a significant adverse impact on long-term cardiovascular function in rats, even they exhibit good nutritional status. So that, the fetal stage adverse events would encode the lifelong disease risk, which could hide in young age. This study remaindered that the research on long-term molecular changes is important, and only nutrition improvement would not totally reverse the damage of IUGR.

Effects of C2 hemisection on respiratory and cardiovascular functions in rats.

High cervical spinal cord injuries induce permanent neuromotor and autonomic deficits. These injuries impact both central respiratory and cardiovascular functions through modulation of the sympathetic nervous system. So far, cardiovascular studies have focused on models of complete contusion or transection at the lower cervical and thoracic levels and diaphragm activity evaluations using invasive methods. The present study aimed to evaluate the impact of C2 hemisection on different parameters representing vital functions (i.e., respiratory function, cardiovascular, and renal filtration parameters) at the moment of injury and 7 days post-injury in rats. No ventilatory parameters evaluated by plethysmography were impacted during quiet breathing after 7 days post-injury, whereas permanent diaphragm hemiplegia was observed by ultrasound and confirmed by diaphragmatic electromyography in anesthetized rats. Interestingly, the mean arterial pressure was reduced immediately after C2 hemisection, with complete compensation at 7 days post-injury. Renal filtration was unaffected at 7 days post-injury; however, remnant systolic dysfunction characterized by a reduced left ventricular ejection fraction persisted at 7 days post-injury. Taken together, these results demonstrated that following C2 hemisection, diaphragm activity and systolic function are impacted up to 7 days post-injury, whereas the respiratory and cardiovascular systems display vast adaptation to maintain ventilatory parameters and blood pressure homeostasis, with the latter likely sustained by the remaining descending sympathetic inputs spared by the initial injury. A better broad characterization of the physiopathology of high cervical spinal cord injuries covering a longer time period post-injury could be beneficial for understanding evaluations of putative therapeutics to further increase cardiorespiratory recovery.

Abstract 13868: Effects of Chronic Electronic Cigarette Vapor Exposures on the Cardiovascular Function in Rats

Background: We investigated the effects of chronic electronic cigarettes with nicotine (E-Cig) exposure on cardiovascular function in rats. Methods: Adult Sprague Dawley rats were exposed to either pure air (n=10) or E-Cig (n=14) for 12 weeks. After 12 weeks of exposure, flow-mediated vasodilation was measured in anesthetized rats with ultrasound to measure femoral artery diameter. Femoral artery flow velocity was measured before and 5 minutes after reperfusion of a 5-minute femoral artery occlusion. Cardiac function was assessed by echocardiogram. A Millar catheter was used to record systemic arterial and LV pressures. Cardiac output was measured using a themodilution catheter. Results: The femoral artery internal diameter and blood flow velocity were comparable between the 2 groups before and after artery occlusion. However, in the E-cig group, blood flow velocity significantly decreased from 55.5 ± 5.2 cm/s prior to occlusion to 41.3 ± 4.1 cm/s after reperfusion (p = 0.005); it remained similar prior to (47.8 ± 3.4 cm/s) and after (47.8 ± 5.5 cm/s) occlusion in the air group. There were no statistically significant differences in left ventricular diastolic and systolic dimensions, LV fractional shortening, heart rate or mean blood pressure (80 ± 3 mmHg in air and 79 ± 5 mmHg in E-cig group) , LV end-diastolic pressure (Ped), end-systolic pressure (Pes), peak -dP/dt, Tau, or cardiac output (48.3 ± 3.3 ml/min in air and 47.6 ± 3.9 ml/min in E-cig group) between the E-Cig and the pure air group. There was a trend toward a reduction in peak LV +dP /dt in the E-Cig group (5574 ± 341 mmHg/s) compared to the air group (6166 ± 238 mmHg/s). LV weight and wall thickness were similar between groups. Conclusions: Twelve weeks of E-Cig exposure did not affect heart rate or blood pressure; but did tend to reduce contractility. E-cigarette exposure slowed the flow-mediated blood flow velocity probably at a microvascular level, possibly by altering endothelial function.

Effect of Entresto (valsartan+sacubitril) in the cardiac function and contractile response of detrusor and corpus cavernosum smooth muscles of heart failure rats.

IntroductionHeart failure (HF) has been closely related to the development of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). New pharmacological therapies aims to restore the neurohumoral balance, among these new proposals, stands out LCZ696 (Entresto), which consists of the association of the Valsartan (ANG‐II receptor antagonist, AT1R) with a Sacubitril (neprilysin inhibitor). However, there is no evidence evaluating the neurohumoral balance and the impact of Entresto on ED and LUTS associated with HF.ObjectiveWe aimed to Investigated the effect of in vitro treatment with Entresto (valsartan+sacubitril) on the contractile response of detrusor and corpus cavernosum (CC) muscles of control rats, as well as the effect of long‐term treatment with Entresto in the cardiovascular, urinary and erectile dysfunctions of HF rats.MethodsFor in vitro protocols, response concentration curves were constructed to phenylephrine (PHE; CC) and carbachol (CCh; detrusor), as well as, response frequency curves to electrical field stimulation (EFS; CC and detrusor) in the absence or presence of valsartan (10μM), sacubitril (10μM) or both drugs. For the chronic protocols, HF was surgically induced through the FAC model, and after 8 weeks, these animals were submitted to cardiac function evaluation (echocardiogram) and subdivided into 3 groups: Sham, HF and HF/Entresto (60mg/day for more 4 weeks). Response concentration curve were constructed to PHE (CC) and CCh (detrusor), and response frequency curve to EFS (CC and detrusor) for all groups. Culture human umbilical vein endothelial cell (HUVEC) monolayers were used to model the endothelial barrier. Electric cell‐substrate impedance sensing (ECIs) was used to study the contribution of valsartan, sacubitril or both drugs (10μM, respect.) to endothelial barrier function.ResultsIn vitro, valsartan, sacubitril or both drugs did not change the contractile responses in the CC or detrusor, independent of stimulated used in control animals. The HF animals presented both reduced of ejection and shortening fraction (p&lt;0.05), as well present cardiac hypertrophy (p&lt;0.05) when compared to the Sham group. Long‐term treatment with Entresto restored the ejection and shortening fraction in the HF/Entresto group (p&lt;0.05). In the CC of HF group the contractile response mediated by PE and EFS (p&lt;0.05) were increased compared to Sham group, being this hypercontractility restored by the Entresto treatment (p&lt;0.05). CCh and EFS induced detrusor smooth muscle contractions, which were greater in HF rats than in Sham rats. The treatment with Entresto restore the detrusor hypercontractility of HF rats (p&lt;0.05). Additionally, only the valsartan enhance the barrier function (P&lt;0.05) of HUVEC monolayer.ConclusionOur data provide evidence that Entresto chronic treatment, restore the detrusor‐ and CC‐contractile response due the improved of endothelial barrier and cardiovascular function in rats with HF, suggesting new multi‐therapeutic properties.Support or Funding InformationFAPESP 2011/21095‐4, CNPq 423987/2016‐0 and NIH R01GM20774

Ablating The Rab-GTPase Activating Protein TBC1D1 Predisposes Rats To High Fat Diet-Induced Cardiomyopathy

While the pathogenesis of diabetic cardiomyopathy is poorly understood, impaired insulin signalling within the heart is thought to contribute to the development of this pathology. TBC1D1, a Rab-GTPase activating protein, is involved in glucose homeostasis and substrate metabolism within skeletal muscle, however, the function of TBC1D1 within the heart is relatively unknown. PURPOSE: To examine the role of TBC1D1 in overall cardiac morphology and substrate utilization using a rat knock-out (KO) model. METHODS: 7 weeks of high-fat feeding was provided as a metabolic perturbation to further elucidate the interaction between TBC1D1 and diet-induced cardiac contractile function. Experiments were conducted at 12 weeks of age, with the exception of cardiomyocyte isolation, which was conducted at 7 weeks of age. Animals were anaesthetized with 2.5% isoflurane before assessments of cardiac function, or surgical removal of the left ventricle. The left ventricle was immediately utilized for bioenergetics assessments, fixed for histology or immediately frozen in liquid nitrogen for Western blotting. RESULTS: In chow-fed animals, TBC1D1 ablation increased plasma membrane GLUT4 content and glucose uptake, as well as plasma membrane FABPpm content and palmitate oxidation, consistent with activating cellular trafficking through the ablation of TBC1D1. While echocardiograms suggested indices of cardiac function were unaltered in chow fed KO animals, when challenged with a 7 week high-fat diet, TBC1D1 KO rats displayed a 4-fold increase in fibrosis in association with attenuated stroke volume, cardiac output and end diastolic volume, suggesting a predisposition to diet-induced cardiomyopathy. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were rates of mitochondrial hydrogen peroxide emission, or markers of oxidative stress. CONCLUSIONS: Altogether, ablation of TBC1D1 improves indices of cardiovascular function in rats fed a standard diet, but increases fibrosis and compromises indices of cardiac function in rats consuming a high-fat diet. Therefore, TBC1D1 may exert cardioprotective effects in the development of diabetic cardiomyopathy. This research is supported by NSERC funding.

Incremental effect of liraglutide on traditional insulin injections in rats with type 2 diabetes mellitus by maintaining glycolipid metabolism and cardiovascular function.

Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, damaged insulin secretion and insulin resistance with high morbidity and mortality. Liraglutide (liragl) and insulin are effective hypoglycemic agents used in T2DM treatment. The potential effect of liragl in combination with insulin on T2DM remains unclear. The aim of the current study was to explore effects of liragl combined with insulin on glycolipid metabolism and cardiovascular function in rats with diabetes. A diabetes model was established in Sprague Dawley rats exposed to a high calorie and high sugar diet in conjunction with intraperitoneal injections of streptozotocin. Results indicated that liragl or insulin used alone decreased glucose and elevated insulin and c-peptide levels. However, their combination revealed greater effects. A significant increase in high-density lipoprotein cholesterol levels along with a decrease in total cholesterol, triglycerides and low-density lipoprotein cholesterol were observed in liragl- and insulin-treated rats compared with STZ-induced diabetes rats. Furthermore, co-administration of liragl and insulin significantly decreased sterol regulatory element-binding protein 1 levels and increased adenosine 5'-monophosphate kinase-α1 and carnitine palmitoyltransferase 1 expression. Combining liragl with insulin reduced myocardial hypertrophy level and gaps between cardiomyocytes compared with liragl or insulin treatment alone. Caspase-3 expression was significantly decreased by combination treatment of liragl and insulin. Oxidative damage was significantly decreased by co-administration of liragl and insulin through enhancing superoxide dismutase expression and reducing malondialdehyde. Furthermore, combination of liragl and insulin significantly reduced myocardial enzyme expression, including myoglobin, creatine kinase-muscle/brain and cardiac troponin I. In summary, the current study demonstrated synergistic effects of liragl and insulin injections on a T2DM rat model by maintaining glycolipid metabolism and cardiovascular function.

Achacha (Garcinia humilis) Rind Improves Cardiovascular Function in Rats with Diet-Induced Metabolic Syndrome.

Garcinia humilis is a fruit known as achachairú. It is native to South American countries such as Bolivia, Peru, and Brazil, but it is also cultivated as achacha in northern Australia. The aim of this study was to determine the phytochemicals in achacha rind and pulp and to investigate these components as potential treatments for the symptoms of metabolic syndrome. Both rind and pulp contain procyanidins and citric acid rather than hydroxycitric acid. Male Wistar rats (8–9 weeks old) were fed with either high-carbohydrate, high-fat, or corn starch diets for 16 weeks. Intervention groups were fed with either diet supplemented with 1.5% G. humilis rind powder or 2.0% G. humilis pulp for the last 8 weeks of the protocol. Rats fed a high-carbohydrate, high-fat diet exhibited hypertension, dyslipidemia, central obesity, impaired glucose tolerance, and non-alcoholic fatty liver disease. G. humilis rind decreased systolic blood pressure, diastolic stiffness, left ventricular inflammatory cell infiltration, and collagen deposition in high-carbohydrate, high-fat diet-fed rats. However, there was no change in glucose tolerance, body weight, or body composition. Therefore, G. humilis rind, usually a food by-product, but not the edible pulp, showed potential cardioprotection with minimal metabolic changes in a rat model of diet-induced metabolic syndrome.

Pharmacological Evaluation of the Effects of Phenylcarbamic Acid Derivatives on Cardiovascular Functions in Rats

Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats' atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

Chronic testosterone administration improves cardiac contractility and has a beneficial effect on the haemostatic system by enhancing fibrinolytic activity and inducing hypocoagulation in healthy rats

This study investigated the effects of chronic supraphysiological dose of testosterone propionate administration cardiovascular function in rats from the perspective of haemostatic function including platelet functions, coagulation, and fibrinolysis. Testosterone significantly enhanced cardiac contractility by enhancing LVSP (10%), dp/dtmax (36.7%), dp/dtmin (14.6%) without altering heart rate, diastolic function, and serum lipid profile. While it has no effect on platelets count, thromboxane B2 levels, and platelet aggregation, testosterone significantly enhanced bleeding time and increased circulatory and thoracic aorta mRNA and protein levels of tPA (46.5%, 58.2%, and 74.3%, respectively) and significantly decreased those of PAI-1 (29.3%, 26.4%, and 32.8%, respectively). While there were no significant changes in PT and aPTT, mRNA and protein levels of prothrombin and factor VII were downregulated in the livers of the testosterone-treated rats (57.7% and 64.9%, respectively). Overall, chronic testosterone administration in rats may act as a cardio-protective agent by modulating haemostasis in rats.

Intermittent hypoxia in utero damages postnatal growth and cardiovascular function in rats

Obstructive sleep apnea (OSA) is common in pregnancy and may compromise fetal and even postnatal development. We developed an animal model to determine if maternal OSA could have lasting effects in offspring. Pregnant Sprague-Dawley rats were exposed to reduced ambient O2 from 21 to 4-5%, approximately once per minute [chronic intermittent hypoxia (CIH)] for 8 h/day during gestation days 3-19. Similarly handled animals exposed to ambient air served as controls (HC). Offspring were studied for body growth and cardiovascular function for 8 postnatal weeks. Compared with HC, prenatal CIH led to growth restriction, indicated by smaller body weight and tibial length, and higher arterial blood pressure in both male and female offspring. Compared with same-sex HC, CIH males showed abdominal obesity (greater ratio of abdominal fat weight to body weight or tibial length), left ventricular (LV) hypertrophy (greater heart weight-to-tibial length ratio and LV posterior wall diastolic thickness), elevated LV contractility (increases in LV ejection fraction, end-systolic pressure-volume relations, and preload recruitable stroke work), elevated LV and arterial stiffness (increased end-diastolic pressure-volume relationship and arterial elasticity), and LV oxidative stress (greater lipid peroxide content). Compared with female CIH offspring, male CIH offspring had more profound changes in blood pressure (BP), cardiac function, myocardial lipid peroxidase (LPO) content, and abdominal adiposity. Rodent prenatal CIH exposure, mimicking human maternal OSA, exerts detrimental morphological and cardiovascular effects on developing offspring; the model may provide useful insights of OSA effects in humans. NEW & NOTEWORTHY Obstructive sleep apnea is common in human pregnancy. Following maternal exposure to chronic intermittent hypoxia, a hallmark of sleep apnea, both sexes of rat offspring showed growth retardation, with males being more vulnerable to hypertension and dysfunctional left ventricular changes. This model is useful to study detrimental effects of maternal obstructive sleep apnea on developing offspring in humans.

Protective effects of resveratrol improve cardiovascular function in rats with diabetes.

Resveratrol is a flavonoid with a stilbene structure that is able to suppress acute pulmonary thromboembolism-induced pulmonary artery hypertension. Furthermore, it possesses anti-cancer and antioxidant properties, is able to regulate blood lipids and increase life expectancy. In the present study, it was evaluated whether the protective effect of resveratrol was able to improve cardiovascular function in rats with diabetes. The effects of resveratrol on blood glucose, body weight, heart/body weight ratio, plasma triglyceride levels, heart rate, aspartate transaminase (AST)/alanine transaminase (ALT) ratio and total plasma insulin were evaluated. Levels of inflammation and oxidative stress were also evaluated using ELISA kits, and the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphorylated (p)-p38 protein were evaluated via western blot analysis. The results demonstrated that administration of resveratrol in rats with diabetes-related myocardial infarction (DRMI) significantly reduced blood glucose, body weight, plasma triglyceride levels, heart rate and AST/ALT ratio (all P<0.01) and significantly increased total plasma insulin (P<0.01). Furthermore, resveratrol significantly reduced levels of inflammation factors (P<0.01) and malondialdehyde, a marker for oxidative stress, in rats with DRMI (P<0.01). Resveratrol significantly increased the expression of eNOS (P<0.01) and suppressed the expression of VEGF and p-p38 (both P<0.01) in rats with DRMI. These results suggest that treatment with resveratrol is able to improve cardiovascular function via inhibition of eNOS and VEGF, and suppression of p38 phosphorylation in rats with DRMI.

Effect of Voluntary Ethanol Consumption Combined with Testosterone Treatment on Cardiovascular Function in Rats: Influence of Exercise Training.

This study evaluated the effects of voluntary ethanol consumption combined with testosterone treatment on cardiovascular function in rats. Moreover, we investigated the influence of exercise training on these effects. To this end, male rats were submitted to low-intensity training on a treadmill or kept sedentary while concurrently being treated with ethanol for 6 weeks. For voluntary ethanol intake, rats were given access to two bottles, one containing ethanol and other containing water, three 24-hour sessions per week. In the last two weeks (weeks 5 and 6), animals underwent testosterone treatment concurrently with exercise training and exposure to ethanol. Ethanol consumption was not affected by either testosterone treatment or exercise training. Also, drug treatments did not influence the treadmill performance improvement evoked by training. However, testosterone alone, but not in combination with ethanol, reduced resting heart rate. Moreover, combined treatment with testosterone and ethanol reduced the pressor response to the selective α1-adrenoceptor agonist phenylephrine. Treatment with either testosterone or ethanol alone also affected baroreflex activity and enhanced depressor response to acetylcholine, but these effects were inhibited when drugs were coadministrated. Exercise training restored most cardiovascular effects evoked by drug treatments. Furthermore, both drugs administrated alone increased pressor response to phenylephrine in trained animals. Also, drug treatments inhibited the beneficial effects of training on baroreflex function. In conclusion, the present results suggest a potential interaction between toxic effects of testosterone and ethanol on cardiovascular function. Data also indicate that exercise training is an important factor influencing the effects of these substances.

A Radio-telemetric System to Monitor Cardiovascular Function in Rats with Spinal Cord Transection and Embryonic Neural Stem Cell Grafts

A Radio-telemetric System to Monitor Cardiovascular Function in Rats with Spinal Cord Transection and Embryonic Neural Stem Cell Grafts

A radio-telemetric system to monitor cardiovascular function in rats with spinal cord transection and embryonic neural stem cell grafts.

High thoracic or cervical spinal cord injury (SCI) can lead to cardiovascular dysfunction. To monitor cardiovascular parameters, we implanted a catheter connected to a radio transmitter into the femoral artery of rats that underwent a T4 spinal cord transection with or without grafting of embryonic brainstem-derived neural stem cells expressing green fluorescent protein. Compared to other methods such as cannula insertion or tail-cuff, telemetry is advantageous to continuously monitor blood pressure and heart rate in freely moving animals. It is also capable of long term multiple data acquisitions. In spinal cord injured rats, basal cardiovascular data under unrestrained condition and autonomic dysreflexia in response to colorectal distension were successfully recorded. In addition, cardiovascular parameters before and after SCI can be compared in the same rat if a transmitter is implanted before a spinal cord transection. One limitation of the described telemetry procedure is that implantation in the femoral artery may influence the blood supply to the ipsilateral hindlimb.

Cardiovascular effects of acute treatment with the antipsychotic drug olanzapine in rats

Treatment with antipsychotics is associated with adverse cardiovascular effects such as orthostatic hypotension and arrhythmias. Despite the higher prevalence of cardiovascular complications in patients with schizophrenia, the effects of antipsychotic drugs on vascular tone and cardiac contractility have received little attention. In order to better understand the cardiovascular effects of antipsychotic drugs, we investigated if the atypical antipsychotic olanzapine alters in vivo cardiovascular function in rats. Male Sprague–Dawley rats were prepared with indwelling catheters. After 4h of recovery from surgery, the mean arterial pressure (MAP), mean circulatory filling pressure (MCFP; index of body venous tone), heart rate, left ventricular peak systolic pressure (LVP) and cardiac contractility (±dP/dt) were measured in conscious, unrestrained rats for 60min after a single injection of olanzapine (3 or 15mg/kg, i.p.) or vehicle. Cardiovascular measurements were not altered at any time points in the vehicle-treated rats. Olanzapine did not affect heart rate, but dose-dependently decreased MAP, MCFP, LVP and +dP/dt. Acute olanzapine treatment in rats thus reduced blood pressure and venous tone, as well as cardiac contractile function. Decreased venous tone may be a contributing factor to orthostatic hypotension commonly observed in patients during initiation of antipsychotic therapy.

Evaluation of cardiovascular toxicity of carbon nanotubes functionalized with sodium hyaluronate in oral regenerative medicine.

It has been demonstrated that carbon nanotubes (CNTs) associated with sodium hyaluronate (HY-CNTs) accelerate bone repair in the tooth sockets of rats. Before clinical application of HY-CNTs, it is important to assess their biocompatibility. Moreover, cardiac toxicity may be caused by the translocation of these particles to the blood stream. The aim of this study was to evaluate possible changes in cardiovascular function in male Wistar rats whose tooth sockets were treated with either CNTs or HY-CNTs (100 μg/mL, 0.1 mL). Blood pressure and heart rate were monitored in conscious rats 7 days after treatment. Cardiac function was evaluated using the Langendorff perfusion technique. The data showed no changes in blood pressure or heart rate in rats treated with either CNTs or HY-CNTs, and no significant changes in cardiac function were found in any of the groups. To confirm these findings, experiments were conducted in rats injected intraperitoneally with a high concentration of either CNTs or HY-CNTs (0.75 mg/kg). The same parameters were analyzed and similar results were observed. The results obtained 7 days following injection indicate that the administration of low concentrations of CNTs or HY-CNTs directly into tooth sockets did not cause any significant change in cardiovascular function in the rats. The present findings support the possibility of using these biocomposites in humans.