bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study on penile corpus cavernosum relaxation induced by Berberis amurensis Rupr (1075.10)
Authors: Tan Rui , Kim Hye Yoom , Cho Kyung Woo , Kang Dae Gill , Lee Ho Sub 
Published: June 2021

Study on Penile corpus cavernosum relaxationinduced by Berberis amurensis RuprRui Tan 1, 2, , Hye Yoom Kim 1,2, Kyung Woo Cho2, Dae Gill Kang 1,2, and Ho Sub Lee 1,2*1College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570‐749, Republic of Korea; 2Hanbang Body‐fluid Research Center, Wonkwang University, Shinyong‐dong, Iksan, Jeonbuk, 570‐749, Republic of KoreaThe aim of the present study is to investigate whether a methanol extract of Berberis amurensis Rupr (BAR) augments penile erection. Preconstracted with phenylephrine (PE) in isolated endothelium‐intact rabbit corpus cavernosum, BAR relaxed penile smooth muscle in a dose‐dependent manner, which was inhibited by pretreatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME), a nitric oxide synthase inhibitor, and 1H‐[1,2,4]‐oxadiazole‐[4,3‐α]‐quinoxalin‐1‐one (ODQ), a soluble guanylyl cyclase (sGC) inhibitor. BAR‐induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA), a nonselective K+ channel blocker for BKCa, IKCa and SKCa, and charybdotoxin, iberiotoxin, apamin, a selective Ca2+ sensitive K+ channel inhibitor, respectively. BAR increased cGMP levels of the corpus cavernosum in a concentration‐dependent manner. In addition, BAR caused increase of peak intracavernous pressure (ICP), ICP/MAP ratio and area under the carve (AUC) in a dose dependent manner in SD rats. Taken together, these results suggest that BAR augments penile erection via NO/cGMP system and Ca2+ sensitive‐K+ Channel in corpus cavernosum.
ACE and iNOS overexpression correlates with vascular reactivity in young Syrian cardiomyopathic hamsters (1075.7)
Authors: Cruz Nildris , Quidgley Jose , Dorna Luisamari , Miranda Jorge , Crespo Maria 
Published: June 2021

Vascular alterations are present in 2‐month‐old Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of HF. Aortic ACE, eNOS, and iNOS mRNA and protein levels were assessed in SCH from 1 to 4 months of age to elucidate the timeframe and the mechanisms underlying these alterations. Total RNA and proteins were extracted from aortas, and quantified with Real‐Time RT‐PCR and Western blot. ACE mRNA and protein were upregulated in 2‐month‐old SCH by 41% and 43%, respectively, when compared to control (CT; P<0.05). Protein levels of iNOS were higher in SCH (482%) than in CT (100%) at 2 months of age. In addition, eNOS mRNA increased by 77% in SCH, whereas eNOS protein levels were 15% lower in SCH than in CT (P<0.05). These findings suggest that the vascular reactivity present in 2‐month‐old SCH is secondary to overactivation of RAS resulting from increased levels of ACE mRNA and protein. A combination of lower eNOS and higher iNOS protein levels may underlie endothelial dysfunction present in SCH at this stage. Altogether, these factors will likely promote vascular hyper‐reactivity in the early stages of heart failure in SCH and eventually trigger cardiac deterioration.Grant Funding Source: Supported by MBRS‐RISE R25‐GM061838
KCNA5 knockout mice demonstrate that Kv1.5 is a component of the native delayed rectifier K+ current in vascular smooth muscle (1077.6)
Authors: Fancher Ibra , Dick Gregory 
Published: June 2021

Voltage‐gated K+ channels (KV) mediate physiologically important delayed rectifier K+ (KDR) currents in vascular smooth muscle (VSM). However, the molecular identity of KV subunits that compose KDR channels in VSM remains unclear. We tested the hypothesis that KV1.5 (KCNA5) underlies KDR channels of VSM. To test this hypothesis, whole‐cell patch clamp experiments were performed on VSM from the aortae of wild type (wt) and KV1.5 knockout (KO) mice. Single VSM were bathed in a Ca2+‐free solution (to eliminate inward currents) and dialyzed with a pipette solution containing 10 mM BAPTA (a Ca2+ chelator to minimize Ca2+‐activated currents). The pipette solution also contained 1 uM penitrem A (a BKCa channel antagonist) and 10 uM glibenclamide (a KATP channel antagonist) in order to study KDR in isolation. KDR current in VSM cells from wt mice was 140 ± 47 pA at +20 mV. In contrast, KDR current at +20 was only 68 ± 14 pA in VSM cells from KO mice. KDR was blocked to a greater degree by DPO‐1 (a KV1.5 channel antagonist) in VSM cells from wt mice. Specifically, DPO‐1 (1 uM) inhibited current 61 ± 6 and 26 ± 8% in VSM cells from wt and KO mice, respectively. These data support the hypothesis that KV1.5 subunits are critical components of KDR channels in VSM. Further, the data lead us to suggest that KV1.5‐containing KDR channels may be important in determining the membrane potential of VSM cells.Grant Funding Source: Supported by T32HL090610
Calcification in vitro: experimental factors that induce nanocrystal formation (1077.9)
Authors: Hortells Luis , Sosa Cecilia , Millán Ángel , Sorribas Victor 
Published: June 2021

Medial vascular calcification (VC) of arteries is frequently observed in chronic kidney disease and diabetes. Pathogenesis in VC is frequently studied on primary cultures of aortic smooth muscle cells. However, several experimental factors can affect the rate of calcification in vitro, which can be misleading in the research of VC pathogenesis. The aim of this work has been the identification of these factors and to improve the adequacy of the model.Calcification was studied as a function of Pi concentration (1‐3 mM), incubation time and media composition (MEM vs. DMEM). We have determined the rate of calcium deposition, medium pH, nucleation rate, degree of crystallization, cell death and osteogene expression.Calcification was more intense with DMEM than MEM due to increased basicity induced by higher bicarbonate content in DMEM. Cell death (as LDH leakage) correlated and preceded calcification. Particle nucleation depended on pH and Pi concentration, and was already observed after 2h (DMEM) or 5h (MEM) of incubation with the cells. Osteogene expression and crystal structure were also modified by the same experimental conditions.
Mitochondrial calcium is decreased by high glucose and is improved by reduction of protein O‐GlcNAcylation in cardiac myocytes (1078.2)
Authors: Diaz Juarez Julieta , Suarez Jorge , Scott Brian , Dillmann Wolfgang 
Published: June 2021

Increased nuclear protein O‐linked β‐N‐acetylglucosamine glycosylation (O‐GlcNAcylation) mediated by high glucose treatment or the hyperglycemia of diabetes mellitus contributes to cardiac myocyte dysfunction. Mitochondrial proteins in cardiac myocytes are also submitted to O‐GlcNAcylation, however, whether excessive O‐GlcNAcylation alters mitochondrial function is incompletely studied. We have previously demonstrated decreased mitochondrial calcium concentration in cardiac myocytes exposed to high glucose. We hypothesize that excessive O‐GlcNAcylation may be responsible of this maladaptive phenomenon and that reducing excessive O‐GlcNAcylation may return mitochondrial calcium levels to normal. Our objective was to test this hypothesis, therefore, we incubated cultured neonatal mouse myocytes in high glucose (HG, 25mM) for 72 hours and inhibited O‐GlcNAcylation by adenoviral expression of a dominant negative mutant of the O‐GlcNAc transferase (dnOGT). As expected, mitochondrial calcium levels were reduced by 20% after HG exposure but were returned to control values after dnOGT expression. In addition, mitochondrial calcium uptake decreased by 52% in HG and was improved by expression of dnOGT, however, did not reach control values. We examined the mitochondrial calcium uniporter (MCU) and found that it is susceptible to be O‐GlcNAcylated and HG further increased O‐GlcNAcylation. In conclusion, our results suggest that excessive O‐GlcNAcylation in hyperglycemia alters mitochondrial calcium homeostasis by increasing O‐GlcNAcylated MCU.Grant Funding Source: Supported by UC MEXUS and VA‐5 I01BX001121‐02‐
miR‐133a ameliorates cardiac dysfunction in diabetes: possibly by restoring β‐adrenergic receptor function and expression (1078.6)
Authors: Nandi Shyam , Liu Xuefei , Zheng Hong , Sharma Neeru , Chavali Vishalakshi , Patel Kaushik , Mishra Paras 
Published: June 2021

Inhibition of microRNA (miR)‐133a causes cardiac hypertrophy and fibrosis. However, the beneficial effects of miR‐133a in cardiac dysfunction remain to be examined. Furthermore, impaired contractility in diabetic hearts has been associated with attenuated expression of β1‐ and β2‐adrenergic receptors (AR). Based on these observations, we hypothesized that augmenting miR‐133a in the circulation will improve cardiac function possibly by enhancing β1‐ and β2‐AR expression in diabetic hearts. Male Sprague‐Dawley rats were injected with streptozotocin (STZ, 45mg/kg, i.v.) to induce diabetes mellitus (plasma glucose >350mg/dL). After 4 weeks these rats were treated with miR‐133a mimic or scrambled control (10^6 lentivirus, i.v.). Two weeks later the left ventricular contractility (dP/dt) were measured under basal conditions and in response to β‐AR agonist isoproterenol (0.05µg/kg, i.v). The miR‐133a treatment increased dP/dt by 25% in diabetic rats under basal condition. In addition, isoproterenol induced increase in dP/dt was significantly increased by administration of miR‐133a in diabetic rats (12618±1086 vs 9256±1103 mmHg/sec). Consistent with these observations mRNA and protein expressions of β1‐ and β2‐AR (measured by RT‐qPCR and immunoblotting) were increased in STZ+ miR‐133a as compared to STZ+ scrambled group (mRNA: β1‐AR, 2.36±0.4 fold and β2‐AR, 3.2±0.4 fold, and protein: β1‐AR, 2.52±0.01 fold and β2‐AR, 4.1±0.01 fold. These results suggest a possible novel beneficial effect of miR‐133a in improving cardiac function in diabetes.Grant Funding Source: NIH grants: HL113281 and HL116205 and DK82956
Innate collateral vessels in the absence of ischemia undergo shear stress similar to normal arterial segments of the same diameter (1079.12)
Authors: Spaan Jos , van Horssen Pepijn , Sochi Taha , Smith Nic , Siebes Maria , van den Wijngaard Jeroen 
Published: June 2021

Some species, including humans, have structural collateral vessels, CV, that can further develop in the presence of coronary stenosis by increasing pressure difference across them. Question is how CV's are maintained in the absence of ischemia.The coronary network of 6 healthy canine hearts was reconstructed in 3D from images obtained with an imaging cryomicrotome after filling with fluorescent replica material (resolution 0.020 mm). CV's were automatically detected. The full coronary network was reconstructed. For all segments, including CV's, diameter and perfused tissue mass, PTM, was derived and shear stress, SS, calculated.Innate collateral connections ranged from 286 to 1015 µm in diameter and were distributed over the myocardial wall with some higher density at the subendocardium: density 2.5 ‐ 5.0 per gram tissue. Highly correlating fractal relations were found between PTM and diameter for normal tree segments and for CV's which fully overlapped. SS in the CV's was equal to neighboring tree segments of similar diameter.Results indicate that collateral segments have the same function in distributing blood, and do so at the same SS, as normal tree segments. Hence, functionally CV's are not different from normal vascular segments and are therefore maintained. CV's form substrate for collateral growth in ischemia.Grant Funding Source: FP7‐ICT‐2007‐224495: euHeart
Connexin 37 and KCa3.1 contribute to P2Y2 receptor initiated endothelial‐derived hyperpolarization (1079.15)
Authors: Sharik Meaghen , Burt Janis , Ruth Peter , Rieg Timo 
Published: June 2021

Nucleotides such as ATP and UTP are important paracrine regulators of vascular tone. Importantly, we previously demonstrated that in vivo activation of P2Y2 receptors (activated by ATP/UTP) causes an acute NO‐independent decrease in blood pressure (BP), indicating this signaling pathway requires an endothelial‐derived hyperpolarization (EDH) response. To define the mechanisms by which in vivo activation of P2Y2 receptors initiates EDH and vasodilation, we studied connexin 37 and 40 (Cx37, Cx40), both part of the myoendothelial gap junction, as well as big‐conductance (KCa1.1, expressed in smooth muscle cells) and intermediate‐conductance K channels (KCa3.1, expressed in endothelial cells), all hypothesized to be part of the EDH response. We compared the effects of the P2Y2/4 receptor agonist, INS45973, in wild‐type (WT) mice and mice lacking Cx37, Cx40, KCa1.1, or KCa3.1 (n=4‐5/genotype) under anesthesia, while monitoring intra‐arterial BP. Acute application of INS45973 (0.01, 0.03, 0.1, 0.3, 1, or 3 mg/kg bw i.v. in 0.5 µl/g bw over 45 sec) dose‐dependently and rapidly (within 15 sec of starting infusion) decreased BP in WT mice (max response % of baseline: ‐38±1%, EC50: 0.8±0.2 mg/kg) for 2‐3 min. Whereas the responses in Cx40‐/‐ and KCa1.1‐/‐ mice were comparable to WT mice (‐41±2%, 0.3±0.1 mg/kg and ‐44±3%, 0.3±0.1 mg/kg, respectively), responses in Cx37‐/‐ and KCa3.1‐/‐ mice were significantly impaired (‐27±1%, 1.2±0.3 mg/kg and ‐13±5%, 1.6±0.8 mg/kg, respectively). Heart rate was not affected in either genotype. Our data indicate that Cx37 and KCa3.1 are required, at least in part, for the P2Y2 receptor‐initiated EDH response and subsequent vasodilation.Grant Funding Source: 10SDG2610034 and P30DK079337
Pannexin1 channel‐mediated ATP release and the vasodepressor response to hypoxia (1079.19)
Authors: Kirby Brett , Petkov Brian , Zhu Hongmei , McMahon Timothy 
Published: June 2021

Plasma ATP is hypothesized to mediate hypoxic vasodilation, and pannexin1 (panx1) channels present in red blood cells (RBCs) and vascular tissue transport ATP in response to hypoxia. We tested the hypothesis that intravascular panx1 channel‐mediated ATP release is obligatory to hypoxia‐induced hypotension in anesthetized mice. Functional loss of panx1‐mediated ATP release to hypoxia was observed in isolated RBCs from mice devoid of panx1 (KO; panx1‐/‐) vs wild‐type controls (WT). Mice were anesthetized with isoflurane, mechanically ventilated, and mean arterial pressure (MAP) was measured via carotid artery catheter during inhalation of 21 and 10% O2. MAP was similar for KO and WT in normoxia, but hypoxia‐induced hypotension was abolished in Panx1‐/‐ vs WT mice (Δ ‐1±3 vs ‐14±3 mmHg). Heart rate during hypoxia did not fall, consistent with hypoxia‐induced peripheral vasodilation. Venous plasma ATP during hypoxia was lower in Panx1‐/‐ vs WT mice (67±6 vs 166±23 nM). These data demonstrate a key role for panx1 channels in governing blood extracellular ATP and the vasodepressor response to hypoxia, consistent with their proposed roles in hypoxic vasodilation.Grant Funding Source: Supported by NIH HL113943
IGF‐1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice (1079.2)
Authors: Toth Peter , Tucsek Zsuzsanna , Tarantini Stefano , Sosnowska Danuta , Gautam Tripti , Mitschelen Matthew , Koller Akos , Sonntag William , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

Aging impairs autoregulatory protection in the brain, exacerbating hypertension‐induced cerebromicrovascular injury, neuroinflammation and development of vascular cognitive impairment (VCI). Despite the paramount importance of the age‐related decline in circulating insulin‐like growth factor‐1 (IGF‐1) levels in brain and cerebrovascular aging, it is not well understood how IGF‐1 deficiency affects the functional adaptation of cerebral arteries to high blood pressure. To test the hypothesis that IGF‐1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF‐1 deficient mice (AAV knockdown of hepatic IGF‐1 [Igf1f/f + MUP‐iCre‐AAV8]) by chronic infusion of angiotensin II and changes in autoregulation of cerebral blood flow andmyogenic constriction of middle cerebral arteries (MCA) were assessed. In hypertensive control mice, the range of cerebral blood flow autoregulation was extended to higher pressure values and the pressure‐induced tone of MCA was increased. In hypertensive IGF‐1 deficient mice autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice the mechanism of adaptation to hypertension involved up‐regulation of a TRPC channel‐dependent pathway and this mechanism was impaired in hypertensive IGF‐1 deficient mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF‐1 deficient mice included exacerbated disruption of the blood‐brain barrier and neuroinflammation (microglia activation, up‐regulation of pro‐inflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF‐1 deficiency impairs autoregulatory protection in the brain of mice with angiotensin II‐induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.Grant Funding Source: Supported by the Nemzeti Fejlesztési Ügynökség and NIH
Cardiac myofilament Caa2+ sensitization disturbs regulation of coronary flow and leads to focal myocardial ischemia and arrhythmias during stress (1079.25)
Authors: Huke Sabine , Bennuri Sirish , Faria Thais , Knollmann Bjorn 
Published: June 2021

Myofilament Ca2+ sensitization has been linked to increased arrhythmia susceptibility, but the underlying mechanism is not completely understood. Mice with the Ca2+ sensitizing TnT‐I79N mutation develop arrhythmias during stress, despite the absence of an overt anatomical substrate. Stress by fast pacing of isolated perfused TnT‐I79N hearts for 16 min elicited arrhythmias (63%) and caused the formation of hypoxic regions (14.1% of total tissue in I79N vs 2.6% in control, Hypoxyprobe) associated with focal cellular energy depletion (Connexin isoforms P0 and pT172‐AMP kinase both increased). The cause for the local energetic supply‐and‐demand mismatch is unclear and we tested if insufficient perfusion is at least in part responsible. Global coronary flow was not decreased in isolated TnT‐I79N hearts. To test if flow distribution was altered, we infused fluorescent 15 µm microspheres and compared the fraction of microspheres inside hypoxic areas with the fraction of hypoxic tissue. Microspheres inside hypoxic regions were drastically reduced, suggesting regional ischemia. These results were reproduced in control hearts treated with the Ca2+ sensitizing drug EMD57033. Next we tested if hypoxia also occurs naturally in TnT‐I79N mice in vivo. Despite expecting low sensitivity due to localized effects, the mRNA expression levels of genes up‐regulated by hypoxia (GLUT1, TUBB3) were increased (0.3fold, 3fold).We conclude that myofilament Ca2+ sensitization disturbs regulation of coronary flow and leads to focal ischemia and arrhythmias during stress. This suggests that myofilament properties of cardiomyocytes importantly contribute to local regulation of coronary flow.Grant Funding Source: supported by AHA 10SDG2640109 and NIH HL71670
Qualitative differences in reflex vagal control do exist controlling regional coronary flow resistance within and between mammalian species (1079.9)
Authors: White Saxon , Hamut Mutalip , Cottee David , Quail Anthony 
Published: June 2021

The literature extensively documents inconsistencies in the vagal and acetylcholine control of coronary blood vessels between species. The reasons may relate to variation in experimental models, but reflex vagal control of coronary flow in man must remain uncertain. In awake canine species with paced hearts baroreflexes activate the vagus to dilate flow resistance vessels in the circumflex (CX) and right (R) coronary beds but have no apparent effect in the anterior descending (AD) bed. The effects therefore vary within one species. Seeking a unifying hypothesis of neural coronary control in 2010 we challenged awake sheep with identical protocols to those used in the dog, where, as in dog R serves only RV. We reported1 that the pattern of regional change between sheep and dog are similar for CX and AD, but the effects for R are opposite. In sheep as aortic perfusion pressure rises 28 mmHg, R flow does not change and the bed constricts (conductance 82%; P<0.001, c.f. dog dilates 118%; P<0.01). The effects in both species are blocked by methscopolamine. These data suggest that evolution of vagal control of the coronary circulation does vary qualitatively within, and, between species. The data also imply that the myocardium known for poor oxygen reserve at rest when facing rapid changes in cardiac work normally calls on beat‐by‐beat, rapid time‐constant hypoxia defence mechanisms. Emerging data2 suggest that myocardial cells may be normally hypoxia‐adapted, using low‐threshold cellular interacting glycolytic and hypoxia‐inducible transcriptional factors. Finally, the data imply a differential pattern of reflex vagal coronary dilator/constrictor effects will apply regionally to the heart of man. 1. Quail A et al, FASEB J. A1034.6, 2010 2. Songyue Yin et al, PLoS ONE 8(9):e74011, 2013Grant Funding Source: Supported by project grants from NHMRC and HMRI Australia
Combination therapy of vagal nerve stimulation and left ventricular assist device maximally reduces the infarct size in ischemia reperfusion model (1080.4)
Authors: Kakino Takamori , Saku Keita , Sakamoto Takafumi , Akashi Takuya , Arimura Takahiro , Nishizaki Akiko , Oga Yasuhiro , Kishi Takuya , Ide Tomomi , Sunagawa Kenji 
Published: June 2021

BACKGROUNDS: Despite the spread of early coronary reperfusion in the management of acute myocardial infarction (AMI), it remains difficult to fully salvage myocardium in the area at risk. We investigated the impact of VNS, LVAD and their combination (VNS+LVAD) on the infarct size in the IR model.METHODS: We allocated 17 dogs into 4 groups, Control (n=5), VNS (n=4), LVAD (n=4) and VNS+LVAD (n=4). We occluded major branches of the left anterior descending coronary artery (90min) and reperfused for the following 300min. We titrated the amplitude of VNS to lower heart rate by 10‐20%. We introduced LVAD to unload LV totally and minimize myocardial oxygen consumption (MVO2).RESULTS: Mean aortic pressure after reperfusion did not differ among 4 groups. Left atrial pressure was much lower in LVAD and VNS+LVAD (Control: 13±1.7, VNS:11±0.72, LVAD: ‐1.6±1.6, VNS/LVAD:‐0.4±1.3 mmHg, p<0.0001). VNS and LVAD reduced the infarct size (relative to Control) by 24% and 88%, respectively. VNS+LVAD reduced the infarct size below the detection threshold (0.0±0%, p<0.0001).CONCLUSIONS: The VNS combined with mechanical LV unloading maximally reduces the infarct size and could serve as a powerful strategy to prevent post MI heart failure in the long term.