Splenic arterial neurovascular bundle stimulation in esophagectomy: A feasibility and safety prospective cohort study.

Introduction: The autonomic nervous system is a key regulator of inflammation. Electrical stimulation of the vagus nerve has been shown to have some preclinical efficacy. However, only a few clinical studies have been reported to treat inflammatory diseases.

Acute effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity and cardiorespiratory responses in dogs.

New Findings: What is the central question of this study? What are the effects of insulin and insulin-induced hypoglycaemia on carotid body chemoreceptor activity in vivo and how do carotid body chemoreceptor stimulation-mediated cardiorespiratory responses in beagle dogs compare during euglycaemia and insulin-induced hypoglycaemia? What is the main finding and its importance? Intracarotid insulin administration leads to sustained increase in carotid body chemoreceptor activity and respiratory response with significant cardiovascular effects. Insulin-induced hypoglycaemia exacerbated NaCN-mediated carotid body chemoreceptor activity and respiratory response with enhanced cardiovascular reflex response. These findings suggest that insulin-induced hypoglycaemia augments the carotid body chemoreceptors to initiate the adaptive counter-regulatory responses to restore the normoglycaemic condition.

Alpha-1 Acid Glycoprotein as a Biomarker for Subclinical Illness and Altered Drug Binding in Rats.

Alpha-1 acid glycoprotein (AGP) is a significant drug binding acute phase protein that is present in rats. AGP levels are known to increase during tissue injury, cancer and infection. Accordingly, when determining effective drug ranges and toxicity limits, consideration of drug binding to AGP is essential.

Strain echocardiography combined with pharmacological stress test for early detection of anthracycline induced cardiomyopathy.

Introduction: Advances in echocardiography, including 2-D speckle tracking to quantitate myocardial strain and strain rate, have improved myocardial functional and mechanical evaluation and may provide a more sensitive assessment of cardiac functional and mechanical changes. Additionally, evaluating myocardial performance induced by a pharmacologic stress test (dobutamine infusion) may further improve the evaluation of potential changes in cardiac function. This study evaluates the use of 2-D speckle tracking strain echocardiography (2DSE) combined with a dobutamine stress test to detect doxorubicin induced cardiomyopathy in the rat.

Technologies: preclinical imaging for drug development.

Preclinical imaging with magnetic resonance imaging (MRI), computerised tomography (CT), ultrasound (US), positron emission tomography (PET) or single-photon emission computed tomography (SPECT) enable non-invasive measures of tissue structure, function or metabolism in vivo. The technologies can add value to preclinical studies by enabling dynamic pharmacological observations on the same animal and because of possibilities for relatively direct clinical translation. Potential benefits from the application of preclinical imaging should be considered routinely in drug development.

Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress.

Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD).

Gastric pH and gastric residence time in fasted and fed conscious beagle dogs using the Bravo pH system.

To further characterize the time course of gastric pH with respect to meals and gastric residence times (GRTs) in dogs, continuous pH measurements were recorded with Bravo capsules, which were attached to the dogs' stomach mucosa or administered as free capsules, respectively. Experiments took place in home or study cages, and meals were administered at designated times. Up until 2 h prior to mealtime, the fasted gastric pH remained constantly acidic (∼2.

Continuing education course #1: non-invasive imaging as a problem-solving tool and translational biomarker strategy in toxicologic pathology.

The continuing education course "Non-Invasive Imaging as a Problem-Solving Tool and Translational Biomarker Strategy in Toxicologic Pathology" provided a thorough overview of commonly used imaging modalities and the logistics required for integration of small animal imaging into toxicologic pathology. Non-invasive imaging (NIN) is gaining acceptance as an important modality in toxicologic pathology. This technology allows nonterminal, time-course evaluation of functional and morphologic endpoints and can be used to translate biomarkers between preclinical animal models and human patients.

Differences in effects on myocardium and mitochondria by angiogenic inhibitors suggest separate mechanisms of cardiotoxicity.

Several multikinase angiogenesis inhibitors demonstrate mitochondrial and/or cardiovascular toxicity, suggesting an on-target pharmacologic effect. To evaluate whether cardiotoxicity is directly related to vascular endothelial growth factor receptor inhibition, we investigated the effects of sunitinib, sorafenib, and pazopanib on myocardial function and structure. We used a rat model to assess myocardial effects of the inhibitors concurrently exposed to the cardiac stressor dobutamine.

Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease.

The evidence is compelling for a role of inflammation in cardiovascular diseases; however, the chronic use of anti-inflammatory drugs for these indications has been disappointing. The recent study compares the effects of two anti-inflammatory agents [cyclooxygenase 2 (COX2) and p38 inhibitors] in a model of cardiovascular disease. The vascular, renal, and cardiac effects of 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one (rofecoxib; a COX2 inhibitor) and 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide [GSK-AHAB, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor], were examined in the spontaneously hypertensive stroke-prone rat (SHR-SP).

Urodynamic measurements by radiotelemetry in conscious, freely moving beagle dogs.

Purpose: Urodynamics have been traditionally recorded in anesthetized or conscious animals implanted with a bladder catheter that is used to artificially fill the bladder while measuring intravesicular bladder pressure. Anesthesia alters the urodynamics and in the conscious state this methodology requires that the dogs be tethered/restrained, which evokes stress and limits the period of continuous urodynamic assessment. A more physiological and chronic method of evaluating pharmacological responses on urodynamics is necessary.

GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog.

Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by beta3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective beta3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective beta3-AR agonist, (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid (GW427353; solabegron) on bladder function in the dog using in vitro and in vivo techniques.

Gastric pH and gastric residence time in fasted and fed conscious cynomolgus monkeys using the Bravo pH system.

Purpose: To measure fasted and fed gastric pH and gastric residence time (GRT) in Cynomolgus monkeys using Bravo radiotelemetry capsules.

Methods: Continuous pH measurements were recorded with Bravo capsules, which were either attached to the monkeys' stomach or administered as free capsules. Meals (either slurry or standard), were administered at designated times with monkeys chair-restrained during slurry meal ingestion.

Effects of p38 MAPK Inhibitor on angiotensin II-dependent hypertension, organ damage, and superoxide anion production.

Angiotensin II (Ang II) activates p38 mitogen-activated protein kinase (p38 MAPK) and increases reactive oxygen species (ROS), but the nature of the relationship in vivo is not fully understood. We assess the effect of SB239063AN, a highly selective, orally active, p38 MAPK inhibitor, on Ang II-dependent hypertension, target-organ damage and ROS production. Sprague-Dawley rats and MAPKAP kinase-2 knockout mice were infused with Ang II.

Carvedilol prevents and reverses hypertrophy-induced cardiac dysfunction.

Background/aims: Histological studies have provided evidence that carvedilol can prevent cardiac hypertrophy in spontaneously hypertensive-stroke prone rats (SP) fed a high-fat and -salt diet. However, the effects of carvedilol on cardiac function have not been studied in these animals. In addition, the ability of carvedilol to reverse established cardiac hypertrophy and dysfunction under these conditions remains to be determined.

Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection.

Objective: Evidence suggests important relationships among chronic inflammatory processes, endothelial dysfunction, hypertension and target organ damage. The present study examined the effects of chronic treatment with an anti-inflammatory p38 mitogen-activated protein kinase (MAPK) inhibitor (SB-239063AN) in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (SHR+l-NAME) model of severe hypertension and accelerated target organ damage.

Methods: SHRs were divided into control (n=16), l-NAME (n=26) and l-NAME+SB-239063AN (n=24) groups.

Eprosartan improves cardiac performance, reduces cardiac hypertrophy and mortality and downregulates myocardial monocyte chemoattractant protein-1 and inflammation in hypertensive heart disease.

Objective: The purpose of this investigation was to determine whether angiotensin II receptor (AII1R) antagonism interferes with cardiac monocyte chemoattractant protein-1 (MCP-1) expression in hypertrophic cardiomyopathy and failure.

Design: We studied the effects of the AII1R antagonist eprosartan on MCP-1 expression, and on the recruitment of macrophages into the myocardium in a model of cardiac hypertrophy and morbidity/mortality.

Methods: Stroke-prone spontaneously hypertensive rats fed a high-salt, high-fat diet (SFD) developed heart failure characterized by left ventricular (LV) hypertrophy/pathology and hypocontractility.

A New Method to Collect Bile and Access the Duodenum in Conscious Dogs.

A novel, totally implantable catheter system that allows complete bile collection and duodenal access in conscious, freely moving dogs is described. Bile collection catheters remained patent for an average of 417 days (range, 711010 days) in eight animals which were used on study. Three animals have been used to validate the models complete collection of bile via biliary recovery of an intravenous dose of 14C-glycocholic acid, and in selected animals, parameters potentially indicative of liver damage (serum alanine aminotransferase, alkaline phosphatase, gamma glutamyltransferase, and total bilirubin levels) were within normal ranges for as many as 14 months after surgery.

A novel method for chronic measurement of respiratory function in the conscious monkey.

Introduction: Chronic measurement of respiratory function in the conscious monkey has been limited by the ability to monitor pleural pressure. Previous attempts to measure pleural pressure chronically in conscious animals have involved surgical implantation of pressure-sensitive catheters directly into the pleural cavity. The success of these techniques has been limited by lung damage and/or tissue growth and encapsulation of the pressure-sensitive catheter with damping or loss of the signal.

Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction.

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions.

Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction.

Background: Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage.

Methods And Results: In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation.

Ultrasound imaging: principles and applications in rodent research.

Ultrasound imaging utilizes the interaction of sound waves with living tissue to produce an image of the tissue or, in Doppler-based modes, determine the velocity of a moving tissue, primarily blood. These dynamic, real time images can be analyzed to obtain quantitative structural and functional information from the target organ. This versatile, noninvasive diagnostic tool is widely used and accepted in human and veterinary medicine.

Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats.

Objective: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).

Methods: SP were fed a high fat (24.

Human urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate.

The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynamic homeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD2s < or = 9) approximately an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the most, if not the most, potent mammalian vasoconstrictor identified to date.