Ventricle Of Rats Research Articles

Visualization of Unconjugated Bilirubin In Vivo with a Novel Approach Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging in a Rat Model.

Unconjugated bilirubin (UCB) visualization is valuable for early bilirubin encephalopathy (BE) diagnosis and management. UCB neurotoxicity is a challenge, necessitating improved imaging modalities for precise localization and characterization. This study developed a noninvasive method for UCB imaging in the brain using chemical exchange saturation transfer (CEST) magnetic resonance imaging, which visualizes UCB distribution through amide-bulk water proton exchange, a process termed bilirubin CEST (Bil-CEST) imaging. Bil-CEST imaging parameters were initially optimized; the exchange rate of the amide protons of UCB was calculated. Bil-CEST imaging characteristics and specificity were assessed using in vitro images of UCB solutions under different conditions and images of other brain metabolites. Bil-CEST maps of the rat brain were collected at the baseline and dynamically, postinjection of the UCB solution or vehicle into lateral ventricles of Sprague-Dawley rats. The model was validated using a water maze and pathological staining. In vitro, the Bil-CEST effect was observed at approximately 5.5 ppm downfield from bulk water. This effect was proportional to the UCB concentration and B1 amplitude. In vivo, Bil-CEST imaging revealed a progressive enhancement following a lateral ventricular UCB injection. Conversely, no significant imaging changes were observed in the vehicle group. Compared with the vehicle group, the UCB group had more hippocampal neuronal apoptosis and worse cognitive function. These findings highlight the utility of Bil-CEST in direct UCB imaging, indicating its potential as a clinically valuable biomarker for BE diagnosis and management.

Acclimation of Hairless Spontaneously Hypertensive Rat to Ambient Temperature Attenuates Hypertension-Induced Pro-Arrhythmic Downregulation of Cx43 in the Left Heart Ventricle of Males

Objectives: Due to poor treatment adherence and lifestyle-based interventions, chronic hypertension is a dominant risk factor predisposing individuals to heart failure and malignant arrhythmias. We investigated the impact of the postnatal acclimation of hairless SHR to ambient temperature that is, for them, below thermoneutrality, on the electrical coupling protein connexin-43 (Cx43) and pro-fibrotic markers in both heart ventricles of male and female hairless SHR rats compared to the wild SHR. Methods: Some 6-month-acclimated male and female hairless SHR as well as age- and sex-matched wild SHR were included and compared with the non-hypertensive Wistar strain. The left and right heart ventricles were examined for Cx43 topology, myocardial structure, and the histochemistry of capillaries. The protein levels of Cx43, relevant protein kinases, and extracellular matrix proteins (ECMs) were determined by immunoblotting. MMP-2 activity was assessed via zymography, and susceptibility to malignant arrhythmias was tested ex vivo. Results: Cx43 and its phosphorylated variant pCx43368 were significantly reduced in the left heart ventricles of wild SHR males, while to a lesser extent in the hairless SHR. In contrast, these proteins were not significantly altered in the right heart ventricles of males or in both heart ventricles in females, regardless of the rat strain. Pro-arrhythmic Cx43 topology was detected in the left heart ventricle of wild SHR and to a lesser extent in hairless SHR males. TGFβ protein was significantly increased only in the left ventricle of the wild SHR males. MMP-2 activity was increased in the right ventricle but not in the left ventricles of both males and females, regardless of the rat strain. Conclusions: The findings indicate that the postnatal acclimation of hairless SHR to ambient temperature hampers the downregulation of Cx43 in the left heart ventricle compared to wild SHR males. The decline of Cx43 was much less pronounced in females and not observed in the right heart ventricles, regardless of the rat strain. It may impact the susceptibility of the heart to malignant arrhythmias.

Influence of apamin on the extracellularly recorded action potentials profiles of subepicardial cardiomyocytes of the rat heart in myocardial infarction

The role of small-conductance Ca²⁺-activated K⁺-channels (SK channels) in the pathogenesis of cardiomyopathies of various etiologies remains poorly understood. The purpose of this work was to evaluate the effect of the blocker of SK channels, apamin, on the extracellularly recorded action potentials (eAPs) of subepicardial myocytes in the left ventricles of sham-operated rats and rats with myocardial infarction caused by ischemia-reperfusion. It was found that local delivery of the SK channel blocker apamin at a concentration of 500 nM to the eAP recording area did not affect the eAP profiles in the group of sham-operated rats but caused a significant slowdown in the repolarization time and a decrease in the afterhyperpolarization phase of eAPs in the group of rats with myocardial infarction. These data suggest that changes in the waveform of eAPs after infarction are associated with increased expression and/or activity of SK channels in subepicardial myocytes. The possible role of these channels in the structural and functional remodeling of the myocardium of the left ventricle of the heart after ischemia-reperfusion is discussed.

BA6b9, a novel sk4 K + channel blocker, attenuates atrial fibrillation substrate in rats with reduced ejection fraction

Abstract Background Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as novel druggable targets for efforts to treat AF. Methods and Findings We examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat post-myocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Interpretation Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

Astaxanthin Supplementation Effects in Right Ventricle of Rats Exposed to Chronic Intermittent Hypobaric Hypoxia.

Thirty two male Wistar rats were randomly assigned to the following groups (n = 8 per group): the normoxia with vehicle (NX), normoxia with astaxanthin (NX + AS), chronic intermittent hypobaric hypoxia with vehicle (CIHH), and chronic intermittent hypobaric hypoxia with astaxanthin (CIHH + AS) groups. CIHH was simulated by 2 days in a hypobaric chamber followed by 2 days at sea level for 29 days. Exposure to CIHH induced RVH and increased lipid peroxidation (MDA), Nox2 expression, and SOD activity, however, it decreased pro-IL-1β expression. Astaxanthin restored oxidative stress markers (Nox2 and MDA), increased GPx activity, and decreased RVH compared to CIHH. Astaxanthin alleviates RVH and reduces Nox2 and MDA levels while increasing GPx activity in rats subjected to CIHH. These findings provide new insights of astaxanthin as a new nutraceutical against high-altitude effects.

CEREBRAL MICROVASCULATURE IN AN EXCLUSIVELY FAT DIET MODEL

The microcirculation system plays a major role in the process of food intake and assimilation by the body. It ensures the distribution of oxygen and nutrients among neurons, taking into account their functional activity. The capillaries of the villi in the choroid plexus of cerebral ventricles remain the main source of cerebrospinal fluid production, which determines most physiological functions of the body. The aim of the study is to identify the peculiarities of remodeling of the microvasculature and vascular plexus of the third cerebral ventricle in rats kept exclusively on a fat diet. Materials and Methods. The work was performed on 20 white mongrel male rats (200–250 g.), divided into control and experimental groups. Animals of the control group were on a regular diet. Rats of the experimental group were fed exclusively with fatty food (sheep tail fat). On the 15th and 30th days, the animals were withdrawn from the experiment. A study of biochemical blood parameters (cholesterol, glucose, and protein) was carried out. After decapitation, the brain was fixed in formalin, brain sections were stained with hematoxylin and eosin (Van Gieson stain). The authors conducted light microscopy and morphometry on an Olympus B×40 microscope (Japan). Results. The animals showed a significant increase in the levels of cholesterol, glucose and albumin in the blood serum under an exclusively fat diet. By the 30th day of the experiment, the smooth muscles of the cerebral arteries undergo paresis, proteolysis, vacuolar dystrophy, hypoplasia with a sharp expansion of the vessel lumen. Signs of myoelastofibrosis are observed in the adventitia. Vein walls are thinned, the lumen is dilated, intravascular thrombi are observed. In the choroid plexus of the 3rd cerebral ventricle, a deficit of plasma flow through the sinusoidal capillaries with compensatory ependymocyte hyperfunction is noted. Conclusion. An exclusively fat diet leads to remodeling of the cerebral microvasculature, including the capillaries of the villi of the choroid plexus of the 3rd ventricle. All changes are compensatory and adaptive in nature. However, by the 30th day of the experiment, some of them become irreversible.

P164 SOLUBLE GUANYLATE CYCLASE STIMULATORS: AN EMERGING OPTION IN THE TREATMENT OF PRESSURE AND VOLUME OVERLOAD INDUCED CHRONIC HEART FAILURE

Pressure and volume overload-induced chronic heart failure (HF) is associated with characteristic cardiac remodeling and ventricular myocardial proteomic alterations, that can lead to the formation of a substrate for arrhythmias. Antiarrhythmic drug therapy is still suboptimal and current therapies are not efficacious enough. The purpose of the current study was therefore to examine the efficiency of nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) stimulator. We used as an experimental model male hypertensive Ren-2 transgenic rats (TGR) (n = 16), normotensive Hannover Sprague–Dawley rats (HSD, n = 17), and a volume-overload HF rat model induced by creating the aortocaval fistula (ACF) in rats of both strains (n = 27). Rats were after the induction of ACF treated by sGC stimulator BAY41-8543 (3 mg/kg/day for 30 weeks) alone or combined with angiotensin-converting enzyme inhibitor (ACEi) Trandolapril (0.25 mg/kg/day for 30 weeks). The age of the animals at the end of the experiment was 40 weeks. Left ventricle tissue and plasma samples were used for further analyses. Blood pressure (BP) was measured by telemetry. Combined treatment with sGC stimulator and ACEi was the most potent in lowering BP. Moreover, supplementation by sGC stimulator alone significantly decreased mortality and increased levels of the antioxidant enzyme superoxide dismutase 1, matrix metalloproteinase 2, total and phosphorylated connexin 43 as well as protein kinase C epsilon, implicated in remodeling of extracellular matrix and intercellular communication, in the left ventricle of TGR rats. Application of the sGC stimulator also slightly normalized elevated collagen deposition and hydroxyproline content in the left ventricular tissue of TGR rats. Unfortunately, we did not observe any effect of the sGC stimulator in the TGR ACF group. These results support the hypothesis that sGC stimulators might represent a class of drugs suitable for the prevention and treatment of related disorders in HF. This work was supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104. Supported by APVV-21-0410, VEGA 2/0006/23, and EXCELES LX22NPO5104.

Contrast efficacy of novel phase convertible nanodroplets for safe CEUS imaging

Microbubble contrast agents in ultrasound/echocardiography are used to increase the echogenicity of the target tissues, thereby raising the contrast resolution of the resultant image. Recently, the trend has shifted toward the development of phase-convertible nanodroplets as ultrasound contrast agents due to their promising theragnostic potential by switching capability at the active site. Herein, we fabricated pre-PGS- perfluoropentane phase convertible nanodroplets and checked their in vitro and in vivo enhancement and safety profile. For this, we performed experiments on 20 male Wistar rats and 2 dogs. Biochemical assays of both rats and dogs included complete blood profiles, liver function tests, and renal function tests. For rat vitals, monitoring and histopathological analysis were also performed. Converted nanodroplets showed excellent contrast enhancement, better than Sonovue upon in vitro testing, with an enhancement time of up to 14 min. In vivo, experiments showed comparable opacification of the ventricles of both rats and dogs. All biochemical assays remained within the normal range during the study period. The histopathological analysis did not show any signs of drug-induced toxicity, showing the safety of these nanodroplets. Pre-PGS-PFP nanodroplets hold great potential for use in echocardiography and abdominal imaging in both human and veterinary applications after clinical trials.

Chronic Partial Sleep Deprivation Increased the Incidence of Atrial Fibrillation by Promoting Pulmonary Vein and Atrial Arrhythmogenesis in a Rodent Model.

Sleep deprivation (SD) is a recognized risk factor for atrial fibrillation (AF), yet the precise molecular and electrophysiological mechanisms behind SD-induced AF are unclear. This study explores the electrical and structural changes that contribute to AF in chronic partial SD. We induced chronic partial SD in Wistar rats using a modified multiple-platform method. Echocardiography demonstrated impaired systolic and diastolic function in the left ventricle (LV) of the SD rats. The SD rats exhibited an elevated heart rate and a higher low-frequency to high-frequency ratio in a heart-rate variability analysis. Rapid transesophageal atrial pacing led to a higher incidence of AF and longer mean AF durations in the SD rats. Conventional microelectrode recordings showed accelerated pulmonary vein (PV) spontaneous activity in SD rats, along with a heightened occurrence of delayed after-depolarizations in the PV and left atrium (LA) induced by tachypacing and isoproterenol. A Western blot analysis showed reduced expression of G protein-coupled receptor kinase 2 (GRK2) in the LA of the SD rats. Chronic partial SD impairs LV function, promotes AF genesis, and increases PV and LA arrhythmogenesis, potentially attributed to sympathetic overactivity and reduced GRK2 expression. Targeting GRK2 signaling may offer promising therapeutic avenues for managing chronic partial SD-induced AF. Future investigations are mandatory to investigate the dose-response relationship between SD and AF genesis.

A high-precision view of intercompartmental drug transport via simultaneous, seconds-resolved, in situ measurements in the vein and brain.

The ability to measure specific molecules at multiple sites within the body simultaneously, and with a time resolution of seconds, could greatly advance our understanding of drug transport and elimination. As a proof-of-principle demonstration, here we describe the use of electrochemical aptamer-based (EAB) sensors to measure transport of the antibiotic vancomycin from the plasma (measured in the jugular vein) to the cerebrospinal fluid (measured in the lateral ventricle) of live rats with temporal resolution of a few seconds. In our first efforts, we made measurements solely in the ventricle. Doing so we find that, although the collection of hundreds of concentration values over a single drug lifetime enables high-precision estimates of the parameters describing intracranial transport, due to a mathematical equivalence, the data produce two divergent descriptions of the drug's plasma pharmacokinetics that fit the in-brain observations equally well. The simultaneous collection of intravenous measurements, however, resolves this ambiguity, enabling high-precision (typically of ±5 to ±20% at 95% confidence levels) estimates of the key pharmacokinetic parameters describing transport from the blood to the cerebrospinal fluid in individual animals. The availability of simultaneous, high-density 'in-vein' (plasma) and 'in-brain' (cerebrospinal fluid) measurements provides unique opportunities to explore the assumptions almost universally employed in earlier compartmental models of drug transport, allowing the quantitative assessment of, for example, the pharmacokinetic effects of physiological processes such as the bulk transport of the drug out of the CNS via the dural venous sinuses.

Participation of kisspeptin, progesterone, and GnRH receptors on lordosis behavior induced by kisspeptin

The neuropeptide kisspeptin (Kiss) is crucial in regulating the hypothalamic-pituitary-gonadal axis. It is produced by two main groups of neurons in the hypothalamus: the rostral periventricular region around the third ventricle and the arcuate nucleus. Kiss is the peptide product of the KiSS-1 gene and serves as the endogenous agonist for the GPR54 receptor. The Kiss/GPR54 system functions as a critical regulator of the reproductive system. Thus, we examined the effect of intracerebroventricular administration of 3 μg of Kiss to the right lateral ventricle of ovariectomized rats primed with a dose of 5 μg subcutaneous (sc) of estradiol benzoate (EB). Kiss treatment increased the lordosis quotient at all times tested. However, the lordosis reflex score was comparatively lower yet still significant compared to the control group. To investigate receptor specificity and downstream mechanisms on lordosis, we infused 10 μg of GPR54 receptor antagonist, Kiss-234, 5 μg of the progestin receptor antagonist, RU486, or 3 μg of antide, a gonadotropin-releasing hormone-1 (GnRH-1) receptor antagonist, to the right lateral ventricle 30 min before an infusion of 3 μg of Kiss. Results demonstrated a significant reduction in the facilitation of lordosis behavior by Kiss at 60 and 120 min when Kiss-234, RU486, or antide were administered. These findings suggest that Kiss stimulates lordosis expression by activating GPR54 receptors on GnRH neurons and that Kiss/GPR54 system is an essential intermediary by which progesterone activates GnRH.

Soluble guanylate cyclase stimulator as an emerging therapeutic option in the management of arrhythmias in heart failure rat model

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This research was supported by VEGA grant no. 2/0002/20 and 2/0006/23, the Slovak Research and Development Agency under contract no. 21-0410, European Regional Development Fund: ITMS2014+: 313011AVG3. This research was also partially supported by the Ministry of Health of the Czech Republic within the project for the development of the research organization [grant number 00023001 (IKEM)—institutional support] and also supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Program EXCELES, Project No. LX22NPO5104)—Funded by the European Union—Next Generation EU Heart failure (HF) is a complex clinical syndrome characterized by a decrease in the efficiency of the heart pump, leading to a decline in hemodynamic status and cardiac remodelling, that can contribute to the formation of a substrate for arrhythmias. Antiarrhythmic drug therapy is still suboptimal and current therapies are not efficacious enough. The purpose of the current study was therefore to examine the efficiency of nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) stimulator. We used as an experimental model male hypertensive Ren-2 transgenic rats (TGR, n = 16), normotensive Hannover Sprague–Dawley rats (HSD, n = 17), and a rat model of HF surgically induced by aortocaval fistula (ACF) in rats of both strains (n = 27). After ACF induction were rats treated by sGC stimulator BAY41-8543 (3 mg/kg/day for 30 weeks) alone or combined with angiotensin-converting enzyme inhibitor (ACEi) Trandolapril (0.25 mg/kg/day for 30 weeks). Age of the animals at the end of the experiment was 40 weeks. Left ventricle tissue and plasma samples were used for further analyses. Treatment by sGC stimulator significantly decreased rats' mortality, and systolic blood pressure, and significantly increased levels of antioxidant enzyme superoxide dismutase 1, matrix metalloproteinase 2, total and phosphorylated connexin 43 as well as protein kinase C epsilon, implicated in remodelling of extracellular matrix and intercellular communication, in the left ventricle of TGR rats. Application of sGC stimulator slightly normalized elevated collagen deposition and hydroxyproline content in the left ventricular tissue of TGR rats. Unfortunately, we did not observe any effect of the sGC stimulator in the TGR ACF group. These results support the hypothesis that sGC stimulators might represent a class of drugs suitable for combating heart failure with partially anti-arrhythmic potential, but further studies are needed.

Early Alteration of Right Ventricle-Pulmonary Artery Coupling in Experimental Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension and right ventricular (RV) dysfunction are major prognostic determinants in patients with heart failure with preserved ejection fraction (HFpEF). The underlying pathomechanisms remain unknown. In this context, we sought to study the pathogenesis of pulmonary hypertension and RV dysfunction in a rat model of obesity-associated HFpEF. HFpEF was induced in obesity-prone rats fed a high-fat diet (n=13) and compared with obesity-resistant rats fed with standard chow (n=9). After 12 months, the animals underwent echocardiographic and hemodynamic evaluation followed by tissue sampling for pathobiological assessment. HFpEF rats presented mild RV pressure overload (with increased RV systolic pressure and pulmonary vascular resistance). No changes in pulmonary artery medial thickness and exvivo vasoreactivity (to acetylcholine and endothelin-1) were observed and RNA sequencing analysis failed to identify gene clustering in HFpEF lungs. However, released nitric oxide levels were decreased in HFpEF pulmonary artery, while lung expression of preproendothelin-1 was increased. In HFpEF rats, RV structure and function were altered, with RV enlargement, decreased RV fractional area change and free wall longitudinal fractional shortening, together with altered right ventricle-pulmonary artery coupling (estimated by tricuspid annular plane systolic excursion/systolic pulmonary artery pressure). Hypertrophy and apoptosis (evaluated by transferase biotin- dUTP nick-end labeling staining) were increased in right and left ventricles of HFpEF rats. There was an inverse correlation between tricuspid annular plane systolic excursion/systolic pulmonary artery pressure and RV apoptotic rate. Plasma levels of soluble suppression of tumorigenicity-2, interleukin-1β, -6 and -17A were increased in HFpEF rats. Obesity-associated HFpEF in rats spontaneously evolves to pulmonary hypertension-HFpEF associated with impaired right ventricle-pulmonary artery coupling that appears disproportionate to a slight increase in RV afterload.

Morphological aspects of the heart of young rats subjected to high and medium intensity progressive resistance physical exercise protocols

Morphological aspects of the heart of young rats subjected to high and medium intensity progressive resistance physical exercise protocols

Brain-Derived Extracellular Vesicles from Dahl Salt-Sensitive Rats with High Salt Diet Increase PVN and SON Vasopressin Levels in Sprague Dawley rats

Extracellular vesicles (EVs), naturally secreted by almost all cell types, encapsulate a broad spectrum of biological molecules, and ferry these contents to the local and distal recipient cells. Under disease conditions, EV-to-cell communication can lead to diverse cell responses and changes. Previously we have demonstrated that brain-derived EVs from hypertensive rats increased inflammation and oxidative stress in primary neurons and hypothalamic paraventricular nucleus (PVN) of the brain, however, the long-term effects of EVs are unclear. PVN is a key hub to mediate blood pressure via its endocrine and autonomic control. Increased vasopressin (AVP) levels have been found in Dahl salt sensitive hypertensive rats, which are produced by PVN and supraoptic nucleus (SON). In this study, we hypothesized that brain-derived EVs from hypertensive rats regulate blood pressure via AVP system. To test this hypothesis, we first labeled brain-derived EVs with Rhodamine dye (Rho-EVs) and studied their bio-distribution via intracerebroventricular (i.c.v.) injection into the normal Sprague Dawley (SD) rats. Rats were euthanized 24 hours after injection, and brain sections containing the PVN and SON regions were stained to test the colocalization of Rho-EVs with neurons (NeuN), astrocytes (GFAP) and microglia (Iba1). Then we injected brain-derived EVs obtained from hypertensive Dahl salt sensitive rats (DSS-EVs) and normotensive Sprague Dawley rats (SD-EVs) into the lateral ventricle (8 μg/rat) in the SD male rats, and the injection was repeated 2 weeks later. Blood pressure and heart rates of each rat were monitored each week using telemetry transducers. 4 weeks post first EVs injections, rats were euthanized, their blood were tested for plasma AVP and norepinephrine (NE) levels, and their brains were tested for AVP and Fos-related antigen 1 (Fra1) mRNA levels. Besides, we also performed biweekly PVN (800 ng/rat) and SON (800ng/rat) injections of DSS-EVs and SD-EVs and measured the AVP and/or Fra1 protein levels with immunostaining. Lastly, we determined the colocalization of Rho-EVs with AVP-containing cells in the PVN and SON. Results show that Rho-EVs are dominantly taken up by neurons in both PVN and SON regions. Biweekly i.c.v. injections of DSS-EVs do not increase blood pressure and heart rate. However, DSS-EVs significantly upregulate mRNA levels of AVP (2.4-fold) and Fra1 (2.5-fold) in the PVN compared to SD-EVs. There is an increasing trend of plasma AVP levels in DSS-EV-treated rats compared to control. Biweekly PVN injections of DSS-EVs significantly increase AVP (1.5-fold) protein levels relative to SD-EVs, and biweekly SON injections of DSS-EVs significantly increase AVP (1.5-fold) and Fra1 (2.6-fold) protein levels relative to SD-EVs. Lastly, we found that Rho-EVs are mainly colocalized with vasopressin-containing cells in the SON. These results suggest that brain-derived EVs cause SON and PVN neuron activation, which in turn may regulate AVP system during hypertensive development. R01HL163159 (Shan); R15HL150703 (Shan); AHA 1807047 (Bi). 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.

The SK4 channel allosteric blocker, BA6b9, reduces atrial fibrillation substrate in rats with reduced ejection fraction.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as attractive druggable target for AF treatment. Here, we examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat postmyocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

The effect of physical activity of varying intensity on cardiomyocyte hypertrophy and myocardial polyploidy in rats

Regular exercise improves cognitive function, reduces the risk of premature death from cardiovascular disease, stroke, diabetes and improves quality of life.Aim: To study the morphological parameters of cardiomyocytes of the left ventricle of the heart and the proliferative activity of rat cardiomyocytes during physical activity of different intensity.Methodology and Research Methods. Outbred male rats (n = 30) were taken as experimental animals and divided into three series. The first series of rats were given light physical activity – the animals swam in the bath for 15 minutes. The animals of the second series were in the bath for 30 minutes (moderate severity), the third series were in the bath until they began to lose strength and sink (in 55–59 minutes). Animals were taken out of the experiment after 10 sessions of water loading. Some rats (5 animals per series) were slaughtered 30 days after the end of the experiment. After extraction, the heart was stained with hematoxylin and eosin, the amount of DNA in the nuclei of cardiomyocytes was determined, binuclear and Ki-67 positive cells were counted, and the diameter of cardiomyocytes was measured. Statistical analysis was carried out in the program “Statistica 10.0”.Results. Histological examination revealed changes only in the myocardium of the left ventricle of rats of the third series: pronounced dystrophic changes in cardiomyocytes. There were cells with necrobiosis, focal necrosis of groups of cardiomyocytes. The highest level of cardiomyocyte polyploidy occurred in the second and third series (the ratio of diploid and tetraploid cardiomyocytes in the control corresponded to 91.6 ± 7.4%; 8.2±6.3%). In these series, there was also a change in the number of binuclear cells (in the control – 12.7 ± 1.9‰). In all series of Ki-67 positive nuclei were not detected.Conclusion. Severe physical activity leads to structural disorders of the myocardium, persistent hypertrophy of cardiomyocytes and is accompanied by a decrease in the proliferative activity of cardiomyocytes.

Collagen Triple Helix Repeat-Containing Protein 1 Is a Novel Biomarker of Right Ventricular Involvement in Pulmonary Hypertension

BackgroundPulmonary hypertension leads to right ventricular failure, which is a major determinant of prognosis. Circulating biomarkers for right ventricular function are poorly explored in pulmonary hypertension. This study aimed to clarify the significance of collagen triple helix repeat-containing protein 1 (CTHRC1) as a biomarker of right ventricular failure in pulmonary hypertension. MethodsA monocrotaline-induced pulmonary hypertension rat model was used to evaluate right ventricular CTHRC1 expression and its relationship with fibrosis. Next, human plasma CTHRC1 levels were measured in controls (n = 20), pulmonary arterial hypertension (n = 46), and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (n = 64) before the first and after the final balloon pulmonary angioplasty. ResultsCTHRC1 expression was higher in the right ventricles of rats with monocrotaline-induced pulmonary hypertension than in those of controls. CTHRC1 was colocalized with vimentin and associated with fibrosis in the right ventricles. Plasma CTHRC1 levels were higher in human patients with pulmonary arterial hypertension (P = 0.006) and CTEPH (P = 0.011) than in controls. Plasma CTHRC levels were correlated with B-type natriuretic peptide (R = 0.355, P < 0.001), tricuspid lateral annular peak systolic velocity (R = –0.213, P = 0.029), and right ventricular fractional area change (R = –0.225, P = 0.017). Finally, plasma CTHRC1 levels were decreased after the final balloon pulmonary angioplasty (P < 0.001) in CTEPH. ConclusionsCTHRC1 can be a circulating biomarker associated with right ventricular function and fibrosis in pulmonary hypertension and might reflect the therapeutic efficacy of balloon pulmonary angioplasty in CTEPH.

Nicotinamide Riboside Attenuates Memory Impairment and Depressive-like Behavior in an Alzheimer’s Disease Animal Model

IntroductionDepression in Alzheimer’s disease (AD) differs from major depression in terms of clinical features and treatment. Antidepressants do not provide the expected benefits in depressive symptoms accompanying cognitive decline in AD, suggesting distinct mechanisms. Emerging research suggest that compromised mitophagy, the selective removal of damaged mitochondria, may contribute to the pathogenesis of AD. However boosting nicotinamide adenine dinucleotide (NAD+) to induce mitophagy reduces amyloid β (Aβ) aggregation and enhances cognitive function in AD models (Kerr et al.,Trends Neurosci 2017;40:151-66). Nevertheless, data on NAD’s impact on depression in AD remains limited.ObjectivesThis study aimed to examine the impact of the NAD+ precursor nicotinamide riboside (NR) on cognitive and neuropsychiatric symptoms in a AD rat model.MethodsTo induce the AD, a single dose of 5 μl Aβ1-42 was injected into each lateral ventricle of rats (day 0), while the control group received an intracerebroventricular (icv) saline (0.9%NaCl).Four experimental groups were designed: control (icv saline+po saline), NR (icv saline+po NR), Aβ (icv Aβ+po saline), and Aβ+NR (icv Aβ+po NR).After the injection, to reduce Aβ clearance (Kang et al. Science. 2009;32 1005-7.) rats were subjected to 96 hours of sleep deprivation.Starting from day 6, rats were given either 700 mg/kg oral NR or saline, and handling test scores were recorded daily.The procedures were repeated daily until the rats were sacrificed on day 28.Behavioral experiments were randomly conducted at the end, and statistical analysis was performed using repeated measures ANOVA, followed by the Tukey post hoc test.ResultsPassive avoidance test results showed that the Aβ group had the shortest latency to enter the dark area. However, the Aβ+NR group exhibited a prolonged latency compared to the Aβ group (F(3,2)=5.5;p&lt;0.05). Aβ injection induced depressive-like behavior in rats, as indicated by the forced swim test (FST) for behavioral despair and the sucrose preference test (SPT) for anhedonia. In AD rats treated with NR (Aβ+NR), Aβ-induced depressive-like behavior was reduced, with lower FST immobility scores (F(3,2)=6.2;p&lt;0.05) and increased sucrose preference in the SPT (F(3,2)=7.5;p&lt;0.05). There were no significant differences in anxiety-like behaviors among the groups, assessed by the time spent in the open arm in the elevated plus maze test (F(3,2)=1.9;p&gt;0.05). During the 28-day monitoring period, the Aβ+NR group of rats exhibited a more rapid decrease in aggression levels compared to the other groups in the handling test. This decrease was significant between days 7 and 10 compared to the Aβ group (F(48,5)=1.5;p&lt;0.05).ConclusionsNR improved memory, reduced depressive behavior, and lowered aggression in AD rats. This suggests that NAD+ precursor NR effectively treats cognitive decline and neuropsychiatric symptoms in an AD model.Disclosure of InterestNone Declared

Proteomic study of left ventricle and cortex in rats after myocardial infarction

Myocardial infarction (MI) induces neuroinflammation indirectly, chronic neuroinflammation may cause neurodegenerative diseases. Changes in the proteomics of heart and brain tissue after MI may shed new light on the mechanisms involved in neuroinflammation. This study explored brain and heart protein changes after MI with a data-independent acquisition (DIA) mode proteomics approach. Permanent ligation of the left anterior descending coronary artery (LAD) was performed in the heart of rats, and the immunofluorescence of microglia in the brain cortex was performed at 1d, 3d, 5d, and 7d after MI to detect the neuroinflammation. Then proteomics was accomplished to obtain the vital proteins in the heart and brain post-MI. The results show that the number of microglia was significantly increased in the Model-1d group, the Model-3d group, the Model-5d group, and the Model-7d group compared to the Sham group. Various proteins were obtained through DIA proteomics. Linking to key targets of brain disease, 14 proteins were obtained in the brain cortex. Among them, elongation of very long chain fatty acids protein 5 (ELOVL5) and ATP-binding cassette subfamily G member 4 (ABCG4) were verified through western blotting (WB). The results of WB were consistent with the proteomics results. Therefore, these proteins may be related to the pathogenesis of neuroinflammation after MI.