Effects of ATP-sensitive potassium channel opener iptakalim against ventricular remodeling and its mechanisms of endothelial protection / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To study the effects of iptakalim (Ipt), an ATP-sensitive potassium channel opener, on cardiac remodeling induced by isoproterenol (ISO) in Wistar rats.</p><p><b>METHODS</b>ISO was given subcutaneously (85 mg/(kg x d), sc, 7 days) to induce cardiac remodeling in rats. The rats in Ipt treated group were administrated with Ipt 3 mg/kg (po) after ISO injection. After treated with Ipt for 6 weeks, the hemodynamic parameters were tested by an eight channel physiological recorder (RM-6000). Then the heart weight was weighed and the cardiac remodeling index was calculated. HE stain and Masson's stain were employed to perform histological analysis, the hydroxyproline(Hyp) content in cardiac tissue was detected by colorimetric method, radioimmunoassay was used to measure the plasma levels of endothelin-1 (ET-1) and prostacyclin (PGI2).</p><p><b>RESULTS</b>Six weeks after ISO injection, the cardiac functions of model group were damaged markedly compared with those of normal group. The characteristics of ventricular remodeling in model group included that the heart weight index, myocyte cross-sectional area, myocardial fibrosis, and the hydroxyproline content in cardiac tissue were all increased significantly. The plasma level of ET-1 was increased, while the plasma level of PGI2 was decreased significantly. These changes could be reversed by Ipt treatment (3 mg/(kg x d) for 6 weeks).</p><p><b>CONCLUSION</b>Ipt can reverse cardiac remodeling induced by isoproterenol in rats. The endothelial protective effect regulating effects of Ipt on the balance between the ET-1 and PGI2 system may be involved in its mechanisms.</p>

Pulmonary hypertension in infants with bronchopulmonary dysplasia / 소아과

An increase in the number of preterm infants and a decrease in the gestational age at birth have resulted in an increase in the number of patients with significant bronchopulmonary dysplasia (BPD) and secondary pulmonary hypertension (PH). PH contributes significantly to the high morbidity and mortality in the BPD patients. Therefore, regular monitoring for PH by using echocardiography and B-type natriuretic peptide (BNP) or N-terminal-proBNP must be conducted in the BPD patients with greater than moderate degree to prevent PH and to ensure early treatment if PH is present. In the BPD patients with significant PH, multi-modality treatment, including treatment for correcting an underlying disease, oxygen supply, use of diverse selective pulmonary vasodilators (inhaled nitric oxide, inhaled prostacyclins, sildenafil, and endothelin-receptor antagonist) and other methods, is mandatory.

Effects of iloprost [a prostacyclin analogue] on the endothelial dysfunction and foot ulcers in diabetic patients with peripheral arterial disease

To asses the efficiency of iloprost [an analogue of prostacyclin] infusion on endothelial functions and amputation rate in diabetic foot ulcers with complicated macroangiopathy Sixty [36 men/ 24 women] type 2 diabetic patients [61.8 +/- 9.7 years, mean +/- SD] with diabetic foot ulcer and peripheral arterial occlusive disease, stage III or more by Wagner classification, and 15 [9 male/ 6 female] healthy controls [60.7 +/- 9.1 years, mean +/- SD] were enrolled in the study. Thirty patients [group I] had iloprost infusion [0.5-2 ng/kg/min for 6 h] for 10 consecutive days. Endothelial functions were determined by brachial arterial flow mediated dilation [FMD] method at stage 0 [basal], 10th and 30th days. Group II patients [n=30] were treated in the same manner as group I except iloprost treatment constituting a patient control group Group I patients showed a significant improvement in the endothelial functions at 10th day, and 30th day [p=0.002] in respect to group II. There were no differences between group I and group II regarding the hospitalization period and amputation rates. Iloprost was well tolerated. Three patients had adverse reactions such as maculo-papular skin eruptions, itching, hypotension and dyspnea due to iloprost infusion; one completed the treatment and 2 had to discontinue the iloprost infusion. Ten-day iloprost infusion therapy to patients with diabetic foot ulcers seems to be efficient in the improvement of endothelial function, but, despite our positive clinical observation, this improvement does not affect the outcome of the amputation rates at 30 days follow up period

The Effect of Prostaglandin E1 on Apotosis in Ischemic Skin Island Flap of Rats

Apoptosis is a physiologic or programmed cell death process which is controlled by genes and it is essential for the function and the appropriate development of multicellular organism. Apoptosis is also thought to be one of the main mechanisms of cell death in ischemic tissues. The effect of prostaglandin E1(PGE1) is proven to be useful in the recovery of ischemic changes by inducing vasodilation of peripheral vessels and platelet disaggregation. Prostaglandin is also known to suppress apoptosis in a serum deprived cell. The purpose of this study is to evaluate the effects of PGE1 on the apoptosis in the ischemic skin island flap. Thirty Sprague-Dawley rats were used. In control group(n=15), 3x5cm sized skin island flap based on the superficial epigastric vessel was elevated and its pedicle was occluded for 14 hours. After removing the vessel clamp, skin flap was reperfused for 5 hours and harvested. In experimental group(n=15), a ischemic skin island flap was also made as in the control group except the interarterial administration of the PGE1 right after elevation of the flap and after removing the clamp. H&E, TUNEL and immunohistochemical stains for p53 and bax proteins were performed. There were ischemic changes in gross and microscopic findings in both groups. Immunohistochemical staining for p53 protein shows many positive cells with nuclear staining in squamous epithelium of the control group, but sparse positive cells in the experimental group. Immunohistochemical stainings for bax protein shows many positive cells with cytoplasmic staining in squamous epithelium of the control group, but sparse positive cells in the experimental group. The apoptotic index was significantly lower in the experimental group(2.39+/-1.76(p=0.0001)) than in the control group(7.53+/-2.05). These data indicate that PGE1 suppresses the apoptosis in the ischemic skin island flap.

IL-1beta Mediated COX-2 Expression in Human Airway Epithelial Cells / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Prostaglandin is one of the important inflammatory mediator in inflammatory diseases. Cyclooxygenase-2 (COX-2) plays a key role in biosynthesis of prostaglandins. In this study, we aimed to investigate COX-2 expression and prostaglandin E2 (PGE2) production by interleukin-1beta (IL-1beta) in cultured human airway epithelial cells. MATERIALS AND METHOD: COX-2 gene expression, and COX-2 protein, PGE2 production by IL-1beta were analyzed by RT-PCR, Western blot, and enzymeimmunoassay (EIA) in cultured human airway NCI-H292 epithelial cells. RESULTS: The COX-2 protein production was increased when the cells were exposed to IL-1beta in a dose dependent manner. The maximum level of COX-2 protein was detected at 20 ng/ml of IL-1beta. After 4 hours, the production of COX-2 protein was detected by IL-1beta(20 ng/ml) and this was held up to 12 hour. The maximum level of COX-2 protein production reached at 8 hour of exposure to IL-1beta and this was held up to 12 hour. The release of PGE2 occurred in the same pattern as the IL-1beta-mediated COX-2 protein production. The COX-2 gene expression was induced by IL-1beta (20 ng/ml). The IL-1beta-mediated COX-2 expression was suppressed by actinomycin D, but was not affected by cycloheximide. CONCLUSION: These results suggest that the IL-1beta-mediated COX-2 expression and the PGE2 production were increased in dose and time dependent manner and regulated in the transcriptional step.

Prostaglandin in regulations of renal blood flow during partial ureteral obstruction in dogs

Ureteral obstruction causes increase in renal blood flow (RBF) and partial impairment of the autoregulation of RBF. Although increased renal prostaglandin production is responsible for the former, it is not clear whether or not it is also responsible for the latter. Therefore, we investigated the role which prostaglandins play in the autoregulation of RBF during an ureteral pressure elevation (40 cmH2O). Since the major mechanism of RBF autoregulation is the tubuloglomerular feedback studying the interaction between ureteral pressure and RBF autoregulation may reveal the role of prostaglandin in tubuloglomerular feedback. To pursue the purpose, six anesthetized dogs were prepared for the measurements of RBF, mean systemic and renal arterial pressure (RAP) and the manipulation of ureteral pressure. The autoregulation curves were determined during both control and elevation of the ureteral pressure, before and after the pretreatment with indomethacin, a cyclooxygenase inhibitor. The desired ureteral pressure was achieved by vertically elevating the water-filled reservoir connected to the ureteral catheter to 40 cm above the kidney level. In response to the elevation of the ureteral pressure, RBF increased from 170 +/- 8 ml cntdot min -1 to 189+/-8, and the systemic arterial pressure didn't change significantly. During spontaneous urine flow, RBF autoregulation was abolished when RAP was reduced to 59+/-3 mmHg. On the other hand, during the ureteral pressure elevation, the autoregulation curves shifted upward and rightward from control, and the pressure when RBF autoregulation was abolished was 74 +/- 3 mmHg. The pretreatment of the dogs with indomethacin failed to affect the lower limit of RBF autoregulation during both control (63 +/- 5 mmHg) and the elevated ureteral pressure (77 +/- 5 mmHg). Since RBF failed to increase in response to the elevated ureteral pressure, RBF autoregulation curves obtained during the elevated ureteral pressure shifted only rightward from indomethacin control. The results indicate that the increased intrarenal level of prostaglandin or prostaglandin-induced vasodilation does not appear to bear any relation to the reduction in the autoregulatory capacity during partial ureteral obstruction. It seems that the partial impairment of the autoregulation during acute ureteral obstruction is due to the consumption of tubuloglomerular feedback mechanism at spontaneous RAP and that prostaglandin is neither mediator nor effector of tubuloglomerular feedback mechanism.

Changes of Prostaglandin E-2 Levels in Cerebrospinal Fluid in Children with Febrile Convulsion / 대한소아신경학회지

PURPOSE: Prostaglandins(PGs) are known to produce a remarkably broad spectrum of effects that embraces practically every biological function, and has a particular physiological role in the central nervous system. Significant increases of PGs levels are seen in certain diseases, such as febrile infection, stroke, schizophrenia, and epilepsy. Prostaglandin is also increased in a response to rising body temperature, and prostaglandin E-2(PGE-2) in lumber cerebrospinal fluid is also increased in febrile convulsion. Intracerebroventricular injection of PGE produces a rise in body temperature and also antagonizes convulsions induced by pentylenetetrazole, penicillin, electric shock. Therefore we studied PGE-2 levels in cerebrospinal fluid of afebrile children, children with febrile convulsion, and febrile children without convulsion. METHODS: The subjects comprised 57 cases with febrile convulsion, 24 cases of afebrile diseases and 9 febrile children without convulsion. All patients were undergoing lumbar puncture and PGE-2 levels in CSF were determined by highly specific radio-immunoassay(Prostaglandin E2 [125I] assay system, Biotra Assays, Amersham Inc.). RESULTS: 1) The CSF PGE-2 levels were significantly higher in children with febrile convulsion(147.3+/-79.3pg/ml) than those in febrile children without convulsion(72.4+/-75.4pg/ml) and afebrile children(19.2+/-28.4pg/ml)(p<0.05). 2) There were no statistical significances of the CSF PGE-2 levels between age and fever in both groups. 3) The CSF PGE-2 levels within 4 hours(176.5+/-65.7pg/m1) after convulsions were significantly higher than those 4 hours after convulsion(93.3+/-74.9pg/ml). CONCLUSION: The CSF PGE-2 levels were significantly higher in children with febrile convulsion than those in febrile children without convulsion and those in afebrile child ran. The CSF PGE-2 levels within 4 hours after convulsion were significantly higher than those 4 hours after convulsion.

Role of Prostaglandins on the Renin-Angiotensin System in Normotensive and Hypertensive Rats

BACKGROUND: Prostaglandin system is known to participate in manifestation of the renin-angiotensin system. However, role of prostaglandins on the renin-angiotensin system in development of hypertension is not well established. This study was to examine whether the role of prostaglandins is altered in experimental hypertension. METHODS: Two-kidney, one-clip(2KIC) renal hypertension was made by clipping the left renal artery with a silver clip(internal gap of 0.2mm) and deoxycorticosterone acetate (DOCA)-salt hypertension by subcutaneous implantation of DOCA(200mg/kg) strip plus saline(1%) drinking. They were used 3 weeks later. Age-matched normal rats served as a control. Femoral artery was cannulated and arterial blood pressure and heart rate were monitored continuously. RESULTS: 1) In normotensive rats, saralasin infusion(20 microg/kg/min, IV) caused a decrease in mean arterial pressure without significant alterations in heart rate. Indomethacin-pretreatment(10mg/kg, IP) abolished the depressor response to saralasin. 2) The depressor response to saralasin was more marked in renal hypertensive rats than in normotensive rats. The magnitude of maximum decrease in blood pressure, however, was comparable between the hypertensive and normotensive rats. Indomethacin-pretreatment did not affect the depressor response to saralasin in renal hypertensive rats. 3) In DOCA-salt hypertensive rats, saralasin infusion rather caused an increase in mean arterial pressure without significant alterations in heart rate. The pressor response to saralasin was not affected by indomethacin-pretreatment. CONCLUSION: These results indicate that prostaglandin system may modify renin-angiotensin system in normotensive rats. It is suggested that mechanisms other than prostaglandin system participate in the full-blown manifestation of renin-angiotensin system in 2KIC renal hypertensive rats.

Evaluation of Cerebrospinal Fluid Levels of Thromboxane B2 and 6-ketoprostaglandin F1alpha in Patients with Aneurysmal Subarachnoid Hemorrhage

In order to find out the relationship between arachidonic acid(AA) metabolites and the development of vasospasm following a subarachnoid hemorrhage(SAH), we evaluated the cerebrospinal fluid(CSF) levels of the two main AA metabolites, prostacyclin(PGI2) and thromboxane A2(TXAZ) by measuring their stable degredation products 6-keto-prostaglandin F1alpha(PGF1) and thromboxane B2(TXB2) using radioimmunoassay methods in 32 patients after an aneurysmal rupture and in 11 patients without an aneurysmal rupture as a control group. We compared the data between aneurysmal ruptured patients and control group patients. We also divided the data of the aneurysmal ruptured patients into 3 groups checking them between 1-4, 5-11, and 12-28 days after the SAH, and compared the data among the groups, then the data was also compared between non-vasospasm and clinical or severe angiographic vasospasm groups of patients. The results showed that the AA metabolism was enhanced after the SAH, The TXB2 increased the greatest amount in 1-4 days after the SAH and significantly decreased statistically 12 days after the SAH(p<0.002). This study also showed that the TXB2 level was significantly higher statistically in 1 to 4 days in the clinical or angiogrophically severe vasospasm group than in the non-vasospasm group of patients(p<0.032). PGF1 did not show any statistically significant changes according to the number of SAH days or a difference between the vasospasm and non-vasospasm groups. This result suggests if the AA metabolites are involved in the pathogenesis of cerebral vasospasm, and the lumbar CSF levels of AA metabolites in aneurysmal patients reflect the arterial synthesis of PGI2 and platelet origin of TXA2, the elevation of TXA2 or other vasoconstrictor prostaglandins is more likely to play a major role in the pathogenesis of vasospasm than PGI2 deficiency. The measurements of the CSF TXB2 in 1 to 4 days after a SAH may have an expectant value in the development of clinical or severe angiographic vasospasm(exclude the accompanying intraventricular hemorrhage patients).