for Pharmacology and Experimental Therapeutics Effect of FK1 052, a Potent 5-Hydroxytryptamine3 and 5- Hydroxytryptamine4 Receptor Dual Antagonist, on Colonic Function in Vivo

ABSTRACT ABBREVIATiONS: 5-HT, 5-hydroxytryptamine; EC, enterochromaffin; 5-MeOT, 5-methoxytryptamine; WRS, wrap-restraint stress; IBS, irritable bowel syndrome; SCC, short-circuit current. 7

EFFECT OF NOCARDIA R UBRA CELL WALL SKELETON ON INTERLEUKIN 1 PRODUCTION FROM MOUSE PERITONEAL MACROPHAGES

Abstract --Nocardia rubra cell wall skeleton (N-CWS) was shown to augment interleukin 1 (IL-1) production from peritoneal resident and exudate macrophages in C3H/HeN mice. The mol. wt of the N-CWS-induced IL-I product was about 17,000 daltons, which is a similar weight to that obtained by lipopolysaccharide stimulation. The stimulation of IL-1 production by N-CWS was seen as early as 8 h after the start of incubation and peak production was observed at 48 h. Profound effects were seen with 10/ag/ml or more of N-CWS. Experiments on the regulation of the N-CWS-augmented IL-I production showed that prostaglandin E2 inhibited the augmentation, and indomethacin (cyclo-oxygenase inhibitor) further augmented it. Leukotriene B4 and AA861 (lipoxygenase inhibitor) had no effect. Our findings suggest that the previously reported adjuvant effect of N-CWS may, in part, be mediated via its ability to stimulate IL-1 production; and that such a stimulation may be blocked by prostaglandins

Metabolic Cycles Are Linked to the Cardiovascular Diurnal Rhythm in Rats with Essential Hypertension

Background: The loss of diurnal rhythm in blood pressure (BP) is an important predictor of end-organ damage in hypertensive and diabetic patients. Recent evidence has suggested that two major physiological circadian rhythms, the metabolic and cardiovascular rhythms, are subject to regulation by overlapping molecular pathways, indicating that dysregulation of metabolic cycles could desynchronize the normal diurnal rhythm of BP with the daily light/dark cycle. However, little is known about the impact of changes in metabolic cycles on BP diurnal rhythm. Methodology/Principal Findings: To test the hypothesis that feeding-fasting cycles could affect the diurnal pattern of BP, we used spontaneously hypertensive rats (SHR) which develop essential hypertension with disrupted diurnal BP rhythms and examined whether abnormal BP rhythms in SHR were caused by alteration in the daily feeding rhythm. We found that SHR exhibit attenuated feeding rhythm which accompanies disrupted rhythms in metabolic gene expression not only in metabolic tissues but also in cardiovascular tissues. More importantly, the correction of abnormal feeding rhythms in SHR restored the daily BP rhythm and was accompanied by changes in the timing of expression of key circadian and metabolic genes in cardiovascular tissues. Conclusions/Significance: These results indicate that the metabolic cycle is an important determinant of the cardiovascula

Modified percutaneous coronary intervention-derived risk models (PARIS and CREDO-Kyoto integer scoring systems) applied to Japanese transcatheter aortic valve replacement patients

Objective Postprocedural ischaemic and bleeding risks after transcatheter aortic valve replacement (TAVR) remain a major concern. Nevertheless, no reliable risk models incorporating both possibilities are currently available. We aimed to assess the accuracy of percutaneous coronary intervention (PCI)-derived models and the performance of a recalibrated model that included variables more applicable to TAVR.Methods This study included 26 869 patients who had been enrolled in a national registry. Ischaemic events were defined as myocardial infarction, stroke, transient ischaemic attack or peripheral embolism at 1 year. Bleeding events were defined as any bleeding based on the Valve Academic Research Consortium-2 consensus document at 1 year. Patterns of Non-adherence to Anti-Platelet Regimen in Stented Patients (PARIS) and Coronary Revascularisation Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) integer scoring systems were tested. The models were recalibrated by applying new variables using the Fine and Gray method.Results The 1-year cumulative incidences for ischaemic and bleeding events were 2.7% and 3.1%. Patients with high PARIS and CREDO-Kyoto risk scores had higher incidences of both ischaemic (3.3% vs 2.4% vs 2.4%, p<0.001 and 2.8% vs 2.0% vs 0.8%, p<0.001) and bleeding events (3.3% vs 2.5% vs 0.8%, p<0.001 and 3.7% vs 3.0% vs 2.4%, p<0.001) when compared with intermediate and low-risk patients. The receiver operating characteristic area under the curves for these models were 0.53, 0.58, 0.56 and 0.55, respectively. After the models were recalibrated to incorporate variables more applicable to TAVR, the performance of ischaemic and bleeding models modestly improved (0.58 and 0.61, respectively).Conclusions The PCI-derived models demonstrated modest accuracy but was inadequate for risk stratification of TAVR patients at 1-year follow-up.Trial registration number 3395

The Circadian Clock Maintains Cardiac Function by Regulating Mitochondrial Metabolism in Mice

<div><p>Cardiac function is highly dependent on oxidative energy, which is produced by mitochondrial respiration. Defects in mitochondrial function are associated with both structural and functional abnormalities in the heart. Here, we show that heart-specific ablation of the circadian clock gene <i>Bmal1</i> results in cardiac mitochondrial defects that include morphological changes and functional abnormalities, such as reduced enzymatic activities within the respiratory complex. Mice without cardiac <i>Bmal1</i> function show a significant decrease in the expression of genes associated with the fatty acid oxidative pathway, the tricarboxylic acid cycle, and the mitochondrial respiratory chain in the heart and develop severe progressive heart failure with age. Importantly, similar changes in gene expression related to mitochondrial oxidative metabolism are also observed in C57BL/6J mice subjected to chronic reversal of the light-dark cycle; thus, they show disrupted circadian rhythmicity. These findings indicate that the circadian clock system plays an important role in regulating mitochondrial metabolism and thereby maintains cardiac function.</p></div

Circadian desynchronization reduces cardiac function in C57BL/6J mice with drug-induced cardiomyopathy.

<p>(A) A light-dark (LD) cycle regimen used to examine the effects of a variable LD schedule on cardiac function. C57BL/6J mice were either maintained on a constant LD schedule (fixed LD cycle group) or were subjected to a 12-h phase shift in LD cycle every 3 days (disrupted LD cycle group). To compare the effects of the LD schedule between animals with healthy hearts and those with cardiomyopathy, either normal saline (NS) or phenylephrine (PE) was continuously infused via an osmotic pump in each LD cycle group. (B) Locomotor activity records of NS-infused (top panel) and PE-infused (bottom panel) mice. Two representative records from animals subjected to the fixed (left column) and disrupted (right column) LD cycle are shown. Activity counts are indicated by the vertical black marks. The records are double-plotted such that 48 h are shown for each horizontal trace. The blue shaded and unshaded areas indicate the dark and light period, respectively. The duration of NS or PE infusion is indicated by the vertical line at the right margin. (C) The ratios of heart weight to body weight (HW/BW) were increased by the PE infusion but were not influenced by the disruption in LD cycle (n = 5–8 per group). (D) The effects of PE, disrupted LD cycle, or both on ventricular function were evaluated using echocardiographic measurements (n = 5–8 per group). LVIDd, LVIDs, and FS are shown in bar graph format. Data are the mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01, two-way ANOVA.</p