Kontracepcija

<div><p>Aims</p><p>To determine the mechanisms by which the α_1A-adrenergic receptor (AR) regulates cardiac contractility.</p><p>Background</p><p>We reported previously that transgenic mice with cardiac-restricted α_1A-AR overexpression (α_1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gα_q/11-coupled receptor in hypertrophy.</p><p>Methods</p><p>Contractility, calcium (Ca²⁺) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from α_1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after α_1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.</p><p>Results</p><p>Hypercontractility without hypertrophy with α_1A-AR overexpression is shown to result from increased intracellular Ca²⁺ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca²⁺ concentration [Ca²⁺]_i transient without changing resting [Ca²⁺]_i. In the <i>absence</i> of agonist, however, α_1A-AR overexpression <i>reduced</i> contractility despite unchanged [Ca²⁺]_i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its Gα_q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the α_1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca²⁺ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective α_1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without α_1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.</p><p>Conclusions</p><p>We report for the first time pleiotropic α_1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.</p></div

Cosupplementation with a synthetic, lipid-soluble polyphenol and vitamin C inhibits oxidative damage and improves vascular function yet does not inhibit acute renal injury in an animal model of rhabdomyolysis

We investigated whether cosupplementation with synthetic tetra-tert-butyl bisphenol (BP) and vitamin C (Vit C) ameliorated oxidative stress and acute kidney injury (AKI) in an animal model of acute rhabdomyolysis (RM). Rats were divided into groups: Sham and Control (normal chow), and BP (receiving 0.12% w/w BP in the diet; 4 weeks) with or without Vit C (100 mg/kg ascorbate in PBS ip at 72, 48, and 24 h before RM induction). All animals (except the Sham) were treated with 50% v/v glycerol/PBS (6 mL/kg injected into the hind leg) to induce RM. After 24 h, urine, plasma, kidneys, and aortae were harvested. Lipid oxidation (assessed as cholesteryl ester hydroperoxides and hydroxides and F 2-isoprostanes accumulation) increased in the kidney and plasma and this was coupled with decreased aortic levels of cyclic guanylylmonophosphate (cGMP). In renal tissues, RM stimulated glutathione peroxidase (GPx)-4, superoxide dismutase (SOD)-1/2 and nuclear factor kappabeta (NFκβ) gene expression and promoted AKI as judged by formation of tubular casts, damaged epithelia, and increased urinary levels of total protein, kidney-injurymolecule-1 (KIM-1), and clusterin. Supplementation with BP ± Vit C inhibited the two indices of lipid oxidation, down-regulated GPx-4, SOD1/2, and NF-κβ gene responses and restored aortic cGMP, yet renal dysfunction and altered kidney morphology persisted. By contrast, supplementation with Vit C alone inhibited oxidative stress and diminished cast formation and proteinuria, while other plasma and urinary markers of AKI remained elevated. These data indicate that lipid- and watersoluble antioxidants may differ in terms of their therapeutic impact on RM-induced renal dysfunctio

Phenolic antioxidants tert-butyl-bisphenol and vitamin E decrease oxidative stress and enhance vascular function in an animal model of rhabdomyolysis yet do not improve acute renal dysfunction

Rhabdomyolysis (RM) caused by severe burn releases extracellular myoglobin (Mb) that accumulates in the kidney. Extracellular Mb is a pro-oxidant. This study tested whether supplementation with tert-butyl-bisphenol (BP) or vitamin E (Vit E, as α-tocopherol) at 0.12% w/w in the diet inhibits acute renal failure (ARF) in an animal model of RM. After RM-induction in rats, creatinine clearance decreased (p < 0.01), proteinuria increased (p < 0.001) and renal-tubule damage was detected. Accompanying ARF, biomarkers of oxidative stress (lipid oxidation and hemeoxygenase-1 (HO-1) gene and protein activity) increased in the kidney (p < 0.05). Supplemented BP or Vit E decreased lipid oxidation (p < 0.05) and HO-1 gene/activity and restored aortic cyclic guanylyl monophosphate in control animals (p < 0.001), yet ARF was unaffected. Antioxidant supplementation inhibited oxidative stress, yet was unable to ameliorate ARF in this animal model indicating that oxidative stress in kidney and vascular cells may not be causally related to renal dysfunction elicited by RM

Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury

Treatments to inhibit or repair neuronal cell damage sustained during focal ischemia/reperfusion injury in stroke are largely unavailable. We demonstrate that dietary supplementation with the antioxidant di-tert-butyl-bisphenol (BP) before injury decreases infarction and vascular complications in experimental stroke in an animal model. We confirm that BP, a synthetic polyphenol with superior radical-scavenging activity than vitamin E, crosses the blood-brain barrier and accumulates in rat brain. Supplementation with BP did not affect blood pressure or endogenous vitamin E levels in plasma or cerebral tissue. Pre-treatment with BP significantly lowered lipid, protein and thiol oxidation and decreased infarct size in animals subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. This neuroprotective action was accompanied by down-regulation of hypoxia inducible factor-1α and glucose transporter-1 mRNA levels, maintenance of neuronal tissue ATP concentration and inhibition of pro-apoptotic factors that together enhanced cerebral tissue viability after injury. That pre-treatment with BP ameliorates oxidative damage and preserves cerebral tissue during focal ischemic insult indicates that oxidative stress plays at least some causal role in promoting tissue damage in experimental stroke. The data strongly suggest that inhibition of oxidative stress through BP scavenging free radicals in vivo contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection.15 page(s

Dietary Protein to Carbohydrate Ratio and Caloric Restriction: Comparing Metabolic Outcomes in Mice

Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake