Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling

Activation of afferent nerves during urinary bladder (UB) filling conveys the sensation of UB fullness to the central nervous system (CNS). Although this sensory outflow is presumed to reflect graded increases in pressure associated with filling, UBs also exhibit nonvoiding, transient contractions (TCs) that cause small, rapid increases in intravesical pressure. Here, using an ex vivo mouse bladder preparation, we explored the relative contributions of filling pressure and TC-induced pressure transients to sensory nerve stimulation. Continuous UB filling caused an increase in afferent nerve activity composed of a graded increase in baseline activity and activity associated with increases in intravesical pressure produced by TCs. For each ∼4-mmHg pressure increase, filling pressure increased baseline afferent activity by ∼60 action potentials per second. In contrast, a similar pressure elevation induced by a TC evoked an ∼10-fold greater increase in afferent activity. Filling pressure did not affect TC frequency but did increase the TC rate of rise, reflecting a change in the length-tension relationship of detrusor smooth muscle. The frequency of afferent bursts depended on the TC rate of rise and peaked before maximum pressure. Inhibition of small- and large-conductance Ca(2+)-activated K(+) (SK and BK) channels increased TC amplitude and afferent nerve activity. After inhibiting detrusor muscle contractility, simulating the waveform of a TC by gently compressing the bladder evoked similar increases in afferent activity. Notably, afferent activity elicited by simulated TCs was augmented by SK channel inhibition. Our results show that afferent nerve activity evoked by TCs represents the majority of afferent outflow conveyed to the CNS during UB filling and suggest that the maximum TC rate of rise corresponds to an optimal length-tension relationship for efficient UB contraction. Furthermore, our findings implicate SK channels in controlling the gain of sensory outflow independent of UB contractility

Flickerlichtprovokation bei Vasospastikern verglichen mit gesunden Kontrollpersonen

BACKGROUND: Vascular dysregulation is considered to be a risk factor in several ophthalmic diseases. The purpose of this study was to evaluate the reaction of retinal vessels to flicker light in otherwise healthy subjects with a vasospastic propensity. PATIENTS AND METHODS: Thirty healthy Caucasians, aged between 18-35 years were recruited for this study and grouped into vasospastics, based on a history of frequent cold hands, even in summer, with concordant findings in nailfold capillary microscopy, or as controls, if such a history was absent. The reaction of the retinal vascular diameter to flicker light was observed in a distance of two to three discs diameters away from the optic nerve head with the retinal vessel analyser. Three phases of flicker light of twenty seconds followed by baseline light phases of eighty seconds were recorded. The maximal vasodilatory amplitude of each flicker phase was determined and the results averaged. RESULTS: The maximal average dilatory amplitude at the arterial side reached (mean +/- SD) 2.9 +/- 1.7 % and 4.8 +/- 2.6 % of the baseline amplitude respectively in vasospastic subjects and in healthy controls (t = 2.34; p = 0.025). The reaction at the venous side was statistically comparable in both groups. CONCLUSIONS: Otherwise healthy, vasospastic subject disclosed an altered reaction of the retinal vasculature to flicker light in this study

Endothelin A-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function

Secondary complications of diabetes mellitus often involve gastrointestinal dysfunction. In the experimental Goto Kakizaki rat, a model of Type II diabetes, hyperglycaemia and reduced glucose clearance is associated with elevated plasma endothelin (ET)-1 levels and selective decreases in nitric oxide synthase in circular muscle, longitudinal muscle and neuronal elements of the gastrointestinal tract. Functionally, this is accompanied by decreased nitrergic relaxatory responses of jejunal longitudinal muscle to tetrodotoxin-sensitive electrical field stimulation. Long-term treatment with a selective ET A-type receptor antagonist, markedly reduced hyperglycaemia and restored plasma glucose clearance rates towards normal. This was associated with a restoration of N(G)-nitro-L-arginine methyl ester-sensitive relaxatory responses of jejunal longitudinal muscle to electrical field stimulation. The results indicate that beneficial effects of ETA receptor blockade on gastrointestinal function may result from an improvement in insulin sensitivity with concomitant reduction of the severity of hyperglycaemia. ETA receptor blockade may represent a new therapeutic principle for improving glucose tolerance in Type II diabetes and could be beneficial in alleviating or preventing hyperglycaemia-related secondary complications in this condition

Echoanatomical patterns of the long saphenous vein in patients with primary varices and in healthy subjects

Objective: To evaluate the pathway of reflux in incompetent long saphenous veins (LSVs), paying particular attention to the role of longitudinal saphenous tributaries in the thigh (accessory saphenous veins, ASVs). Design: Prospective study in a group of patients with primary varices. Comparison with the anatomical patterns in a group of normal subjects. Setting: Private phlebology practice. Patients: Sixty-seven patients with primary varices (100 limbs) and 66 subjects without varices and with competent saphenous veins (120 limbs). Methods: Duplex ultrasound evaluation of the saphenous system in the thigh of patients and healthy subjects. The 'eye' ultrasonographic sign was used as the marker to distinguish the LSV from the longitudinal tributary veins of the thigh. Results: In 57% of limbs in patients with varices, reflux followed the saphenous vein, while in 43% the reflux spilled outside the LSV into an ASV (h or S types). When reflux followed the saphenous vein, no large calibre ASVs could be observed. In 30% of limbs in control subjects a parallel tributary vein with a similar calibre was found joining the LSV. Conclusion: Clinically visible varices in the thigh rarely comprise the LSV itself, but are usually dilated ASVs, the reflux stream passing from the proximal LSV into a more superficial ASV. The distal LSV running parallel beneath is often competent. In subjects with healthy LSVs, a large competent tributary vein is already present in the thigh in 30% of cases. This suggests that superficial deviation of reflux flow into an ASV in patients with varices may not arise from haemodynamically acquired changes, but could have a congenital origin. This could even be a predisposing factor in the development of varices

Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy

BACKGROUND: New chemotherapy regimens are increasingly used in metastatic colorectal cancer to the liver before surgery. Some clinical observations have suggested that chemotherapy may affect liver regeneration. AIMS: The aim of this study was to evaluate liver damage and liver regeneration after chemotherapy treatment in a model of partial hepatectomy. METHODS: C57BL/6 mice were repeatedly treated with intraperitoneal injections of either saline or different chemotherapy regimens including the drugs 5-fluorouracyl (5-FU), irinotecan, oxaliplatin, gemcitabine and combined treatments with 5-FU/irinotecan, 5-FU/oxaliplatin. A 70% partial hepatectomy was performed 1 week after the last injection. Ki-67 and PCNA immunohistochemistry were performed to assess liver regeneration, serum liver enzymes and histology analysis to evaluate injury. RESULTS: A variety of chemotherapeutic agents used at maximum tolerated doses compatible with survival affected body weight and blood cell levels. However, these regimens did not affect liver injury before and after hepatectomy nor did they impair liver regeneration. Liver histology showed no steatosis, fibrosis or inflammation before hepatectomy. We therefore tested whether chemotherapy in presence of diet-induced steatosis may trigger injury. Even under these conditions, we did not observe histological signs of inflammation or sinusoidal injury. CONCLUSIONS: Liver injury and liver regeneration are not impaired after neoadjuvant chemotherapy with 5-FU, irinotecan, oxaliplatin and gemcitabine in non-tumoural liver parenchyma. In addition, combined treatments disclose no adverse effects on liver regeneration. Chemotherapy alone induces no histological alterations even in the presence of steatosis