Enhanced Central Sympathetic Tone Induces Heart Failure with Preserved Ejection Fraction (HFpEF) in Rats

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague-Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20 ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5 μg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708 mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studie

A one-dimensional zigzag coordination polymer: catena-poly[[[triaqua­cadmium(II)]-[μ-2,2′-(5-methyl-1,3-phenyl­enedi­oxy)diacetato-κ4 O,O′:O′′,O′′′]] monohydrate]

In the title one-dimensional coordination polymer, {[Cd(C11H10O6)(H2O)3]·H2O}n, the 2,2′-(5-methyl-1,3-phenyl­enedi­oxy)diacetate dianions connect CdII ions in a head-to-tail fashion to generate zigzag chains. The coordination geometry of the Cd atom is distorted penta­gonal bipyramidal. There are O—H⋯O hydrogen bonds between the carboxyl O atoms, the aqua ligands and the uncoordinated water mol­ecules

Poly[diaqua­(μ-oxalato)(μ-2-oxido­pyridinium-3-carboxyl­ato)praseo­dymium(III)]

In the title complex, [Pr(C6H4NO3)(C2O4)(H2O)2]n, each PrIII ion is coordinated by eight O atoms from two 2-oxynicotinate ligands, two oxalate ligands and two water mol­ecules, displaying a distorted bicapped square-anti­prismatic geometry. The carboxyl­ate groups link adjacent praseodymium metal centres, forming layers parallel to the bc plane. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds

Effects of Metoclopramide and Ranitidine on Preoperative Gastric Contents in Day-Case Surgery

This prospective, randomized, double-blinded study was performed to evaluate the effects of intravenous metoclopramide and ranitidine on preoperative gastric contents in outpatients receiving intravenous anesthesia for laparoscopic gynecologic surgery. Fifteen minutes before the induction of anesthesia, the Z-M group (n = 20) received 50 mg ranitidine and 10 mg metoclopramide intravenously and the control group (n = 20) received the same volume of normal saline. Before the surgery, a 14-F multiorifice nasogastric tube was inserted to aspirate the gastric contents of patients under sedation with propofol and midazolam. The mean pH values of the gastric fluid were 2.7 ± 2.0 (SD) [median 1.6 (range: 1.2-7.2)] in the control group, and 6.1 ± 1.9 [median 6.8 (range 1.4-7.8)] in the Z-M group. The mean aspirated volumes (mL) were 15.3 ± 10.4 (SD) [median 11.0 (range: 5.0-44.0)] in the control group, and 6.9 ± 10.0 (SD) [median 4.5 (range: 0-38.0)] in the Z-M group. There were significantly more high-risk (gastric fluid volumes > 25 mL and pH < 2.5) patients in the control group (4/20, 20%) than in the Z-M group (1/20, 5%). In conclusion, intravenous prophylactic ranitidine and metoclopramide may be an easy and useful method to decrease the volume while increasing the pH of gastric contents, and therefore may reduce the number of patients at risk for aspiration pneumonitis in ambulatory laparoscopic procedures who receive an anesthesia

Poly[[bis­[μ-1,2-bis­(4-pyrid­yl)ethene]bis­(trichloro­acetato)­cadmium(II)] monohydrate]

In the crystal structure of the title compound, {[Cd(C2Cl3O2)2(C12H10N2)2]·H2O}n, the CdII ion lies on a twofold rotation axis and 1,2-bis­(4-pyrid­yl)ethene ligands bridge symmetry-related CdII ions, forming a two-dimensional structure. Two trichloro­acetate ligands complete the coordination around the CdII ion, forming a distorted octa­hedral environment. In the crystal, solvent water mol­ecules, which also lie on twofold rotation axes, form inter­molecular O—H⋯O hydrogen bonds, which connect the two-dimensional structure into a three-dimensional network. The crystal studied was an inversion twin, the refined ratio of twin components being 0.75 (4):0.25 (4)

A one-dimensional ladder-like coordination polymer: poly[[hexa­aqua­bis(μ-5-nitro­benzene-1,3-dicarboxyl­ato-κ3 O,O′,O′′)(μ-oxalato-κ4 O,O′:O′′,O′′′)diyttrium(III)] trihydrate]

In the crystal structure of the title one-dimensional coordination polymer, [Y2(C8H3NO6)2(C2O4)(H2O)6]·3H2O, each YIII ion is bridged to its neighbours by two 5-nitro­benzene-1,3-dicarboxyl­ate (nbdc) dianions and one oxalate dianion (located on an inversion centre) to form a ladder-like polymeric structure. The two carboxylate groups of nbdc assume different modes of coordination, one is chelating whereas the other is monodentate. Three water mol­ecules coordinate to the YIII ion to complete an eight-coordinate distorted dodecahedral geometry. The ladder-like polymers are assembled together by hydrogen bonding and π–π stacking [centrio–centriod distance = 3.819 (9) Å] in the crystal structure

Bis(4,4′-bipyrid­yl)bis{2-[4,6-bis­(carboxy­methyl­sulfan­yl)-1,3,5-triazin-2-ylsulfan­yl]acetato}zinc(II)

In the title compound, [Zn(C9H8N3O6S3)2(C10H8N2)2], the central ZnII ion, situated on a center of inversion, adopts an octa­hedral geometry coordinated by four O atoms from two carboxyl­ate groups and two carboxylic groups of two symmetry-related TTTA ligands and two N atoms from two bpy mol­ecules {TTTA is 2,2′,2′′-[1,3,5-triazine-2,4,6-triyltris(sulfanedi­yl)]triacetic acid and bpy is 4,4′-bipyridine}. These mononuclear units are connected through complementary O—H⋯X hydrogen bonds, as well as through weak C—H⋯X (X = O and N) inter­actions, resulting in a three-dimensional supra­molecular architecture

Cell-penetrating peptides as transporters for morpholino oligomers: effects of amino acid composition on intracellular delivery and cytotoxicity

Arginine-rich cell-penetrating peptides (CPPs) are promising transporters for intracellular delivery of antisense morpholino oligomers (PMO). Here, we determined the effect of L-arginine, D-arginine and non-α amino acids on cellular uptake, splice-correction activity, cellular toxicity and serum binding for 24 CPP−PMOs. Insertion of 6-aminohexanoic acid (X) or β-alanine (B) residues into oligoarginine R8 decreased the cellular uptake but increased the splice-correction activity of the resulting compound, with a greater increase for the sequences containing more X residues. Cellular toxicity was not observed for any of the conjugates up to 10 μM. Up to 60 μM, only the conjugates with ⩾ 5 Xs exhibited time- and concentration-dependent toxicity. Substitution of L-arginine with D-arginine did not increase uptake or splice-correction activity. High concentration of serum significantly decreased the uptake and splice-correction activity of oligoarginine conjugates, but had much less effect on the conjugates containing X or B. In summary, incorporation of X/B into oligoarginine enhanced the antisense activity and serum-binding profile of CPP−PMO. Toxicity of X/B-containing conjugates was affected by the number of Xs, treatment time and concentration. More active, stable and less toxic CPPs can be designed by optimizing the position and number of R, D-R, X and B residues

A chiral three-dimensional network in poly[μ-4,4′-bipyridine-di-μ-formato-cadmium(II)]

In the title compound, [Cd(HCOO)2(C10H8N2)]n, the CdII ion, located on a position with 2.22 site symmetry, is surrounded by two 4,4′-bipyridine ligands and four formate ligands in a distorted octahedral CdN2O4 coordination. The 4,4′-bipyridine ligands bridge the metal ions, forming one-dimensional chains along different directions, which are further connected by formate ligands into a topologically (1010.124.14)(10)3 three-dimensional network

Delivery of steric block morpholino oligomers by (R-X-R)4 peptides: structure–activity studies

Redirecting the splicing machinery through the hybridization of high affinity, RNase H- incompetent oligonucleotide analogs such as phosphoramidate morpholino oligonucleotides (PMO) might lead to important clinical applications. Chemical conjugation of PMO to arginine-rich cell penetrating peptides (CPP) such as (R-Ahx-R)4 (with Ahx standing for 6-aminohexanoic acid) leads to sequence-specific splicing correction in the absence of endosomolytic agents in cell culture at variance with most conventional CPPs. Importantly, (R-Ahx-R)4–PMO conjugates are effective in mouse models of various viral infections and Duchenne muscular dystrophy. Unfortunately, active doses in some applications might be close to cytotoxic ones thus presenting challenge for systemic administration of the conjugates in those clinical settings. Structure–activity relationship studies have thus been undertaken to unravel CPP structural features important for the efficient nuclear delivery of the conjugated PMO and limiting steps in their internalization pathway. Affinity for heparin (taken as a model heparan sulfate), hydrophobicity, cellular uptake, intracellular distribution and splicing correction have been monitored. Spacing between the charges, hydrophobicity of the linker between the Arg-groups and Arg-stereochemistry influence splicing correction efficiency. A significant correlation between splicing correction efficiency, affinity for heparin and ability to destabilize model synthetic vesicles has been observed but no correlation with cellular uptake has been found. Efforts will have to focus on endosomal escape since it appears to remain the limiting factor for the delivery of these splice-redirecting ON analogs