Atherosclerosis is the biological basis of ischemic heart disease and ischemic stroke, the leading causes of death in the world. After decades of studies, the understanding of atherosclerosis has ...evolved dramatically, and inflammation has been recognized as one of the most relevant pillars in all phases of atherosclerotic disease. Nevertheless, only recently, the trial CANTOS, and subsequent outcome studies with colchicine, finally provided proof-of-concept evidence that anti-inflammatory therapies were able to reduce cardiovascular events with no influence on lipid levels. These landmark studies inaugurated an era of clinical and pre-clinical studies of immunomodulatory strategies focused on reduction of cardiovascular risk. Although there are promising results in the field, selection of the most appropriate immunomodulatory therapy and identification of patients who could benefit the most, are still enormous challenges. Further research is imperative before we can finally advance towards regular use of anti-inflammatory agents to reduce atherosclerotic events in our clinical practice.
Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) interact in the regulation of neuromuscular function in the
gut. They are also potent intestinal secretogogues that coexist in the ...enteric nervous system. The aims of this study were:
(1) to investigate the interaction between NO and VIP in inducing fluid secretion in the rat jejunum, and (2) to determine
whether the NO effect on intestinal fluid movement is neurally mediated. The single pass perfusion technique was used to study
fluid movement in a 25 cm segment of rat jejunum in vivo . A solution containing 20 m m l -arginine, a NO precursor, was perfused into the segment. The effect of the NO synthase inhibitors ( l -NAME and l -nitroindazole ( l -NI)) and the VIP antagonist (4Cl-D-Phe 6 ,Leu 17 VIP (VIPa)) on l -arginine-induced changes in fluid movement, expressed as μl min â1 (g dry intestinal weight) â1 , was determined. In addition, the effect of neuronal blockade by tetrodotoxin (TTX) and ablation of the myenteric plexus
by benzalkonium chloride (BAC) was studied. In parallel groups of rats, the effect of l -NAME and l -NI on VIP-induced intestinal fluid secretion was also examined. Basal fluid absorption in control rats was (median (interquartile
range)) 65 (45â78). l -Arginine induced a significant fluid secretion (â14 (â20 to â5); P < 0.01). This effect was reversed completely by l -NAME (60 (36â65); P < 0.01) and l -NI (46 (39â75); P < 0.01) and partially by VIPa (37 (14â47); P < 0.01). TTX and BAC partially inhibited the effect of l -arginine (22 (15â32) and 15 (10â26), respectively; P < 0.05). The effect of VIP on fluid movement (â23 (â26 to â14)) was partially reversed by l -NAME (24 (8.4â35.5); P < 0.01) and l -NI (29 (4â44); P < 0.01). The inhibition of VIP or NO synthase prevented l -arginine- and VIP-induced intestinal fluid secretion through a neural mechanism. The data suggest that NO enhances the release
of VIP from nerve terminals and vice versa. Subsequently, each potentiates the other's effect in inducing intestinal fluid
secretion.
Impairment of small intestinal absorption has been described in patients with ulcerative colitis and in animal models of experimental colitis. The pathophysiology of this dysfunction has not been ...elucidated. The aim of this study was to investigate the effect of chemical colitis on jejunal fluid absorption and determine the role of the enteric nervous system and some putative neurotransmitters. In a rat model of iodoacetamide-induced colitis, jejunal net fluid absorption was evaluated by the in vivo single-pass perfusion technique. The effects of 1) tetrodotoxin (TTX), 2) benzylalkonium chloride (BAC), 3) capsaicin, 4) vasoactive intestinal polypeptide (VIP) antagonism, 5) nitric oxide (NO) synthase (NOS) inhibition, and 6) 5-hydroxytryptamine type 3 and 4 (5-HT(3) and 5-HT(4)) receptor antagonism on the changes in fluid movement were investigated. A significant decrease in jejunal net fluid absorption was found 2 and 4 days after colitis induction: 26 (SD 14) and 28 (SD 19) microl x min(-1) x g dry intestinal wt(-1), respectively P < 0.0002 compared with sham rats at 61 (SD 6.5) microl x min(-1) x g dry intestinal wt(-1). No histological changes were evident in jejunal sections. TTX and BAC reversed this decrease in fluid absorption: 54 (SD 13) and 44 (SD 14) microl x min(-1) x g dry intestinal wt(-1) (P = 0.0005 and P = 0.019, respectively, compared with colitis). Ablation of capsaicin-sensitive primary afferent fibers had a partial effect: 45 (SD 5) microl x min(-1) x g dry intestinal wt(-1) (P = 0.001 and P = 0.003 compared with colitis and sham, respectively). Constitutive and neuronal NOS inhibition and VIP antagonism returned jejunal net fluid absorption to normal values: 66 (SD 19), 61 (SD 5), and 56 (SD 14) microl x min(-1) x g dry intestinal wt(-1), respectively. 5-HT(3) and 5-HT(4) receptor antagonism had no effect. Chemical colitis is associated with a significant decrease in jejunal net fluid absorption. This decrease is neurally mediated and involves VIP- and NO-related mechanisms.
In this paper, we propose a new dynamic model to describe the hysteresis phenomenon in harmonic drives. The experimental observation of the dynamic torque-displacement relationship for a harmonic ...drive shows a hysteresis characteristic indicating the simultaneous presence of energy storage and energy dissipation mechanisms. To completely characterize these mechanisms and yet have a simple representation for control, we develop a new hysteresis model using the heredity concept of dynamic systems. This model represents the hysteresis phenomenon by a combination of a nonlinear stiffness component and a nonlinear damping component leading to a mathematically well-posed nonlinear differential equation. The parameters of the model are identified using optimization techniques. We present some important mathematical properties of the model that give insight into model behavior and thus establish a mathematical basis for control. Numerical simulations in comparison with experimental data using our Harmonic Drive Test Apparatus verify the accuracy of the proposed model to represent the complex hysteresis dynamics of harmonic drives.
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