Endothelin receptor antagonists in a beagle model of pulmonary hypertension: Contribution to possible potential therapy?

Objectives.This study investigated the pharmacologic effect of endothelin receptor antagonists on cardiopulmonary hemodynamic variables in a beagle model of pulmonary hypertension.Background.We recently developed a beagle model of pulmonary hypertension that allows accurate determination of cardiopulmonary hemodynamic variables and is associated with elevated plasma endothelin-1 concentrations similar to those in pulmonary hypertension in humans.Methods.Twelve beagles (pulmonary hypertension, n = 6; control group, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (an ETA receptor antagonist), RES-701-1 (an ETB receptor antagonist), nitroglycerin and prostaglandin E1. Pulmonary hypertension was induced in experimental beagles 8 weeks after injection with 3 mg/kg body weight of dehydromonocrotaline.Results.FR139317 lowered pulmonary artery and systemic arterial pressures in both pulmonary hypertensive and control beagles, with a significantly greater effect on pulmonary artery pressure in pulmonary hypertensive dogs. RES-701-1 tended to increase pulmonary artery pressure only in pulmonary hypertensive beagles. Nitroglycerin depressed pulmonary artery and systemic arterial tone equally well in control and pulmonary hypertensive animals. Prostaglandin E1produced a greater decrease in systemic arterial pressure in pulmonary hypertensive than in normal beagles despite having the same effect on pulmonary artery pressure in both.Conclusions.ETA receptor antagonists decrease pulmonary artery pressure in a beagle model and may therefore be clinically useful for treatment of pulmonary hypertension

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin-related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 μM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs

Clinical Experience of Laser Angioplasty for the Cardiovascular Disease

In recent years, lasers are being utilized in cardiovascular surgery. Since the 1980's we have investigated angioplasty using an Argon laser for patients with obstructive arterial diseases. This technique aims to open the obstructive arterial lumen. Based on the excellent results of experimental studies, the technique has been clinically applied. Laser angioplasty was carried out in 84 patients with stenotic or obstructive lesions occluding more than 75% of peripheral and coronary arteries angiographically. They consisted of 74 cases with intermittent claudication and 10 cases with angina pectoris. Laser angioplasty for the peripheral arterial disease was performed under local anesthesia in the inguinal region under angioscopic guidance. On the other hand, laser coronary angioplasty was simultaneously undertaken at the time of coronary artery bypass grafting for a patient with multiple coronary stenoses. The initial success rate by laser angioplasty for the peripheral artery was 91% in the stenotic lesions and 71% in the obstructive lesions. The cumulative patency rate was 94% in the stenotic lesions and 83% in the occlusive lesions. A follow-up study of 66 months was carried out for patients with clinical success, excluding the cases where an angiogram showed occlusion within 1 week after laser angioplasty. Consequently, excellent long-term results could be clinically obtained. Based on the satisfactory results in the peripheral artery, coronary laser angioplasty was employed in 10 patients with angina pectoris. There were no complications by laser. Thus, the feasibility of laser application was apparently confirmed and laser angioplasty might be recommended for patients with atherosclerotic changes, especially for small arteries

Effects of phlebotomy on the growth of ferric nitrilotriacetate-induced renal cell carcinoma.

The ferric nitrilotriacetate-induced carcinogenesis model is unique in that reactive oxygen species-free radicals are involved in the carcinogenic process. But the effects of iron-withdrawal in the progression of renal cell carcinoma are not well understood. We performed repeated phlebotomies on animals that had been administered ferric nitrilotriacetate in the initiation stage of renal cell carcinoma (phlebotomy group), and compared the development of renal tumors with those not receiving repeated phlebotomies (non-phlebotomy group). Ferric nitrilotriacetate-treated male Wistar rats were randomly divided into 2 groups: a phlebotomy group (21 rats) and a non-phlebotomy group (17 rats). Ten age-adjusted normal rats were also observed as a normal group. Hematocrit was maintained under 25% in the phlebotomy group. Hematocrit levels in the normal group and in the non-phlebotomy group were not significantly different. As a result, the incidence of renal cell carcinoma was not significantly different between phlebotomy and non-phlebotomy animals. However, the total weight of the renal cell carcinoma was significantly heavier in the animals from non-phlebotomy group than in those from the phlebotomy group (23.64 g +/- 18.54 vs. 54.40 g +/- 42.40, P &#60; 0.05). The present study demonstrated that phlebotomy after the administration of ferric nitrilotriacetate did not reduce the incidence of renal cell carcinoma. In addition, we showed that iron withdrawal at the promotion stage of carcinogenesis will retard tumor growth.</p

Reaction-Diffusion Pattern in Shoot Apical Meristem of Plants

A fundamental question in developmental biology is how spatial patterns are self-organized from homogeneous structures. In 1952, Turing proposed the reaction-diffusion model in order to explain this issue. Experimental evidence of reaction-diffusion patterns in living organisms was first provided by the pigmentation pattern on the skin of fishes in 1995. However, whether or not this mechanism plays an essential role in developmental events of living organisms remains elusive. Here we show that a reaction-diffusion model can successfully explain the shoot apical meristem (SAM) development of plants. SAM of plants resides in the top of each shoot and consists of a central zone (CZ) and a surrounding peripheral zone (PZ). SAM contains stem cells and continuously produces new organs throughout the lifespan. Molecular genetic studies using Arabidopsis thaliana revealed that the formation and maintenance of the SAM are essentially regulated by the feedback interaction between WUSHCEL (WUS) and CLAVATA (CLV). We developed a mathematical model of the SAM based on a reaction-diffusion dynamics of the WUS-CLV interaction, incorporating cell division and the spatial restriction of the dynamics. Our model explains the various SAM patterns observed in plants, for example, homeostatic control of SAM size in the wild type, enlarged or fasciated SAM in clv mutants, and initiation of ectopic secondary meristems from an initial flattened SAM in wus mutant. In addition, the model is supported by comparing its prediction with the expression pattern of WUS in the wus mutant. Furthermore, the model can account for many experimental results including reorganization processes caused by the CZ ablation and by incision through the meristem center. We thus conclude that the reaction-diffusion dynamics is probably indispensable for the SAM development of plants

CD56-positive cells with or without synaptophysin expression are recognized in the pancreatic duct epithelium: a study with adult and fetal tissues and specimens from chronic pancreatitis.

We observed the distribution of CD56+ epithelial cells in the pancreatic duct system using 25 fetal, one infantile, 3 normal adult, 4 diabetic, and 8 chronically inflamed pancreatic tissue samples. In the early stage of gestation (12 to 17 weeks), CD56+ cells were commonly seen in the immature tubular structures. They were often continuous to pancreatic islets, and their distribution was similar to that of synaptophysin (Syn)+ cells, suggesting that they are precursors of islet neogenesis. Their number decreased in proportion to gestational age. Instead, from 24 weeks of gestation, luminal cell clusters that were common in interlobular ducts revealed CD56+. These cell clusters were unrelated to islet neogenesis and Syn expression. Similar CD56+ luminal cell clusters were also observed in cases of chronic pancreatitis, whereas they were scarce in normal adult and diabetic tissues. CD56+ cells were also occasionally seen in intralobular ducts, intercalated ducts, and centroacinar cells in cases of chronic pancreatitis. We conclude that there are two types of CD56+ epithelial cells in the pancreatic duct system: CD56+ endocrine cells are numerous during the early stage of gestation, when islet neogenesis appears, while CD56+ luminal cells may represent developmental and regenerative changes of pancreatic ducts.</p