Normotensive Control Rats Research Articles

Comparison of Cardioprotective Potential of Cannabidiol and β-Adrenergic Stimulation against Hypoxia/Reoxygenation Injury in Rat Atria and Ventricular Papillary Muscles

Background: Hypoxia is one of the most significant pathogenic factors in cardiovascular diseases. Preclinical studies suggest that nonpsychoactive cannabidiol (CBD) and β-adrenoceptor stimulation might possess cardioprotective potential against ischemia-reperfusion injury. The current study evaluates the influence of hypoxia-reoxygenation (H/R) on the function of atria and ventricular papillary muscles in the presence of CBD and the nonselective β-adrenoceptor agonist isoprenaline (ISO). Methods: The concentration curves for ISO were constructed in the presence of CBD (1 µM) before or after H/R. In chronic experiments (CBD 10 mg/kg, 14 days), the left atria isolated from spontaneously hypertensive (SHR) and their normotensive control (WKY) rats were subjected to H/R following ISO administration. Results: Hypoxia decreased the rate and force of contractions in all compartments. The right atria were the most resistant to hypoxia regardless of prior β-adrenergic stimulation. Previous β-adrenergic stimulation improved recovery in isolated left atria and right (but not left) papillary muscles. Acute (but not chronic) CBD administration increased the effects of ISO in left atria and right (but not left) papillary muscles. Hypertension accelerates left atrial recovery during reoxygenation. Conclusion: H/R directly modifies the function of particular cardiac compartments in a manner dependent on cardiac region and β-adrenergic prestimulation. The moderate direct cardioprotective potential of CBD and β-adrenergic stimulation against H/R is dependent on the cardiac region, and it is less than in the whole heart with preserved coronary flow. In clinical terms, our research expands the existing knowledge about the impact of cannabidiol on cardiac ischemia, the world′s leading cause of death.

Exaggerated postnatal surge of orexin neurons and the effects of elimination of excess orexin on blood pressure and exaggerated chemoreflex in spontaneously hypertensive rats.

An overactive orexin (OX) system is associated with neurogenic hypertension and an exaggerated chemoreflex in spontaneously hypertensive rats (SHRs). However, the chronology and mechanism of this association is unclear. We hypothesized that increased postnatal neurogenesis of OX neurons in SHRs precedes and contributes to the aberrant increase in mean arterial blood pressure (MAP) and the exaggerated response to hypercapnia during postnatal development. Using immunohistochemical methods and bromodeoxyuridine, we mapped the timeline of orexin neuron neurogenesis and maturation during early postnatal development. We then used whole-body plethysmography with EEG and EMG to map the development of mean arterial pressure (MAP) and state regulation. Finally, we used OX-targeted saporin toxin to determine the effects of eliminating excess OX neurons on the elevated MAP and exaggerated chemoreflex in adult SHRs. We found that both SHRs and Wistar-Kyoto (WKY) rats experienced postnatal increases in OX neurons. However, SHRs experienced a greater increase than WKY rats before P15, which led to significantly more OX neurons in SHRs than age-matched WKY controls by P15-16 (3,720 ± 780 vs. 2,406 ± 363, p = 0.005). We found that neurogenesis, as evidenced by BrdU staining in OX-positive neurons, was the primary contributor to the excess OX neurons in SHRs during early postnatal development. While SHRs develop more OX neurons by P15-16, SHRs and normotensive WKY control rats have similar MAP during postnatal development until P25 in wakefulness (81.6 ± 6.6 vs. 67.5 ± 6.8mmHg, p = 0.006) and sleep (79.3 ± 6.1 vs. 66.6 ± 6.5, p = 0.009), about 10 days after the surge of OX neurons. By selectively eliminating excess (∼30%) OX neurons in SHRs, we saw a significantly lowered MAP and hypercapnic ventilatory chemoreflex compared to non-lesioned SHRs at P40. Additionally, we found unique signatures in state indicative of the attention defecit phenotype commonly associated with this model. We suggest that the postnatal increase of OX neurons, primarily attributed to exaggerated postnatal OX neurogenesis, may be necessary for the development of higher MAP and exaggerated chemoreflex in SHRs, and modulation of the overactive OX system may have a potential therapeutic effect during the pre-hypertensive period.

Microbiota-derived acetate attenuates neuroinflammation in rostral ventrolateral medulla of spontaneously hypertensive rats.

Increased neuroinflammation in brain regions regulating sympathetic nerves is associated with hypertension. Emerging evidence from both human and animal studies suggests a link between hypertension and gut microbiota, as well as microbiota-derived metabolites short-chain fatty acids (SCFAs). However, the precise mechanisms underlying this gut-brain axis remain unclear. The levels of microbiota-derived SCFAs in spontaneously hypertensive rats (SHRs) were determined by gas chromatography-mass spectrometry. To observe the effect of acetate on arterial blood pressure (ABP) in rats, sodium acetate was supplemented via drinking water for continuous 7 days. ABP was recorded by radio telemetry. The inflammatory factors, morphology of microglia and astrocytes in rostral ventrolateral medulla (RVLM) were detected. In addition, blood-brain barrier (BBB) permeability, composition and metabolomics of the gut microbiome, and intestinal pathological manifestations were also measured. The serum acetate levels in SHRs are lower than in normotensive control rats. Supplementation with acetate reduces ABP, inhibits sympathetic nerve activity in SHRs. Furthermore, acetate suppresses RVLM neuroinflammation in SHRs, increases microglia and astrocyte morphologic complexity, decreases BBB permeability, modulates intestinal flora, increases fecal flora metabolites, and inhibits intestinal fibrosis. Microbiota-derived acetate exerts antihypertensive effects by modulating microglia and astrocytes and inhibiting neuroinflammation and sympathetic output.

DISTINCT CARDIAC CONNEXIN-43 EXPRESSION IN HEMODYNAMICALLY UPLOADED AND UNLOADED HEART MAY IMPACT VULNERABILITY TO MALIGNANT ARRHYTHMIAS

Objective: Experimental and clinical studies suggest that myocardial hypertrophy in response to hypertension and hyperthyroidism increases propensity to cardiac arrhythmias. While these are rare in conditions resulting in myocardial atrophy, such as hypothyroidism or type-1 diabetes mellitus (T1DM). One of the crucial factors impacting the susceptibility of the heart to life-threatening arrhythmias is gap junction channel protein connexin-43 (Cx43), which ensure cardiac cell-to-cell coupling for electrical signal propagation that induce contraction. We aimed to explore abundance of Cx43 protein and its cardiomyocyte topology in hemodynamically uploaded hypertrophied versus unloaded hypotrophic cardiac phenotype. Design and method: Analysis were performed in left ventricular tissue of adult male rats of following groups: 1. spontaneously hypertensive rat (SHR); 2. normotensive Wistar Kyoto rats (WKY) treated for 8-weeks with L-thyroxine (0.15 μg/kg, i.v.) to induce hyperthyroid status; 3. WKY rats treated with methimazol (0.05% solution, p.o.) to induce hypothyroid status; 4. WKY rats treated with strepotozotocin (50mg/kg, i.p.) to induce T1DM. Animals were compared with non-treated normotensive control rats. Results: Comparing to healthy non-treated rats there was a decrease of total myocardial Cx43 protein and its variant phosphorylated at serine368 in SHR and hyperthyroid rats. Besides, enhanced abnormal localisation of Cx43 was demonstrated on lateral sides of hypertrophied cardiomyocytes. In contrast, total Cx43 protein and its serine368 variant were increased in atrophied left ventricle of hypothyroid and T1DM rats. It was associated with less pronounced alterations in Cx43 topology. In parallel, the abundance of PKC epsilon, which phosphorylates Cx43 at serine368 that stabilize Cx43 function and distribution was reduced in hypertrophied heart while enhanced in atrophied once. Conclusions: Findings suggest that differences in the abundance of cardiac Cx43, its variant phosphorylated at serine368 and Cx43 topology may explain, in part, distinct propensity of uploaded and unloaded heart to malignant arrhythmias. It suggests that hemodynamically overloaded heart might benefit from interventions promoting unloading. This research was supported by VEGA grants 2/0002/20, 2/0006/23, Slovak Research and Development Agency under the Contract no. 21-0410

Central Autonomic Nervous System Balanced by Electroacupuncture in Hypertension

Overexcitation of sympathetic activity strongly related to increased blood pressure (BP) is decreased by electroacupuncture (EA). Reflex elevated BP response and elevated neuronal activity in the rostral ventrolateral medulla (rVLM), a central region for sympathetic outflow are reduced by stimulation of somatosensory nerves during a 30 min EA. However, it is unclear if the medullary nucleus ambiguus (NA) related to parasympathetic activity also is influenced by EA during elevated BP. In hypertensive subjects, EA therapy over deep peroneal and tibial nerves (ST36-37+SP6-7) decreases high BP. We hypothesize that a course of EA treatments decreases high BP by reducing rVLM and simultaneously increasing NA neuronal activity in hypertensive rats. Dahl salt-sensitive rats were fed either a standard rat diet or 4% salt rat diet developing hypertension. Normotensive control rats were acclimated to handling and restraining while Sham-EA (absence of electrical input to acupuncture needles) and EA treated hypertensive rats were acclimatized also to needling. Sham-EA or EA was given twice a week for 30 minutes in awake hypertensive rats for 5 weeks. BPs were measured with tail-cuff CODA system. At end of 10 weeks, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) neuronal (NeuN) expressions were evaluated by immunohistochemistry as well as neuronal activity were determined by extracellular recordings in the rVLM and NA in Sham-EA, EA treated rats, and control rats. BP of control rats was at 130.3±1.7 mmHg (n=6) at end of experiment. BP significantly decreased by 25.9% in EA treated (138.04±1.8 mmHg, n=6) compared to Sham-EA (186.3±2.3 mmHg, n=7) hypertensive rats. Cardiovascular pre-sympathetic neuronal activity in rVLM significantly was decreased by 43% (1.33±0.10 to 0.75±0.13 sp/s, n=10) while the pre-parasympathetic activity in NA was increased by 96% (0.70±0.08 to 1.37±0.13 sp/s, n=12) in EA compared to Sham-EA treated hypertensive rats. Control rats rVLM activity was 0.23± 0.07 sp/s (n=4) and NA activity was 2.71±0.56 sp/s (n=5). Also, numbers of rVLM neurons expressing TH and NeuN were decreased (from 96 to 73) and NA neurons expressing ChAT and NeuN were increased (from 35 to 107) in Sham-EA compared to EA treated hypertensive rats. In normal control rats, rVLM showed 69 TH neurons and NA demonstrated 134 ChAT neurons. In conclusion, the BP lowering EA effect likely involved central autonomic rebalance by activating both sympathoinhibition and parasympathoexcitation. National Institute of Health National Center for Complementary & Integrative Health Grant AT011306 This is the full abstract presented at the American Physiology Summit 2023 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.

Prolyl oligopeptidase activity (POP) in early stage and medicated schizophrenia and in an animal model for schizophrenia study: In vivo effects of psychopharmacological substances on enzyme activity

Prolyl oligopeptidase (POP) is an enzyme highly expressed in the central nervous system, playing important roles in neurodevelopment, memory and learning. Moreover, changes in POP activity in peripheral blood have been associated with various neuropsychiatric disorders. Herein, the POP activity was measured by monitoring the hydrolysis of a specific MCA peptide substrate in plasma or homogenate of selected brain regions from a validated animal model for schizophrenia (SCZ) studies, namely spontaneously hypertensive rats (SHR), compared with control normotensive Wistar rats (NWR), before and after the treatment with antipsychotics. We also evaluated POP activity in plasma from patients with early stage or with chronic schizophrenia (SCZ) relative to paired healthy controls (HCs). No significant differences in POP activity were observed for patients in early stage or with chronic SCZ compared to HCs. POP activity was significantly lower in the plasma of SHR compared to NWR, with no changes in activity observed after a chronic treatment with typical or atypical antipsychotics. Interestingly, a significant decrease in POP activity was observed solely in prefrontal cortex of the SCZ animal model but not in any other brain region or plasma of NWR or SHR after the chronic treatment with antipsychotics. Despite the well-known cognitive impairments improvement in vivo demonstrated for the POP inhibitors, our data suggest the lack of correlation between the activity of this enzyme and early stage or chronic SCZ, as well as no significative pharmacological responses to psychoactive compounds were noticed for this enzyme here.

Luteolin Attenuates Hypertension via Inhibiting NF-κB-Mediated Inflammation and PI3K/Akt Signaling Pathway in the Hypothalamic Paraventricular Nucleus.

Luteolin is widely distributed among a number of vegetal species worldwide. The pharmacological effects of luteolin are diverse and amongst antioxidant, free radical scavenging, and anti-inflammatory activities. Preliminary study showed that luteolin can ameliorate hypertension. However, the precise mechanism needs further investigation. There is no evidence that luteolin affects the paraventricular nucleus of the hypothalamus (PVN), a brain nucleus associated with a critical neural regulator of blood pressure. Our main aim was to explore the effect of luteolin on the PI3K/Akt/NF-κB signaling pathway within the PVN of hypertensive rats. spontaneously hypertensive rats (SHRs) and corresponding normotensive control rats, the Wistar Kyoto (WKY) rats were divided into four groups and subsequently treated for 4 weeks with bilateral PVN injections of either luteolin (20 µg/0.11 µL, volume: 0.11 µL/h) or vehicle (artificial cerebrospinal fluid). luteolin infusion to the PVN significantly decreased some hemodynamic parameters including the mean arterial pressure (MAP), heart rate (HR), circulating plasma norepinephrine (NE) and epinephrine (EPI). Additionally, there was a decrease in the expressions of the phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT), levels of reactive oxygen species (ROS), NAD(P)H oxidase subunit (NOX2, NOX4) in the PVN of SHRs. Meanwhile, the expression of inflammatory cytokines and the activity of nuclear factor κB (NF-κB) p65 in the PVN of SHRs were lowered. Furthermore, immunofluorescence results showed that injection of luteolin in the PVN reduced the expression of tyrosine hydroxylase (TH), and increased that of superoxide dismutase (SOD1) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN of SHRs. Our novel findings revealed that luteolin lowered hypertension via inhibiting NF-κB-mediated inflammation and PI3K/Akt signaling pathway in the PVN.

Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats.

We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.

Identification of Hypothalamic Long Noncoding RNAs Associated with Hypertension and the Behavior/Neurological Phenotype of Hypertensive ISIAH Rats.

Long noncoding RNAs (lncRNAs) play an important role in the control of many physiological and pathophysiological processes, including the development of hypertension and other cardiovascular diseases. Nonetheless, the understanding of the regulatory function of many lncRNAs is still incomplete. This work is a continuation of our earlier study on the sequencing of hypothalamic transcriptomes of hypertensive ISIAH rats and control normotensive WAG rats. It aims to identify lncRNAs that may be involved in the formation of the hypertensive state and the associated behavioral features of ISIAH rats. Interstrain differences in the expression of seven lncRNAs were validated by quantitative PCR. Differential hypothalamic expression of lncRNAs LOC100910237 and RGD1562890 between hypertensive and normotensive rats was shown for the first time. Expression of four lncRNAs (Snhg4, LOC100910237, RGD1562890, and Tnxa-ps1) correlated with transcription levels of many hypothalamic genes differentially expressed between ISIAH and WAG rats (DEGs), including genes associated with the behavior/neurological phenotype and hypertension. After functional annotation of these DEGs, it was concluded that lncRNAs Snhg4, LOC100910237, RGD1562890, and Tnxa-ps1 may be involved in the hypothalamic processes related to immune-system functioning and in the response to various exogenous and endogenous factors, including hormonal stimuli. Based on the functional enrichment analysis of the networks, an association of lncRNAs LOC100910237 and Tnxa-ps1 with retinol metabolism and an association of lncRNAs RGD1562890 and Tnxa-ps1 with type 1 diabetes mellitus are proposed for the first time. Based on a discussion, it is hypothesized that previously functionally uncharacterized lncRNA LOC100910237 is implicated in the regulation of hypothalamic processes associated with dopaminergic synaptic signaling, which may contribute to the formation of the behavioral/neurological phenotype and hypertensive state of ISIAH rats.

Anti-inflammatory effects of endothelin receptor blockade in left atrial tissue of spontaneously hypertensive rats.

ObjectiveIn spontaneously hypertensive rats (SHR) atrial remodeling has been shown to involve increase in endothelin (ET) signaling. Furthermore, inflammatory processes may further contribute to tissue remodeling. The aimed of this study was to investigate whether an endothelin receptor antagonist, macitentan, could reduce left atrial (LA) remodeling in arterial hypertension.MethodsMolecular characterization of atria was performed in SHR at the age of 8 months and their age-matched normotensive control rats (WKY). SHR were treated with macitentan and, for comparison with a blood pressure reducing drug, with doxazosin. After two months of treatment, molecules involved in endocardial inflammation and atrial calcium handling were assessed. The molecular changes provoked by rapid-pacing (RAP) were analyzed in atrial tissue slices.ResultsDoxazosin reduced the systolic blood pressure compared with the untreated SHR (159 ± 26 vs. 176 ± 17; P < 0.05) or macitentan (vs. 189 ± 21; P < 0.05). Macitentan lowered the increased levels of atrial ET-1 and abrogated the pacing-induced upregulation of preproET-1-mRNA in atrial slices from SHR. Macitentan reduced the elevated levels of atrial 8-isoprostanes, the increased expression of pro-inflammatory ICAM-1 and IL-8, the phosphorylation of MAP kinases, ERK and p38, the phosphorylation of NF-κB and the expression of VCAM-mRNA. Major Ca2+-regulating proteins and markers of hypertrophy and fibrosis, however, were not affected. Doxazosin elicited similar changes, except for the alterations in ET-1 levels, NF-κB phosphorylation and VCAM-mRNA.ConclusionMacitentan reversed pro-inflammatory remodeling in hypertensive atria in a blood pressure-independent manner, which might prevent endocardial dysfunction and thereby, thrombogenesis in arterial hypertension.

Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (− 62%) in SHRob as compared with controls. RDN reduced RAGE expression (− 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (− 57% CML and − 51% HMGB1) with reduced pro-inflammatory NFkB activation (− 96%), IL-6 production (− 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (− 33%), collagen type I content (− 72%), accompanied by reduced LA myocyte hypertrophy (− 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

Alterations of the gut microbial community structure and function with aging in the spontaneously hypertensive stroke prone rat

Gut dysbiosis, a pathological imbalance of bacteria, has been shown to contribute to the development of hypertension (HT), systemic- and neuro-inflammation, and blood–brain barrier (BBB) disruption in spontaneously hypertensive stroke prone rats (SHRSP). However, to date individual species that contribute to HT in the SHRSP model have not been identified. One potential reason, is that nearly all studies of the SHRSP gut microbiota have analyzed samples from rats with established HT. The goal of this study was to examine the SHRSP gut microbiota before, during, and after the onset of hypertension, and in normotensive WKY control rats over the same age range. We hypothesized that we could identify key microbes involved in the development of HT by comparing WKY and SHRSP microbiota during the pre-hypertensive state and longitudinally. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and fecal microbiota analyzed by16S rRNA gene sequencing. SHRSP showed significant elevations in SBP, as compared to WKY, beginning at 8 weeks of age (p < 0.05 at each time point). Bacterial community structure was significantly different between WKY and SHRSP as early as 4 weeks of age, and remained different throughout the study (p = 0.001–0.01). At the phylum level we observed significantly reduced Firmicutes and Deferribacterota, and elevated Bacteroidota, Verrucomicrobiota, and Proteobacteria, in pre-hypertensive SHRSP, as compared to WKY. At the genus level we identified 18 bacteria whose relative abundance was significantly different in SHRSP versus WKY at the pre-hypertensive ages of 4 or 6 weeks. In an attempt to further refine bacterial candidates that might contribute to the SHRSP phenotype, we compared the functional capacity of WKY versus SHRSP microbial communities. We identified significant differences in amino acid metabolism. Using untargeted metabolomics we found significant reductions in metabolites of the tryptophan-kynurenine pathway and increased indole metabolites in SHRSP versus WKY plasma. Overall, we provide further evidence that gut dysbiosis contributes to hypertension in the SHRSP model, and suggest for the first time the potential involvement of tryptophan metabolizing microbes.

Diet Supplemented with Chrysophyllum albidum G. Don (Sapotaceae) Fruit Pulp Improves Reproductive Function in Hypertensive Male Rats.

Hypertension has been implicated as a risk factor of reproductive disorders. High blood pressure may trigger impaired sperm quality and biomarkers of reproductive disorders. This study aims to investigate the effect of diet supplemented with Chrysophyllum albidum fruit pulp (FP) on sperm parameters, reproductive hormones, and antioxidant markers in testes and epididymis of hypertensive rats. Male Wistar rats were divided into seven groups (n = 10): normotensive control rats [NC], cyclosporine (25mg/kg)-induced hypertensive rats [Hypert], hypertensive rats treated with captopril (10mg/kg/day) [Hypert + Capt], hypertensive [Hypert + 2%FP and Hypert + 4%FP], and normotensive [2%FP and 4%FP] rats treated with 2% and 4% of diet supplemented with African star apple fruit's pulp [FP]. Hemodynamic parameters (arterial pressure, diastolic, and systolic pressure), sperm count, sperm motility, reproductive hormones, reactive oxygen species, and malondialdehyde levels were assessed. Diet supplemented with FP fed to hypertensive rats reduced mean arterial pressure, diastolic and systolic blood pressure, and heart rate. Furthermore, FP improved sperm quality in hypertensive rats by increasing sperm count, sperm motility with a concomitant reduction in sperm abnormality. FP also increased 3β and 17β-hydroxysteroid hydrogenase (3β-HSD and 17β -HSD) activities, as well as testosterone, luteinizing hormone, and follicle-stimulating hormone levels. Besides, FP triggered a significant increase in 3β-HSD, 17β -HSD, and STAR expression in rats' testicular tissues. Diet supplemented with FP also reduced ROS and malondialdehyde levels and triggered an increase in thiol levels, catalase, and glutathione-S-transferase activities. This study revealed that FP supplemented diet improved sexual function in cyclosporine-induced hypertensive rats by reducing blood pressure and modulation of sperm parameters, steroidogenic enzymes, and reproductive hormones.

Short-Term Intervention with Garlic-Based diets Modulates mRNA Expression of Calmodulin, Inositol-1,4,5-Trisphosphate Receptor-1, and Intracellular Adhesion Molecule in Cyclosporin-Induced Prehypertensive Wistar Rats

This study assessed the short term effect of Allium sativum-based diets on mRNA expression of Calmodulin (CaM), Inositol Trisphosphate receptor (IP3R) and Intracellular adhesion molecule (ICAM-1) in the heart and aorta of cyclosporin-induced prehypertensive rats. Plasma levels of Ca2+ and Tumor Necrosis Factor-alpha (TNF-alpha) were also determined. The experimental rats used for this study were randomly allocated into 7 groups (n=4): normotensive control rats (fed basal diet); untreated prehypertensive rats (fed basal diet); prehypertensive rats (fed 10% and 20% Allium sativum based diets respectively); normotensive rats (fed 10% and 20% Allium sativum based diets respectively); prehypertensive rats treated with 10mg/kg captopril respectively for 7 days. Induction of hypertension with cyclosporin caused significant increase (p < 0.05) in mRNA expression of CaM, IP3R and ICAM-1, accompanied by increased (p < 0.05) systolic and diastolic blood pressures, plasma Tumor Necrosis Factor-alpha (TNF-alpha) and Ca2+ levels. These effects were considerably reversed by Allium sativum-based diets fed to the prehypertensive rats. These findings provide evidence which suggest that CaM, IP3R, and ICAM-1 are also upregulated in prehypertension, but are modulated by short term dietary intervention with garlic.

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism.

We investigated the influence of cannabidiol (CBD) on blood pressure (BP) and heart rate (HR) in spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats. Hypertension was connected with increases in cardiac and plasma markers of lipid peroxidation in both models, whereas cardiac endocannabinoid levels decreased in SHR and increased in DOCA-salt. CBD (10 mg/kg once a day for 2 weeks) did not modify BP and HR in hypertension but counteracted pro-oxidant effects. Moreover, it decreased cardiac or plasma levels of anandamide, 2-arachidonoylglycerol and oleoyl ethanolamide in DOCA-salt and inhibited the activity of fatty acid amide hydrolase (FAAH) in both models. In the respective normotensive control rats, CBD increased lipid peroxidation, free fatty acid levels and FAAH activity. In conclusion, chronic CBD administration does not possess antihypertensive activity in a model of primary and secondary (DOCA-salt) hypertension, despite its antioxidant effect. The latter may be direct rather than based on the endocannabinoid system. The unexpected CBD-related increase in lipid peroxidation in normotensive controls may lead to untoward effects; thus, caution should be kept if CBD is used therapeutically.

Is 3 Weeks of Exercise Enough to Change Blood Pressure and Cardiac Redox State in Hypertensive Rats?

Abstract The investigation was aimed to evaluate the effects of 3-weeks swimming exercise on blood pressure and redox status in high-salt-induced hypertensive rats. Male Wistar albino rats (n=40, 6 weeks old) were divided into 4 groups: 1. hypertensive rats that swam for 3 weeks; 2. sedentary hypertensive control rats; 3. normotensive rats that swam for 3 weeks; 4. sedentary normotensive control rats. Hypertensive animals were on high concentrated sodium (8% NaCl) solution for 4 weeks (period of induction of hypertension). After sacrificing, hearts were isolated and perfused according to Langendorff technique at gradually increased coronary per-fusion pressure from 40–120 cmH2O. The oxidative stress markers were determined in coronary venous effluent: the index of lipid peroxidation (measured as TBARS), nitrites (NO2 −), superoxide anion radical (O2 −) and hydrogen peroxide (H2O2). Swimming did not lead to significant changes in levels of TBARS, NO2 −, O2 − in any of compared groups while levels of H2O2 were significantly higher in swimming hyper-tensive group comparing to swimming normotensive group at coronary perfusion pressure of 80–120 cmH2O. Our results indicate that the short-term swimming start to reduce blood pressure. In addition it seems that this type of swimming duration does not promote cardiac oxidative stress damages.

Ganglionic Long-Term Potentiation in Prehypertensive and Hypertensive Stages of Spontaneously Hypertensive Rats Depends on GABA Modulation.

The sympathetic nervous system (SNS) regulates body functions in normal and pathological conditions and is characterized by the presence of a neuroplastic phenomenon, termed ganglionic long-term potentiation (gLTP). In hypertension, either in spontaneously hypertensive rats (SHR) or in humans, sympathetic hyperfunction, such as elevated SNS outflow and changes in synaptic plasticity have been described. Because enhanced SNS outflow is detected in the hypertensive stage and, more importantly, in the prehypertensive phase of SHR, here we explored whether synaptic plasticity, particularly gLTP, was modified in the superior cervical ganglia (SCG) of prehypertensive SHR. Furthermore, considering that GABA modulates sympathetic synaptic transmission and gLTP in Wistar rats, we studied whether GABA might modulate gLTP expression in SHR. We characterized gLTP in the SCG of young prehypertensive 6-week-old (wo) and adult hypertensive (12 wo) SHR and in the SCG of Wistar Kyoto (WKy) normotensive control rats of the same ages. We found that gLTP was expressed in 6 wo SHR, but not in 12 wo rats. By contrast, in WKy, gLTP was expressed in 12 wo, but not in 6 wo rats. We also found that gLTP depends on GABA modulation, as blockade of GABA-A subtype receptors with its antagonist bicuculline unmasked gLTP expression in adult SHR and young WKy. We propose that (1) activity-dependent changes in synaptic efficacy are altered not only during hypertension but also before its onset and (2) GABA may play a modulatory role in the changes in synaptic plasticity in SHR, because the blockade of GABA-A receptors unmasked the expression of gLTP. These early changes in neuroplasticity and GABA modulation of gLTP could be part of the sympathetic hyperfunction observed in hypertension.

The protective effect of dronedarone on the structure and mechanical properties of the aorta in hypertensive rats by decreasing the concentration of symmetric dimethylarginine (SDMA).

Background and aimsDronedarone is a new multichannel-blocking antiarrhythmic for the treatment of patients with atrial fibrillation. Our group has demonstrated that dronedarone produces regression of cardiac remodeling; however, its effect on the remodeling of the elastic arteries has not yet been reported. We aim to assess the effects of dronedarone on the regression of thoracic aortic remodeling in spontaneously hypertensive rats (SHRs).MethodTen-month-old male SHRs were randomly assigned to an intervention group (SHR-D), where the animals received dronedarone treatment (100 mg/kg), to a control group (SHR) where rats were given vehicle, or to a group (SHR-A) where they were given amiodarone. A fourth group of normotensive control rats (Wistar-Kyoto rats, WKY) was also added. After two weeks of treatment, we studied the structure, the elastic fiber content of the thoracic aorta using histological techniques and confocal microscopy, and the vascular mechanical properties using an organ bath and isometric tension analysis. A mass spectrometric determination of symmetric dimethylarginine (SDMA) concentrations was performed.ResultsSHR group developed the classic remodeling expected from the experimental model: outward hypertrophic remodeling, increased elastic fiber content and wall stiffness. However, the SHR-D group showed statistically significantly lower values for aortic tunica media thickness, wall to lumen ratio, external diameter, cross-sectional area, volume density of the elastic fibers, wall stiffness, and aortic SDMA concentration when compared to the SHR group. These parameters were similar in the SHR and SHR-A groups. Interestingly, the values for tunica media thickness, volume density of the elastic fibers, wall stiffness, and SDMA concentration obtained from the SHR-D group were similar to those measured in the WKY group.ConclusionThese results suggest that dronedarone improves the structure and passive mechanical properties of the thoracic aorta in hypertensive rats, and that this protective effect could be associated with a reduction in the concentration of aortic SDMA.

Exercise training attenuates hypertension and cardiac hypertrophy via time‐related regulation on ACE and ACE2 axes

Appropriate exercise training (ExT) has been shown to lower high blood pressure. However, prehypertension ExT has rarely been concerned. This study tested whether prehypertension ExT protects against hypertension and cardiac remodeling in spontaneously hypertensive rats (SHR), and explored the underlying mechanisms by examining cardiac angiotensin converting enzyme (ACE) and ACE2 axes. Low-intensity ExT was started in male SHR and control Wistar-Kyoto rats prior to the onset of hypertension, and lasted for either 8 or 16 weeks. Blood pressure (BP) was measured biweekly by the tail-cuff method. Cardiac function and remodeling were assessed, and ACE and ACE2 axes were determined after the final ExT. The results showed that prehypertension ExT slowed down the onset and progression of hypertension in SHR. In parallel, the hypertrophy in hypertensive heart was attenuated, myocardial fibrosis was reduced, and the impairment of left ventricular diastolic function was relieved. In SHR myocardium, the elements of ACE-AngII-AT1 axis were homogeneously and progressively increased, whereas those of ACE2-Ang(1–7)-MAS axis were heterogeneously decreased. Different time-related responses were observed for the key effecters, Ang II and Ang(1–7). Myocardial Ang II was increased progressively in SHR, and was reduced consistently by ExT. In contrast, Ang(1–7) was decreased only after 16-week sedentariness, which was abolished by ExT. Besides, 16-week ExT increased Ang(1–7) in normotensive control rats. In summary, prehypertension ExT attenuates hypertension and cardiac remodeling. Down-regulation of Ang II seems to serve as a protective mechanism throughout ExT, while up-regulation of Ang(1–7) is involved after a relatively long period of ExT. Support or Funding Information This work was supported by the National Natural Science Foundation of China (No. 81372111, 81670295), and the Natural Science Foundation of Fujian Province of China (No. 2014J01339). mRNA and protein levels of ACE and AT1 in left ventricles of WKY and SHR after 8 or 16 weeks of exercise training. mRNA and protein Expression of ACE2 and MAS receptor in left ventricles of WKY and SHR after 8 or 16 weeks of exercise training. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats

Caffeic acid (CAA) and chlorogenic acid (CHA) are important members of hydroxycinnamic acid with natural antioxidant and cardio-protective properties. The present study aimed to determine the effect of CAA and CHA on systolic blood pressure, heart rates (HR) as well as on the activity of the angiotensin-1-converting enzyme (ACE), acetylcholinesterase (AChE), butrylcholinesterase (BChE) and arginase in cyclosporine-induced hypertensive rats. Experimental rats were distributed into 7 groups (n = 6): normotensive control rats; hypertensive rats (induced rats) as well as hypertensive- treated groups with captopril (10 mg/kg/day), CAA (10 and 15 mg/kg/day) and CHA (10 and 15 mg/kg/day), respectively. The experiment lasted for 7 days and the systolic blood pressure (SBP) and heart rates were recorded using tail-cuff method. Oral administration of captopril, caffeic acid and chlorogenic acid normalized hypertensive effect caused by cyclosporine administration. CAA and CHA significantly (P < 0.05) reduced SBP and HR, activity of ACE, AChE, BChE and arginase in the treated hypertensive rats compared with cyclosporine induced-hypertensive rats. Likewise, CAA and CHA improved nitric oxide (NO) bioavailability, increased catalase activity and reduced glutathione content while malondialdehyde (MDA) level was reduced compared with cyclosporine hypertensive rats. Findings from this study shows that CAA and CHA exhibited blood pressure lowering properties and reduced activities of key enzymes linked to the pathogenesis of hypertension in cyclosporine-induced rats. These might be some of the possible mechanisms of action by which their cardio-protective properties are exhibited.